REVIEW ARTICLE published: 15 March 2013 doi: 10.3389/fnins.2013.00035 Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders

K. MacDonald*andD. Feifel

Department of Psychiatry, University of California, San Diego, San Diego, CA, USA

Edited by: Concerns regarding a drought in psychopharmacology have risen from many quarters. Idan Shalev, Duke University, USA From one perspective, the wellspring of bedrock medications for anxiety disorders, Reviewed by: depression, and schizophrenia was serendipitously discovered over 30 year ago, the Eric Fliers, University of swell of pharmaceutical investment in drug discovery has receded, and the pipeline’s Amsterdam, Netherlands Salomon Israel, Duke University, flow of medications with unique mechanisms of action (i.e., glutamatergic agents, CRF USA antagonists) has slowed to a trickle. Might oxytocin (OT)-based therapeutics be an oasis? *Correspondence: Though a large basic science literature and a slowly increasing number of studies in human K. MacDonald, Department of diseases support this hope, the bulk of extant OT studies in humans are single-dose Psychiatry, University of California, studies on normals, and do not directly relate to improvements in human brain-based San Diego, 200 W. Arbor Dr. MC 8216, San Diego, CA 92103, USA. diseases. Instead, these studies have left us with a field pregnant with therapeutic e-mail: [email protected] possibilities, but barren of definitive treatments. In this clinically oriented review, we discuss the extant OT literature with an eye toward helping OT deliver on its promise as a therapeutic agent. To this end, we identify 10 key questions that we believe future OT research should address. From this overview, several conclusions are clear: (1) the OT system represents an extremely promising target for novel CNS drug development; (2) there is a pressing need for rigorous, randomized controlled clinical trials targeting actual patients; and (3) in order to inform the design and execution of these vital trials, we need further translational studies addressing the questions posed in this review. Looking forward, we extend a cautious hope that the next decade of OT research will birth OT-targeted treatments that can truly deliver on this system’s therapeutic potential.

Keywords: oxytocin, pharmacology, humans, intranasal administration, psychiatry, drug development

OXYTOCIN: TOOL OR TREATMENT? like gene knockout and optogenetic manipulation of specific cen- Over the last several decades, the nonapeptide oxytocin (OT) has tral circuits (Stoop, 2012). Each of these progressive steps has been cast in two roles on the stage of human neuroscience. First allowed us to ask and answer increasingly specific questions about and most dramatic has been its remarkable and ever-expanding the nature of the central OT system and its contribution to role as a powerful mediator of myriad aspects of our uniquely the bonded, social nature we share with fellow mammals. The social brains (MacDonald and MacDonald, 2010). Beginning culmination of several decades of sophisticated translational neu- with its evolutionary origin 10,000 years ago—when the progen- roscience research has been a decade-long groundswell of human itor nonapeptide vasotocin was orchestrating decision-making in studies which have ensconced OT and its sister nanopeptide vaso- marine animals (Grimmelikhuijzen and Hauser, 2012)—a series pressin with testosterone, estrogen, and cortisol in the pantheon of vital advances have ratcheted forward our understanding of of centrally active hormones critical to understanding human this vital central system. These include its initial discovery as a behavior. uterotonic component of pituitary extract over a century ago OT has also been cast for a second, as-yet unfulfilled role as (Dale, 1906); the concept (novel at the time) of neurosecretion, a therapeutic tool to ameliorate suffering from brain-based dis- the “glandular activity” of hormone-secreting neurons (Scharrer ease. Promise notwithstanding, its performance here has been a and Scharrer, 1945); the vital technique of immunoflourescent bit more pedestrian. Although it has been safely used for decades visualization of OT-producing neurons (Swaab et al., 1975) in obstetrics to induce and augment labor, the suggestion that which allowed the subsequent histological characterization of the OT may have therapeutic value in the treatment of a host of human central OT system (Loup et al., 1991); the more recent brain-based conditions (addiction, anxiety, autism, mood disor- sequencing and synthesis of the peptide (Du Vigneaud, 1956), ders, and schizophrenia) has not for the most part been bolstered and the gene for the receptor (Kimura et al., 1992); and finally, by clinical investigations with meaningful therapeutic endpoints. increasingly sophisticated translational research using techniques More precisely, despite an enormous amount of anticipation that

www.frontiersin.org March2013|Volume7|Article35| 1 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

OT’s effects in preclinical studies can be translated into OT-based 2012, we note ongoing treatment trials of intranasal (IN) OT in treatments for psychiatric disorders, few studies have actually autism, schizophrenia and schizoaffective disorder, frontotempo- delivered OT as a bona-fide therapeutic agent, using chronic daily ral dementia, major depressive disorder and treatment resistant dosing, targeting core symptoms of specific disease states, and depression, post-traumatic stress disorder, borderline person- assessing safety, tolerability, and clinical outcomes. From a clin- ality disorder, and drug dependence (i.e., alcohol, marijuana) ical perspective, the current portfolio of OT research is flush with (www.clinicaltrials.gov). Therewith, we anticipate that the next more therapeutic hints than help, and exogenous OT has—thus several years will show a corresponding increase in actual clin- far—acted more decisively in its role as a pharmacological probe ical data. To date, however, there have been a relatively limited than a therapeutic palliative. number of patient-targeted clinical OT trials, with the majority These contrasting roles come into apposition at a time in being single-dose (Table 1). Given the limited number of studies the history of psychiatric therapeutics which some have called that have been conducted evaluating OT’s potential as a bona-fide a“crisis”(Fibiger, 2012). To whit, despite significant advances treatment for clinical brain disorders, one could conclude that in our understanding of the brain bases of human psychiatric almost all of the much-anticipated therapeutic potential of this disease, our abilities to reduce suffering and restore function in neuropeptide remains to be proven. psychiatric disease remains woefully inadequate (Holma et al., 2008; Lieberman and Stroup, 2011; Volkow and Skolnick, 2012). IMPORTANT QUESTIONS FOR DEVELOPING Many or most of the foundational therapeutic medications in our OXYTOCIN-TARGETED THERAPEUTICS psychiatric armamentarium (i.e., antidepressants, antipsychotics) Most preclinical and translational studies conducted to date—as were discovered serendipitously decades ago. Several promising well as single-dose studies in normals—attempt to answer the new therapeutic classes of drugs for CNS conditions have failed question: “what does OT do?” A pragmatic, treatment-oriented to pass late-stage drug development. Stymied by these repeated, clinician may wish to restate the question, asking: “what does costly product failures, many pharmaceutical companies have OT do when used as drug?” More specifically, “what effects does abjured investing in this therapeutic arena. These pharmaceuti- OT have when given chronically to patients with psychiatric ill- cal realities stand in stark contrast to the significant prevalence ness?” Sadly, in spite of a decade of high-profile studies, we and toll of brain-based diseases. Though these setbacks pose would be hard-pressed to answer this question for the majority a challenge to drug development, we maintain optimism that of putative indications. Delving deeper, three-linked facts make OT-based therapeutics may provide relief, though as discussed this clinically oriented query even more incisive: (1) as men- below, development of OT-targeted therapeutics has its own tioned, the vast majority of published OT studies are single-dose challenges. studies in normals; (2) in normals, the single-dose effects of In this review, we approach OT from the perspective of lifesaving psychiatric medications [i.e., antipsychotics, serotonin researcher-clinicians interested in the development of OT- reuptake inhibitors (SSRIs)] are often either negligible (Harmer targeted pharmaceuticals for the abridgement of human psy- et al., 2003; Murphy et al., 2009)oraversive(Belmaker and chiatric disease. Given intense interest in this molecule and the Wald, 1977; Harmer et al., 2008); (3) in psychiatric patients, the ever-mushrooming literature, this review has a necessarily limited short-term effects of some medications are the opposite of their scope. Herein, we constrain our discussion to arenas of signifi- effect when given chronically [i.e., short-term anxiogenesis with cant, direct relevance to the development of OT-based therapeu- SSRIs (Kent et al., 1998)]. As such, though in some cases single- tics, and direct interested readers to several recent, well-referenced dose effects in normals can be linked to longer-term benefits in reviews on other vital aspects of OT including details of its neu- patient populations [i.e., enhancement of emotional processing rophysiology and interaction with arginine vasopressin (AVP) as a biomarker for antidepressant activity (Harmer et al., 2009a; (Stoop, 2012), implications of genetic variations in the OT recep- Tranter et al., 2009)], we should be circumspect when extrapolat- tor (OTR; Ebstein et al., 2012; Kumsta and Heinrichs, 2013), and ing too directly from these studies to the effects of chronic dosing OT’s role in human development (Gordon et al., 2011; Feldman, in psychiatrically ill samples. For all these reasons, multi-week, 2012). daily dose, randomized placebo-controlled trials—the mainstay for evaluating the therapeutic efficacy and safety of investigational BRAIN DISORDERS FOR WHICH OXYTOCIN MAY HAVE psychotropic drugs—are needed to advance the field from the THERAPEUTIC EFFICACY stage of optimistic speculation into the realm where definitive As mentioned above, as the result of its revealed effects on behav- verdicts can be obtained. Only then will we be able to deci- ior and brain processes observed in both animal studies and trans- sively answer the vital question asked by our treatment-seeking lational studies in humans, OT has been proposed as a potential clinician. treatment for a wide range of brain disorders: addiction, anxiety Beyond these sorely needed proof-of-concept clinical trials, the disorders, autism-spectrum and other developmental disorders, development of OT-targeted therapeutics for CNS disease faces a borderline personality disorder, mood disorders, and schizophre- significant number of challenges. In the sections below—in the nia. For a more complete background on OT’s preclinical profile form of 10 questions—we attempt to identify and describe them and the justification for these therapeutic speculations see the fol- (Table 2). En toto, these questions span a wide spectrum of issues lowing recent, extensive reviews (Slattery and Neumann, 2010; that need to be addressed in order to complete the bench-to- MacDonald and Feifel, 2012a; McGregor and Bowen, 2012; Modi bedside arc with OT. Of note, the question of the role of several and Young,2012; Neumann and Landgraf, 2012). As of November important individual factors (variations in the OT and CD38

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 2 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders (Continued) ability to accurately otional significance to speech intonation. behaviors. speech comprehension and assign em cooperative partner, increased trust and preference, and increased gaze to eyes.elevated (2) OT IN plasma OT levels, but less than controls. Improved performance on the RMET. moderated by attachment anxiety and avoidance. and caused a trend tomoderated decreased by cortisol. trauma, Results self-esteem, and attachment style. with 48 IU. doing the RMET activated higher orderareas cognitive and insula with OT. (2)reaction OT time caused in slower depressed group. responses to personal combat imagery prompts, verses placebo and IN AVP-treated subjects. babies as more difficult, but describedrelationship the quality as more positive. Up to 70 U/h IV24 IU OT subjects OT showed improvements in affective 18 IU (Age 12–15); (1)24 OT IU caused (Age stronger 16–19) interactions with 40 IU24–48 IU OT attenuated subjective post-stressor dysphoria, 40 IU Eye-gaze improved with 24 IU; cortisol decreased (1) Compared with controls, depressed20 patients IU24 IU OT subjects had the lowest mean physiologic OT-treated mothers were sadder and described comprehension game and eye contact performance cortisol response heart rate variability, cortisol responses (fMRI) to RMET GSR, facial EMG) to personal trauma prompts of mother-infant relationship 18) Parameter studied Dosing Findings < , sex, age (if N 10 F,4 M6 F,8 M Neuroeconomic trust game Post 40 stressor IU subjective mood, 8 F17 M OT impeded trust and prosocial behavior, Reaction43 time M and brain Social cognition (RMET) Physiologic responses (HR, 40 IU OT improved RMET scores. AutismAutismAutism and 14 Asperger’s M, 1 F 11 M, 2 F 15 MAutism and Asperger’s Repetitive behaviors 16 M, age 12–19Borderline Social personality behavior in a multiplayer disorder Affective speech SocialBorderline cognition: personality RMET disorder Up to 70 U/h IVFragile-X syndrome OT caused a significant reduction in repetitive Major 8 depressive M, age 13–28disorder Eye gaze frequency, heart rate, Major depressive disorder Post-traumatic stress disorder Postnatal depression 25 F Self-reported mood and ratings SINGLE-DOSE TRIALS Table 1 | Studies using oxytocin in patients with brain-basedReferences illness. Hollander et al., 2003 Hollander et Population al., 2007 Andari et al., 2010 Guastella et al., 2010 Bartz et al., 2011a Simeon et al., 2011 Hall et al., 2012 Pincus et al., 2010 MacDonald et al., 2011b Pitman et al., 1993 Mah et al., 2013

www.frontiersin.org March2013|Volume7|Article35| 3 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders (Continued) gender interaction. × Improvement in social interaction and communication, irritability and aggressive behavior. compared to controls, and OT improvedpatients ability to of recognize most emotions. 20 IU dose improved emotion recognition. to fearful faces; OT normalized this effect. medial prefrontal cortex and anterior cingulate cortex; OT reduced this hyperactivity. self-evaluation of appearance and speech performance; these benefits did not generalizea into sustained positive effect over exposurealone. therapy OT-treated patients required less lorazepam, had lower alcohol withdrawal scores, and lower subjective distress. endpoints; RMET, repetitive behaviors, and QOL improved. Males showed significant decrease in anxietyweek at 2, females showed trend increasewith in trend anxiety, significance drug OT caused slightly improved mood, abdominaland pain discomfort. Adjunctive OT improved depressive and anxiety symptoms and quality of life overweeks. the course of 6 months of IN OT (8 IU daily) 24 IU10 IU, 20 IU24 Patients IU had deficit in emotion recognition 10 IU dose caused decreased emotion recognition; 24 IU Patients exhibited bilateral amygdala hyperactivity 24 IU Patients had heightened activity to sad faces in OT-treated subjects demonstrated24 improved IU twice-daily for 3 days 6 w of 24 IU BID Though no significant changes on primary 1 w, then 40 IU twice-daily for 2 weeks 40 IU twice daily for 13 weeks several weeks behavior checklist, CGI emotion discrimination test) intensity of facial emotions emotional face matching task with fearful, angry, happy faces emotional face matching task of happy and sad (vs. neutral) faces anxiety, speech performance and appearance. lorazepam use repetitive behaviors, social responsiveness, RMET, YBOCS, WHOQOL subjective parameters 18) Parameter studied Dosing Findings < , sex, age (if N 18 M18 M Brain responses (fMRI) to Brain responses (fMRI) to 16 M, 3 F7 M, 6 F Social function/cognition, 49 F HAM-A1M Constipation and associated HAM-D,STAI,Q-LES-Q Upto36IUover 20 IU twice-daily for Autism 1 F, age 16 Social interaction, aberrant Alcohol dependence 9 M, 2 F Alcohol withdrawal scores, SchizophreniaSchizophrenia (1) 24 M, 6F(2) 21 MSocial anxiety disorder Emotion recognition (hexagon (generalized) 7 M, 6 FSocial anxiety disorder (generalized) Judgment of presence and Social anxiety disorder 25 M Self-rated aspects of social Autism-spectrum disorder Generalized anxiety disorder Irritable bowel syndrome Major depressive disorder # * * MULTIPLE-DOSE TRIALS/CASE REPORTS Pedersen et al., 2013 Table 1 | Continued ReferencesAverbeck et al., 2011 Goldman et al., Population 2011 Labuschagne et al., 2010 Labuschagne et al., 2011 Guastella et al., 2009 Kosaka et al., 2012 Anagnostou et al., 2012 Feifel et al., 2011 Ohlsson et al., 2005 Scantamburlo et al., 2011

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 4 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders l magnetic sal; IU, international units; No difference in trichotillomania symptoms. No effect on symptoms. No change in obsessive-compulsive disorder symptoms. OT subjects had asignificant statistically improvement in BDI. OT induced “rapid therapeutic effects” and “hospitalizations were prevented.” (1) OT improved PANSS, CGI at 3(2) w OT caused time improved point verbal memory. OT improved PANSS scores, and social cognition. OT improved PANSS total, positive and negative scales by week 4. Effects onwas positive more clinically symptoms robust. Improvement in several areas of sexualthough function, no benefit in social avoidance or anxiety. Improvements in self and clinician-rated “asthenodepressive, apathodepressive, hypochondriac symptoms” compared with conventional antipsychotic agents. te; IM, intramuscular; IN, intrana 7 aire; RMET, reading the mind in the eyes test; STAI, state-trait × times daily) for 1 week weeks (dosed four times daily) (2) 2 M treated with 54 IU 160 IU or 320 IU(divided IN four times daily) for 1 week IU-25 IU IM daily 6–10 injections 20 IU twice-daily for 1week,40IU twice-daily for 2 weeks 2 weeks. 1 week, then 40 IU twice-daily for 8 weeks total 10 “active units” IV or IN twice-daily 20 IU twice daily over several weeks days every other week for 2 weeks obal impression scale; EMG, electromyography; F, female; fMRI, functiona symptoms, anxiety, mood and memory (2) verbal memory symptoms (not a standardized scale) sexual function 18) Parameter studied Dosing Findings < e scale; Q-LES-Q, quality of life enjoyment and satisfaction questionn scale for anxiety; HAM-D, Hamilton rating scale for depression; HR, heart ra , sex, age (if N 3 M, 9 F3 F,4 Obsessions M and compulsions (1) 18 IU IN for 6 Obsessive compulsive disorder , arginine vasopressin; BDI, Beck depression inventory; CGI, clinical gl Trichotillomania 2 F Trichotillomania symptoms 160 IU (divided four Obsessive compulsive disorder Obsessive compulsive disorder SchizophreniaSchizophrenia Not mentioned Underspecified 12 M,Schizophrenia 3 FSchizophrenia 17 M, 3 F (1) PANSS, CGI, side effects 10 IU-15 IU IV; 20 33 M,Schizophrenia 7 F PANSS, social cognition 27 MSocial anxiety disorder PANSS 1 24 M IU twice-daily for Subsets of schizophrenia Social anxiety symptoms, 20 IU twice-daily for * * Feifel et al., 2010 Feifel et al., 2012a Though not in a psychiatric population per se, the length of this study and effect on mood warranted inclusion. Abbreviations: ASD, autistic spectrumresonance disorder; imagery; AVP GSR, galvanic skin response; HAM-A, Hamilton rating Table 1 | Continued Referencesden Boer and Westenberg, 1992 Population Epperson et al., 1996a Bujanow, 1972 (1) (2) Pedersen et al., 2011 Modabbernia et al., 2013 Bakharev et al., 1984 MacDonald and Feifel, 2012b Epperson et al., 1996b *Case reports. # anxiety Inventory; YBOCS, Yale Brown obsessive compulsive scale; WHOQOL, world health organization quality of life scale. IV, intravenous; M, male; OT, oxytocin; PANSS, positive and negative syndrom

www.frontiersin.org March2013|Volume7|Article35| 5 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

Table 2 | Ten questions for the development of oxytocin-targeted IN OTs antipsychotic (Feifel et al., 2010, 2012a; Pedersen et al., therapeutics for brain disorders. 2011; Modabbernia et al., 2013)andanxiolytic(Feifel et al., 2011) effects may take weeks to emerge to a clinically meaningful 1. How do acute and chronic oxytocin administration differ? degree. Unfortunately for the development of OT-targeted ther- 2. How do oxytocin’s therapeutic-like effects in healthy subjects apeutics, then, the large number of extant IN OT studies may translate to patient with brain disorders? not speak directly to key issues relevant to the effects of chronic 3. How do oxytocin’s therapeutically relevant effects differ in men and women? OT administration. As discussed below in section “What is the 4. What is the optimal therapeutic dose range for oxytocin? Role of Vasopressin Receptors in Oxytocin’s Effects?” however, the 5. What is oxytocin’s optimal therapeutic dosing schedule? discovery and development of biomarkers which track with clin- 6. Can native oxytocin be improved upon? ical outcomes and syndromes would significantly improves the 7. Is intranasal delivery of oxytocin the optimal route? clinical gain from single-dose trials (de Oliveira et al., 2012a). 8. What is the role of vasopressin receptors in oxytocin’s effects? Examples relevant to OT include the abovementioned single-dose 9. Monotherapy vs. augmentation: can oxytocin treat on its own or is it antidepressant effects on emotional processing (Harmer, 2008) better suited to augment other established treatments? and the attenuation of the anxiogenic effects of CO2 inhala- 10. Are there identifiable biomarkers for oxytocin’s therapeutic effects? tion (Bailey et al., 2007). We anticipate that future biomarker and pharmacokinetic studies in humans treated with acute and chronic OT will build on the few single-dose, functional-imaging receptor, sex, and early experience) in clinical response to OT is trials in humans with psychiatric illness (Labuschagne et al., 2010, covered in an accompanying mini-review (MacDonald, 2012)in 2011; Pincus et al., 2010) to illuminate these important clinical this special section. questions.

HOW DOES ACUTE AND CHRONIC OXYTOCIN ADMINISTRATION HOW DO OXYTOCIN’S THERAPEUTIC-LIKE EFFECTS IN HEALTHY DIFFER? SUBJECTS TRANSLATE TO PATIENT WITH BRAIN DISORDERS? The vast majority of published studies of IN OT—even those A second pharmacodynamic issue that requires more study con- done in patient samples (Table 1)—have used only a single- cerns the difference between OT’s effects in normal vs. psychiatri- application dosing paradigm. In stark contrast, almost all treat- cally ill samples. Just as a host of individual differences signifi- ments for the most debilitating brain disorders are delivered cantly influence response to OT in normal samples (MacDonald, chronically, with most achieving their maximal clinical effects 2012), so it is likely that OT’s effects will differ between healthy after weeks of daily administration. Furthermore, as intimated and clinical populations. For example, in a functional imaging above, the acute and chronic effects of medications are often dia- studyoftheeffectsofOTonbrainactivityduringtheread- metrically opposite, as seen in the case of SSRIs, which are a ing the mind in the eyes test (RMET), OT-mediated alteration first-line chronic treatment for anxiety disorders, yet can cause in brain activity differed significantly between untreated patients anxiety after a single-dose (Spigset, 1999; Birkett et al., 2011). with depression and normal subjects (Pincus et al., 2010). A One process that contributes to the difference between acute second, unpublished set of data from our group found that and chronic drug administration is “tachyphylaxis” or “toler- patients with depression had an anxiogenic response to single- ance” in which the acute effects of a drug dissipate with repeated dose IN OT given in a psychotherapy context, in contrast to administration. At a cellular level, persistently stimulated recep- acute anxiolytic effects reported in normals (Heinrichs et al., tors like the OTR may become desensitized or may be expressed 2003; de Oliveira et al., 2012a,b). Additionally, Bartz et al. has in smaller numbers on cell surfaces, via several processes, includ- demonstrated that many patients with borderline personality ing one called internalization. Notably, internalization has been disorder have divergent responses to OT that those seen in nor- demonstrated to occur with the OTR (Gimpl and Fahrenholz, mals, with OT-decreasing trust and cooperation (Bartz et al., 2001). 2011a). On the other hand, some acute neural responses (atten- Specifically in the case of OT, basic science research supports uation of amygdala activity) are seen in both patient groups the fact that that there are often significant differences between (Labuschagne et al., 2010) and normals (Zink and Meyer- the effects of acute and chronic administration of OT (Kramer Lindenberg, 2012)(Figure 1). Notwithstanding these similarities, et al., 2003; Bowen et al., 2011; Keebaugh and Young, 2011; Bales the findings from several single-dose studies indicating that the and Perkeybile, 2012). Furthermore, though the neurobiological effects of OT may differ between patients with psychiatric disease mechanism of certain of OT’s effects (i.e., acute anxiolysis) have and those without calls for caution when extrapolating clini- been carefully dissected in animal models (Viviani and Stoop, cal effects of OT in patients from the study of its effects in 2008; Yoshida et al., 2009; Viviani et al., 2011; Knobloch et al., normals. 2012; Stoop, 2012, for review), the mechanism of action of ther- There may be, moreover, significant associations between the apeutic later-onset effects of chronic OT treatment—the mode OT system and certain psychiatric disease states or endophe- of treatment most salient to human brain disorders—remains notypes. One component of this distinction is covered in an unknown. accompanying mini-review (MacDonald, 2012), which discusses On this latter point, the small body of research in which the clinical import of research on variations in the OTR and the chronic IN OT has been given to psychiatrically ill patients indi- CD38 ectoenzyme. Though many of the studies in this growing cates that like currently used medications from other classes, literature are in normals, certain genetic variations in aspects of

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 6 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

FIGURE 1 | Intranasal oxytocin: potential therapeutic regulation of brain endogenous OT system, which secretes OT into the peripheral circulation function in psychiatric illness. Several important aspects of intranasally (right pullout), and has both direct, “wired” and diffusion-mediated central delivered OT (IN OT) treatment of brain-based illness are represented. One effects (Landgraf and Neumann, 2004; Stoop, 2012). Through these potential way that IN OT may cross the blood-brain barrier and cause mechanisms, IN OT impacts the function of amygdala-anchored central effects is represented: directly via extraneuronal/perineuronal routes connectivity networks in normals (Kirsch et al., 2005; Sripada et al., 2013), along trigeminal or olfactory nerve pathways (Thorne and Frey, 2001; Ross as well as important brain regions (amygdala, insula, anterior cingulate, et al., 2004; Dhuria et al., 2010; Renner et al., 2012a,b). Other mechanisms medial prefrontal cortex) in patients with psychiatric illness (Labuschagne of entry (bulk flow, lymphatic channels, intraneuronal transport, active or et al., 2010, 2011; Pincus et al., 2010). For simplicity, not all brain areas passive transport from vasculature) are discussed in references and the impacted by OT are shown; see Bethlehem et al. (2012); Zink and text. IN OT may cause some of its central effects by stimulating the Meyer-Lindenberg (2012) for recent, detailed reviews.

the OT system have been associated with disease states (Kumsta 1991; Ito and Jameson, 1997). Given endogenous AVPs role in and Heinrichs, 2013). In addition to these known variations natriuresis, these patients present clinically with symptoms of in the OT system, one could assume that certain individuals progressive functional AVP deficiency, including polyuria, and (and perhaps certain diagnostic groups) have an as-yet undoc- polydipsia (Robertson, 1995). Currently, more than 60 clinically umented state of more significant functional OT deficiency akin relevant genetic variants of the AVP prohormone have been iden- to that found in central diabetes insipidus (DI). Specifically, in tified (Christensen et al., 2013). Returning to OT, then, variants of the genetic form of central DI called familial neurohypophyseal “OT deficient” animals have been created via genetic alterations of diabetes insipidus (FNDI), variations in the AVP prohormone the OT gene or its receptor (Young et al., 1996; Bernatova et al., gene (AVP-neurophysin II) on chromosome 20 result in inade- 2004; Lee et al., 2008; Nishimori et al., 2008): these animals dis- quate protein folding and dimerization. These changes cause the play a range of behavioral abnormalities. As such, although no aberrant protein to be retained in the neuron, ultimately lead- OT-related genetic syndrome akin to FNDI has yet been charac- ing to cell death of hypothalamic magnocellular neurons in the terized in humans, the abovementioned findings raise the inter- supraoptic nucleus and paraventricular nucleus (Bergeron et al., esting question of the possibility of an “OT-deficiency syndrome”

www.frontiersin.org March2013|Volume7|Article35| 7 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

which manifests with deficits in the production and/or function (Feifel et al., 2011). This trial demonstrated a trend-level dose-by- of either the hormone, the receptor, or other components of the gender effect such that males treated with OT showed a significant system (i.e., the ectoenzyme CD38). clinical improvement in HAM-A scores with OT, whereas females did not. En toto, the abovementioned sex differences indicate that HOW DO OXYTOCIN’S THERAPEUTICALLY RELEVANT EFFECTS DIFFER delineation of the role of sex and sex hormones in the response to IN MEN AND WOMEN? chronic OT treatment will be critical. Given OT’s intimate evolutionary involvement with reproductive function, it should not be surprising to find that is has distinct WHAT IS THE OPTIMAL THERAPEUTIC DOSE RANGE FOR OXYTOCIN? effects on the brains of males and females. Indeed, the histological Despite the groundswell of IN OT research, we know very little structure for OT neurons is sexually dimorphic (de Vries, 2008) about either the optimal dose or dosing parameters of IN OT for and sex biases in behavioral responses to OT have been frequently any CNS indication, and single-dose studies, though informative, found in animal studies (Williams et al., 1994; Cho et al., 1999; speak somewhat peripherally to this important issue. Noteworthy Bales and Carter, 2003; Bales et al., 2007a). Estrogen increases OT is that animal research indicates a discrepancy between the effects and OTR production (Patisaul et al., 2003; Windle et al., 2006; of both dose (Windle et al., 1997; Kramer et al., 2003; Bales Choleris et al., 2008), whereas testosterone promotes hypothala- et al., 2007b) and single vs. chronic dosing of OT (Bales and mic OTR-binding (Johnson et al., 1991)aswellasproductionof Perkeybile, 2012). Aside from optimizing therapeutic effect, dos- AVP (Delville et al., 1996), which has many opponent actions to ing issues are also important in terms of side effects, given that OT (Neumann and Landgraf, 2012). OT has some cross-affinity with AVP receptors which mediate its Though the question of the meaning and measurement of potential diuretic and natriuretic effects (Gimpl and Fahrenholz, OT levels is still subject to active study (see section “What is 2001), and have been noted in a single case report of high- Oxytocin’s Optimal Therapeutic Dosing Schedule?” below), men dose IN OT (Ansseau et al., 1987). An illuminating primate and women show differences in plasma OT levels (Ozsoy et al., study in this regard indicated that perhaps due to cross-reactivity 2009; Gordon et al., 2010; Holt-Lunstad et al., 2011; Weisman with AVP, [which potentiates stress responses (Legros, 2001)], et al., 2012c), as well as sex-specific behavioral correlations chronic higher-dose IN OT (200 IU) did not attenuate cortisol with OT (Gordon et al., 2010; Zhong et al., 2012). In addi- (ACTH) responses, whereas a lower-dose (50 IU) did (Parker tion, amygdala-prefrontal cortical connectivity—which can be et al., 2005). impacted by OT in normal subjects (Sripada et al., 2013)and Largely due to prior precedent (vs. pharmacological rationale), anxiety patients (Labuschagne et al., 2011)—may be related in a the majority of published human studies have tested OT in single gender-specific way to the development of anxiety and depressive doses in the 20–40 IU range (MacDonald et al., 2011a), though disorders (Burghy et al., 2012). Furthermore, numerous stud- dosesaslowat10IU(Goldman et al., 2011) and as high as 160 ies in the growing OTR literature note sex-specific associations IU daily (Epperson et al., 1996a,b) have been reported. The few between genetic variants in the OTR gene and personality charac- chronic-dosing studies cited herein have used a dose range of teristics (Stankova et al., 2012), neural responses to emotionally 24–40 IU BID (Feifel et al., 2010, 2012a; Pedersen et al., 2011; salient cues (Tost et al., 2010), pair-bonding (Walum et al., 2012), Modabbernia et al., 2013). Importantly, very few studies have hypothalamic gray matter volume (Tost et al., 2010), and empa- directly compared the effects of two or more doses, a standard thy (Wu et al., 2012). On the other hand, several studies in strategy in dose-finding clinical trials. this area have failed to find a sex bias (Rodrigues et al., 2009; In one the first clinical study to examine effects of multi- Saphire-Bernstein et al., 2011; Feldman, 2012). pledosesofOTinthesameclinicalsubject,Goldmanetal. With regards to clinical studies of the effects of IN OT, a sex demonstrated that in patients with schizophrenia, 10 IU caused difference in its effects has been demonstrated in some single- a decrement in ability to identify facial emotions (due to dose studies (Hurlemann et al., 2010), including studies of OT’s increased false-response rate), whereas 20 IU improved emo- effects on the amygdala (Domes et al., 2010; Rupp et al., 2012), tion recognition in polydipsic relative to non-polydipsic patients and interpersonal behavior (Liu et al., 2012). Again, these effects (Goldman et al., 2011). This dose-related finding is interesting are variable: many other studies in this area have not found an given that more placebo-controlled IN OT trials have been done effect of sex [see Bartz et al. (2011b), for review]. in schizophrenia than any other indication. In a study of men Focusing on the few multi-week clinical trials of OT in psychi- withfragileXsyndrome,24IUbutnot48IUINOTimproved atric populations, the three published clinical trials in schizophre- eye gaze frequency, whereas 48 IU but not 24 IU decreased social- nia included a disproportionate number of males (62 males stress induced salivary cortisol levels (Hall et al., 2012). A study treated vs. 13 females), consistent with most clinical trials of in normals on the effect of OT on exercise-induced increased in this disorder (Feifel et al., 2010, 2012a; Pedersen et al., 2011; salivary cortisol levels demonstrated that 24 IU but not 48 IU Modabbernia et al., 2013). The number of women included in attenuated this effect (Cardoso et al., 2012). Another related study each trial was not sufficient to analyze for a sex-by-drug effect. in normal men found that IV OT (titrated to a level 10 times Though schizophrenia is the clinical disorder with the largest higher than physiologically normal baseline levels) demonstrated number of separate randomized trials using IN OT, the first study a linear, dose-response OT effect on ACTH and cortisol (Legros to intimate a sex moderation effect of OT was a randomized, et al., 1984). Finally, a recent study documented that salivary OT double-blind, within-subjects crossover study of OT (40 IU BID levels in normal subjects remained similarly elevated for up to for 3 weeks) in patients with generalized anxiety disorder (GAD) 7 h, regardless of which of 2 doses of IN OT patients received

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 8 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

(16 or 24 IU) (van Ijzendoorn et al., 2012). In light of these find- levels and naturalistic, centrally mediated behaviors (i.e., parent- ings suggesting that OT’s effects may be dose-dependent, more ing, breastfeeding) (Feldman, 2012; Weisman et al., 2012b;for studies are needed in which more than 1 dose—preferably a range review), the concordance between OT measured in different body of doses—are directly compared. Clearly, we need to understand spaces (saliva, plasma, CSF) and central effects is still a matter of whether a dose-response relationship exists regarding the effects active debate (Carter et al., 2007; Neumann, 2007). of OT on core disease symptoms, and whether such dose-response A variety of important controversies and questions surround relationships are disease specific. the measurement of OT levels. Though space does not permit a full elaboration on the topic, its relevance to many of the ques- WHAT IS OXYTOCIN’S OPTIMAL THERAPEUTIC DOSING SCHEDULE? tions in this review warrants a discussion. First, we note that In addition to an inadequate understanding regarding the dose- there have been controversies regarding the validity and reliabil- response curve for most therapeutically relevant effects of OT, ity of measurement of OT levels in urine (Anderson, 2006; Young there is very little known regarding its optimal therapeutic- and Anderson, 2010), saliva (Horvat-Gordon et al., 2005), and dosing frequency (e.g., once daily, twice daily, etc.). In addition plasma (Szeto et al., 2011) [and see references in Carter et al. to knowing the optimal dose range, dose frequency data is criti- (2007); Szeto et al. (2011); Weisman et al. (2012c); Zhong et al. cal for successful design of future proof-of-concept clinical trials. (2012)]. One aspect of this controversy regards the measurement Typically, dosing schedule is based upon the plasma half-life of of OT via immunoassay: the most cost-effective measurement the drug in question. However, this heuristic is likely not applica- technique for large samples. Notably, a recent report questioned ble to the CNS effects of OT, particularly OT delivered IN, given both (1) the accuracy of both radioimmunoassays (RIA) and its putative direct access to the brain via this route of admin- enzyme immunoassays (EIAs) and (2) the necessity of the techni- istration (Born et al., 2002). Specifically, whereas the plasma cal step of sample extraction which can changes by up to 100-fold half-lifeofIVOTislessthan10min(Mens et al., 1983), it the measured levels of the peptide (Szeto et al., 2011). Most lasts much longer in the CSF, and studies measuring plasma OT recent studies that measure either plasma or saliva OT levels use have found elevated levels of the peptide lasting more than 1 h a commercial OT-Elisa kit (Assay-Design, MI, USA), which has after a single IN administration (Burri et al., 2008; Gossen et al., been validated for linearity, cross reactivity, matrix effects, accu- 2012). racy, precision, and recovery (Carter et al., 2007) though the Relevant here are single-dose studies measuring both salivary use of extraction techniques in different studies is variable. In (Huffmeijer et al., 2012; Weisman et al., 2012a)andplasmaOT support of the validity of this assay, across a broad range of dif- levels (Burri et al., 2008; Andari et al., 2010; Domes et al., 2010; ferent studies—including several very large samples (Weisman Gossen et al., 2012), which indicate that IN OT quickly ele- et al., 2012c; Zhong et al., 2012)—these techniques have pro- vates peripheral OT levels, and that, these levels remain above duced congruent results, with most of them finding reasonable baseline for some time. In terms of mechanism, in addition to correlations between saliva and plasma OT levels (Grewen et al., direct absorption via the nasal vasculature, it is thought that IN 2010; Feldman et al., 2011; Hoffman et al., 2012), and between OT may also elevate peripheral OT levels by entering the brain OT levels and a wide range of OT-dependent biological pro- and stimulating OT neurons to secrete endogenous OT from cesses (White-Traut et al., 2009; Grewen et al., 2010; Feldman, central stores into the peripheral circulation (Neumann et al., 2012). 1996)(Figure 1). This suggestion is supported by the fact that A second, related issue surrounding the measurement and OT neurons operate in a feed-forward “bursting” mechanism, meaning of peripheral OT levels is that of endogenous fluctua- such that exogenous or endogenous OT stimulates further pul- tions in OT levels. Though OT has a diurnal rhythm of daytime satile OT release (Renaud et al., 1984; Rossoni et al., 2008), part rise and night-time decline in mice (Zhang and Cai, 2011)and of a locally regulated positive-feedback mechanism (Neumann primates (Amico et al., 1990), the bulk of data does not sup- et al., 1996). This ongoing release from endogenous OT stores, port significant diurnal variations in plasma OT in humans mediated partially through glutamatergic mechanisms (Jourdain (Amico et al., 1983; Kuwabara et al., 1987; Challinor et al., et al., 1998; Israel et al., 2003), could certainly contribute to the 1994; Kostoglou-Athanassiou et al., 1998; Turner et al., 2002; sustained peripheral blood levels seen in IN OT studies. After Graugaard-Jensen et al., 2008), [but see Forsling et al. (1998), IN delivery, peripheral OT levels are elevated starting between Landgraf et al. (1982) for evidence of a nocturnal nadir]. CSF lev- 10 (Andari et al., 2010) and 30 (Gossen et al., 2012)minand els may differ, as there is some evidence for a diurnal variation stay elevated for between 150 min (Gossen et al., 2012)tosev- in this body space (Amico et al., 1983; Kuboyama et al., 1988). eral hours (Burri et al., 2008; van Ijzendoorn et al., 2012), in These data on circadian fluctuations stand apart from studies spite of OTs short plasma half-life (Mens et al., 1983). Vitally, of dynamic fluctuations in OT levels in states like pregnancy it is currently impossible to distinguish between transnasally (Kuwabara et al., 1987; Fuchs et al., 1992; Lindow et al., 1996), absorbed exogenous OT and endogenously secreted OT, so the breastfeeding (Jonas et al., 2009; Grewen et al., 2010), orgasm relative contribution of these two sources to subsequently mea- (Carmichael et al., 1987), parenting (Feldman, 2012), and certain sured OT levels is unknown. Moreover, though animal studies stressors (Nussey et al., 1988; Sanders et al., 1990). Also related are have demonstrated some concordance between intraneuronal lev- documented increases in peripheral OT levels due to both natural els of OT and peripheral OT levels (Wotjak et al., 1998; Cushing variations in estrogen levels (Mitchell et al., 1981; Shukovski et al., and Carter, 2000; Wigger and Neumann, 2002), and though sev- 1989) and the ingestion of exogenous estrogen which is known eral human studies show concordance between peripheral OT to increase the magnocellular release of OT (Wang et al., 1995)

www.frontiersin.org March2013|Volume7|Article35| 9 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

and plasma OT levels (Amico et al., 1981; Silber et al., 1987; cases, medicinal chemists have managed to design small non- Uvnas-Moberg et al., 1989; Michopoulos et al., 2011). Adding peptidergic molecules that bind a specific peptide receptor and complexity is that data on fluctuations in plasma OT levels across are either inactive at that receptor (antagonist) or mimic the the menstrual cycle are mixed, with studies in different healthy actions of the endogenous peptide (agonist). In general this strat- and clinical populations showing both variation (Shukovski et al., egy has been much more successful in producing antagonists 1989; Salonia et al., 2005; Liedman et al., 2008)andlackofvaria- than agonists (Manning et al., 2012). However, the corpus of tion (Stock et al., 1991; Kostoglou-Athanassiou et al., 1998; Light preclinical and translation research with OT suggests that it is et al., 2005) in normally cycling women, with both estrogen and OT agonists, not antagonists, that have promise as treatments progesterone levels playing a role. for several psychiatric disorders. With regards to OT, several A third, yokedpairoftopics related to OTlevels are (1) the cor- low-molecular weight non-peptidergic OT agonists have been relations between peripheral and central OT levels (see discussion developed that penetrate the brain after peripheral administra- above) and (2) the correlation of OT levels and different disease tion (Pitt et al., 2004; Ring et al., 2010). The only non-peptide states. Regarding the latter, investigators have studied OT levels OT agonist with experimental evidence for an OT-like behavioral and their relationship to aspects of autism (Modahl et al., 1998; profile is WAY-277464, which had 87% of the binding affin- Al-Ayadhi, 2005), eating disorders (Hoffman et al., 2012; Lawson ity of OT and significant greater selectivity for the OTR (Ring et al., 2012), post-traumatic stress disorder (Seng et al., 2013), et al., 2010). Though it exhibited an OT-like anxiolytic behavioral schizophrenia (Goldman et al., 2008; Keri et al., 2009; Rubin and physiological profile in several animal tests (four-plate test, et al., 2011), social anxiety disorder (Hoge et al., 2008, 2012)and elevated zero maze, stress-induced hyperthermia), and also an depression (Scantamburlo et al., 2007; Parker et al., 2010). An OT-like preclinical antipsychotic profile [reversing amphetamine- important but uninvestigated clinical question is whether a tran- and MK-801-induced disruption of prepulse inhibition (PPI)], sient or chronic increase of peripheral OT levels via treatment it did not have an OT-like antidepressant profile [no reduced with IN OT (Andari et al., 2010; Gossen et al., 2012)corre- immobility in the tail suspension test (TST)] (Ring et al., 2010). lates with OT-responsive clinical symptoms or treatment-related An interesting corollary finding in this study—one that speaks symptomatic improvement (e.g., whether OT levels may function to the mechanism of action of OT’s antidepressant-like effects as a biomarker). in the TST—was that a selective OTR antagonist failed to block Returning, then, to the clinical issue of OT dose and frequency: these antidepressant effects, indicating WAY-27744’s effect may though the abovementioned studies of OT levels,—including be mediated through a different receptor system (i.e., AVPR: also post-dose OT levels—are somewhat informative regarding the infra vida section “Is Intranasal Delivery of Oxytocin the Optimal task of determining an optimal OT dose and frequency, to date, Route?”) (Ring et al., 2010) and raising similar questions for OT. there have been no published studies examining the time course In any case, as a result of both pharmacological and market fac- of the brain-mediated effects of IN OT, nor of their correlation tors, development of WAY-277464 was not pursued by Wyeth with peripheral OT levels. Such studies would greatly enhance (Manning et al., 2012). our ability to optimize OT dose frequency for therapeutic ends. Because of the difficulty of developing a non-peptide OT ago- In fact, most studies of IN OT in humans examine its effects nist, medicinal chemists have utilized another approach to the at a single time point, typically 30–60 min after administration. problem of stimulating the OT system: chemical modification For these reasons, in addition to studies examining a range of of the native peptide or an active fragment to increase its resis- doses of IN OT, studies examining OT’s brain effects over a tance to enzymatic degradation and increase metabolic stability. range of time points are needed to inform optimal OT treatment This process has produced carbetocin: an uterotonic OT analog design. with a peripheral half-life of 85–100 min, significantly longer than OT’s (Hunter et al., 1992). Carbetocin—produced by Ferring CAN NATIVE OXYTOCIN BE IMPROVED UPON? Pharmaceuticals—is approved in 23 countries outside the United Though the native nonapeptide OT has significant advantages in States for post-partum hemorrhage, but there are no published terms of therapeutic modulation of the central OT system, there studiesinvestigatingitsCNSeffectsinhumans.Thoughapotent are problems with peptides. Specifically, neuropeptides like OT uterotonic agent, carbetocin has about 10-fold lower affinity for lack many “drug-like” properties, especially as regards CNS indi- the OTR than OT (Engstrom et al., 1998; Gimpl et al., 2005), and cations. Though they have certain advantages over other chemical has been shown to lack anxiolytic efficacy (elevated plus maze) medicinal classes (i.e., evolved specificity for unique functions when delivered peripherally, vs. OT, which has anxiolytic effi- and receptors, limited drug–drug interactions, little accumulation cacy when delivered peripherally (McCarthy et al., 1996; Ring in tissues, few side-effects), neuropeptides also carry unique lia- et al., 2006). In another experiment, peripheral carbetocin failed bilities as medications related to their molecular nature (Manning to produce antipsychotic-like effects on PPI (Feifel et al., 2012b). et al., 2012; McGonigle, 2012). These shortcomings include a brief Interestingly, carbetocin did demonstrate an antidepressant-like plasma half-life and poor oral bioavailability due to their degrada- profile in the forced swim test when administered peripherally tion by plasma and gastric proteases, as well as limited penetrance and centrally (Chaviaras et al., 2010), and does have short-term of the blood-brain barrier due to their large size and hydrophilic anxiolytic effects when delivered centrally (Mak et al., 2012). It nature (McGonigle, 2012). would be very instructive to determine carbetocin’s effects on Technological advances in medicinal chemistry, however, centrally mediated processes, especially on clinical symptoms of are providing specific solutions to these challenges. In a few pyschiatric disorders in humans.

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 10 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

Besides biochemical modifications of the molecules them- acids (Riekkinen et al., 1987; Born et al., 2002). These studies selves, alternative drug delivery systems (i.e., patches, micro- found that IN delivery increased both CSF levels and plasma lev- spheres, liposomes) can also improve the pharmacokinetic profile els of AVP (Riekkinen et al., 1987; Born et al., 2002). Indirect of peptides and represent another approach to addressing the support for this hypothesis comes from findings that both vaso- challenges of therapeutic modulation of endogenous peptide sys- pressin and OT administered IN have central effects [Fehm et al. tems (Patil and Sawant, 2008; Manning et al., 2012; McGonigle, (2000) and references therein]. Though contemporary critiques 2012). As an example, a mucoadhesive buccal OT patch has been have raised important questions about the details of whether nasal tested in animals and was able to deliver OT continuously over 3 h OT gets directly into the brain, and if so, how (Churchland and (Li et al., 1997). Notably, the efficacy of this or other alternative Winkielman, 2012), support for the direct-to-brain notion comes OT delivery systems on centrally mediated processes has not yet fromrecentstudiesinprimatesthatfoundthatINOTdoubles been tested in human or animal studies. CSF OT levels within 35 min (Chang et al., 2012), strong evi- Aside from the delivery of OT or non-peptide OT analogs dence of central penetration, given that extant evidence supports to the CNS, there are several other ways to impact the central that endogenous OT in the CSF derives from central not periph- OT system [reviewed in Modi and Young (2012)]. These include eral sources (McEwen, 2004). Further support comes from recent, inhibition of the non-specific enzyme that degrades OT in the unpublished rodent data indicating that IN OT elevates OT lev- CSF [aminopeptidase placental-leucineaminopeptidase (P-LAP) els in the extracellular fluid in the hippocampus and amygdala (Chai et al., 2008; Albiston et al., 2011)] and the use of drugs (Rainer Landgraf, pers. communication). Studies with other IN- that may stimulate OT release from endogenous stores via the delivered peptides showing perineuronal transport are also of serotonergic (Jorgensen et al., 2003a) and melanocortin receptors interest in this regard (Chen et al., 1998; Renner et al., 2012b; (Sabatier, 2006) found on OT neurons. Drugs like the sero- Zhu et al., 2012). On the other hand, increased central levels tonin 1a agonist buspirone (Bagdy and Kalogeras, 1993; Jorgensen of OT after IN administration can occur indirectly via elevated et al., 2003b), 3,4 methlyenedioxymethamphetamine (MDMA) levels of OT in the peripheral circulation, thus the evidence or ecstasy (Thompson et al., 2007; Dumont et al., 2009; Broadbear described above does not represent definitive evidence of a direct et al., 2011), and the uniquely effective antipsychotic clozaril nose-to-brain mechanism, nor whether IN-administered OT has (MacDonald and Feifel, 2012a), have been proposed to exert some advantages over peripheral or even orally administered OT in of their pharmacological activity via stimulation of the central OT terms of brain penetration or reduced peripheral side effects. system. Indeed, at least one study examining this issue concluded that Devunetide (an 8-amino acid peptide) administered IN to rats IS INTRANASAL DELIVERY OF OXYTOCIN THE OPTIMAL ROUTE? entered the brain via the peripheral blood system (Morimoto As mentioned above, a prominent pharmacokinetic issue with et al., 2009). As such, given potential disadvantages of IN delivery synthetic OT involves getting this relatively large, hydrophilic (i.e., reliance on patients for consistent dose delivery), the issue of molecule into the brain, given its poor penetration of the blood- whether the IN route or another route is optimal for OT-targeted brain barrier (McEwen, 2004). IN application of peptidergic therapeutics is still an open question. drugs to the CNS has been proven since 1989 (Frey, 1991), and is a delivery system increasingly utilized for a variety of drugs WHAT IS THE ROLE OF VASOPRESSIN RECEPTORS IN OXYTOCIN’S for a range of putative central indications, including memory EFFECTS? (Benedict et al., 2007) and multiple sclerosis (Ross et al., 2004). Due to their close evolutionary relationship, the pharmaco- Delivering a peptide IN capitalizes first on the heavily vascularized logical story of the OT system is interleaved with that of its nasal mucosa, which drains through both fenestrated epithelium “sister” hormone AVP. Pivotally, though they have evolved to and via several facial veins (facial and sphenopalatine), into the serve very different functions, these two neuropeptides differ by peripheral circulation, circumventing first pass metabolism (Zhu only 2 amino acids (Gimpl and Fahrenholz, 2001). In terms et al., 2012). In this way, IN delivery simulates IV delivery: drugs of receptors, 4 G-protein-coupled receptors have been iden- delivered IN may reach the brain via active transport or diffusion tified that bind these peptides in both humans and rodents: from the blood compartment across the blood-CSF or blood- AVPR1a, AVPR1b, AVPR2, and OTR (Gimpl and Fahrenholz, brain barrier (Thorne and Frey, 2001; Morimoto et al., 2009). 2001; Grimmelikhuijzen and Hauser, 2012). Of these receptors, Beyond this, a direct-to-the-brain path of entry after IN delivery AVPR1a is the most abundantly expressed in the brain, whereas of peptides and other drugs has been proposed via two possible AVPR1b has more limited brain expression and AVPR2 exists mechanisms (Figure 1): (1) intraneuronal active uptake along the almost exclusively in the periphery (Stoop, 2012). Pertaining olfactory or trigeminal nerve into the brain; and (2) extraneu- to OT-directed therapeutics, it is important to note that OT ronal passive diffusion into the CSF through perineural clefts in is relatively selective, binding to AVP receptors with ∼1% the the nasal epithelium which provide a gap in BBB (Illum, 2004; affinity it binds to OTRs, whereas AVP is non-selective, bind- Thorne et al., 2004; Renner et al., 2012a,b)and(Dhuria et al., ing with similar affinity to both OTR and AVPRs (Lowbridge 2010; Chapman et al., 2012; Zhu et al., 2012 for references and et al., 1977; Mouillac et al., 1995; Manning et al., 2012). Also details). important is that population-level genetic studies of OT and In point of fact, direct-to-the-brain delivery of IN OT was AVPR1a receptors in humans indicate that both systems appear extrapolated from studies with OT’s sister nanopeptide vaso- to be responsible for important behavioral phenotypes in humans pressin, which differs from OT by the substitution of two amino (Prichard et al., 2007; Walum et al., 2008, 2012; Levin et al., 2009;

www.frontiersin.org March2013|Volume7|Article35| 11 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

Meyer-Lindenberg et al., 2009; Kumsta and Heinrichs, 2013). In MONOTHERAPY vs. AUGMENTATION: CAN OXYTOCIN TREAT ON ITS terms of conceptualizing their role in mammalian behavior, it OWN OR IS IT BETTER SUITED TO AUGMENT OTHER ESTABLISHED appears that differences in receptor co-expression and region- TREATMENTS? specific density—parameters which vary meaningfully in rodents The discovery of the molecular mechanisms wherein experience (see Veinante and Freund-Mercier, 1995; Huber et al., 2005; becomes written in the nervous system (Kandel and Squire, 1999), Young et al., 2006; Raggenbass, 2008), and humans (Loup et al., and the growing understanding that OT’s effects vary signifi- 1991)—influence the different roles of these two nonapeptides in cantly based on context (Bartz et al., 2011b), opens the possi- the CNS, and many models suggest these related peptides have bility for pharmacological augmentation of learning-based treat- somewhat opposing roles in terms of anxiety and behavioral mea- ments, including computer-based cognitive training programs sures of coping (Legros, 2001; Neumann and Landgraf, 2012). (i.e., Vinogradov et al., 2012)andmanyformsofpsychother- Notwithstandingthislargerframework,evidencealsoexistssug- apy (see Choi et al., 2010). Several medications have already gesting some of OTs activities, including both its putative central been examined in this capacity, including the NMDA partial ago- therapeutic effects (Schorscher-Petcu et al., 2010; Sala et al., nist d-cycloserine (DCS) (Otto et al., 2010), the NMDA receptor 2011), as well as some of its potential side effects [i.e., hypona- antagonist ketamine, (Krupitsky et al., 2002), the beta-blocker tremia (Seifer et al., 1985; Stratton et al., 1995)] may be mediated propranolol (Kindt et al., 2009), and the serotonergic-enhancer bybindingtoAVPreceptors(Liggins, 1963; Li et al., 2008). MDMA (“ecstasy”), an amphetamine-related CNS stimulant A number of specific agonists and antagonists for each of which may exert some of its effects via the OT system (Parrott, the four different nonapeptide receptors have been developed 2007; Dumont et al., 2009). Evidence that OT enhances neuro- (Manning et al., 2012), and have allowed more precise delineation genesis (Leuner et al., 2012), the beneficial effects of social sup- of the role of the different receptors in the activities of each of port (Heinrichs et al., 2003), social salience and social memory these nonapeptides. Specifically, whereas OT (but not AVP) nor- (Hurlemann et al., 2010; Guastella and MacLeod, 2012)alsosug- malizes deficits in OT and CD38 knockout mice (Ferguson et al., gest that OT is a good candidate for such “augmentation” trials. 2000; Jin et al., 2007), both OT and AVP normalize defects in In the case of schizophrenia, for example, it may be valuable OT-receptor knockout mice, which demonstrate an autism-like to examine OTs effects when given in conjunction with cogni- profile (deficits in social behavior, seizures) (Sala et al., 2013). tive enhancement therapies already demonstrated to have benefit This latter experiment indicated that ICV delivery of both OT (Chou et al., 2012; Twamley et al., 2012). Aside from OT’s ability and AVP reduced some of these autism-like difficulties via the to augment learning-based treatments, we note that OT’s bene- AVPV1a receptor (Sala et al., 2013). A second, related experi- fits in schizophrenia have all been when it is given in conjunction ment found that some of OTs analgesic activity in mice is related with established antipsychotics (i.e., a pharmacological “augmen- to AVPV1a, as demonstrated by OT’s lack of analgesic activ- tation” strategy) (Feifel et al., 2010, 2012a; Pedersen et al., 2011; ity in AVPR1a knockout mice and the ability of an AVPR1a Modabbernia et al., 2013) and that the role of OT as a primary receptor antagonist to block the effect (Schorscher-Petcu et al., antipsychotic needs investigation. 2010). More speculative, but related, is “OT therapy by proxy” With regard to any putative therapeutic effect of OT, OT- wherein OT given to an adult in a social context (i.e., parent and mediated activation of AVP receptors may have four potential child) may cause OT-driven changes in the child without direct consequences on OT’s behavioral effects: potentiation, media- drug administration to this sensitive population (Naber et al., tion, attenuation, or no impact. The same holds true for any 2010; Weisman et al., 2012b). Current studies of OT’s “augmen- possible side effects of OT. Elucidating the role AVP receptor tation” effect in patients have been limited to one single-dose activation plays in each of OT’s putative therapeutic effects is study and have demonstrated limited success on primary clinical therefore important in order to inform development of drugs to endpoints (Guastella et al., 2009). optimally target central OT/AVP systems. Knowledge gained from this effort would determine whether energy should be directed ARE THERE IDENTIFIABLE BIOMARKERS FOR OXYTOCIN’S toward developing OT agonists with greater selectivity for OTR THERAPEUTIC EFFECTS? than OT itself, or toward compounds with more balanced affin- Biomarkers are objectively measured characteristics that relate to ity for OTR and one or more AVP receptor types. Highlighting the cause, clinical course, and treatment of illness (Frank and this issue, a recent animal study revealed that AVP1a activa- Hargreaves, 2003). In drug development, biomarkers optimize tion (via desmopressin, an AVP receptor agonist) and blockade the efficiency of clinical drug studies by facilitating the detection (via atosiban, an OT/AVP1a receptor antagonist) produced anx- of early signals of drug response (Wiedemann, 2011). Properties iogenic and anxiolytic effect, respectively (Mak et al., 2012). of an optimal pharmacological biomarker include: high sensi- Based on this, an OTR agonist with no cross-affinity for AVPR1a tivity and specificity for clinical outcomes; relatively inexpen- wouldbeexpectedtohavesuperioranxiolyticefficacyanda sive, and low-risk; interpretable by clinicians in many different compound that acted as a dual OTR agonist/AVPR1a antagonist practice locations; a dose-response relationship; and a plausible might have even greater efficacy. Also worth mention here is a link with pharmacology and pathogenesis (Dumont et al., 2005; very recent human trial of the vasopressin V1b receptor antago- Wiedemann, 2011; Baskaran et al., 2012; Leuchter et al., 2012). nist SSR149415, which showed negligible anxiolytic effects, and For a variety of reasons—including a chasm between our under- antidepressant effects that warrant further study (Griebel et al., standing of the short-term neurobiological effects of drugs and 2012). later clinical improvements—these characteristics are of special

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 12 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

import in neuropsychiatry research (Wiedemann, 2011). In this optimal use of a shrinking pool of funding for OT research field, specifically, a wide variety of biomarkers relevant to OT are (driven in part by OT’s lack of patent exclusivity). in different stages of utilization and development, including lab- oratory markers (serum markers, genetic tests), electrophysiolog- FROM DEARTH TO BIRTH, AND PRECLINICAL TO CLINICAL ical markers (EEG, MEG, facial EMG, GSR), brain imaging tech- RESEARCH—HELPING OXYTOCIN DELIVER niques (fMRI, PET), and behavioral measures (challenge tests, We believe the above review supports two broad conclusions cue exposure tasks, PPI, fear-potentiated startle) (Wiedemann, about OT as potential therapeutic agent for CNS disease. First, 2011). Most of these putative biomarkers have been utilized in the last decade of translational and clinical research has pro- conjunction with OT, and this is one arena where single-dose vided a great deal of reason to be cautiously optimistic that OT studies have been invaluable in terms of OT’s development OT-based treatments may be developed to help ease the dearth as a pharmaceutical. Though there has been relatively little clin- in novel treatments for psychiatric illness. Secondly, and some- ically oriented biomarker research with OT (i.e., correlation of what in contrast, the translation of OT’s therapeutic promise has a biomarker with meaningful clinical syndromes or outcomes), been remarkably slow, considering clinical studies with OT are the extant OT literature contains several promising candidates: not hindered by the typical limitations imposed by non-approved heart-rate variability (HRV) (Kemp et al., 2012), skin conduc- investigational drugs (i.e., costly animal and human safety and tance (GSR) (de Oliveira et al., 2012b), stressed cortisol responses toxicity testing before testing in proof-of-concept human trials). (Ditzen et al., 2009; Quirin et al., 2011; Simeon et al., 2011; As discussed above, single-dose studies in normal subjects—and Cardoso et al., 2012; Linnen et al., 2012), facial affect recog- a much-smaller set of single-dose studies in clinical populations nition (Fu et al., 2007, 2008; Harmer et al., 2009a,b), pupil (Table 1)—has left the field pregnant with anticipation about responses (Leknes et al., 2012), EEG measures (Perry et al., OT’s potential therapeutic utility. In our opinion, however, direct 2010), MEG (Hirosawa et al., 2012), and a variety of functional tests of this utility are now past due. We need to help OT imaging (fMRI) parameters, including alteration of default-mode deliver. network (Sripada et al., 2013), responses to naturalistic social The fact that there are only a few published small, multi-week stimuli (Riem et al., 2011, 2012), and stress-induced amygdala clinical trials of OT is problematic. More single-dose studies— responsivity and connectivity patterns (Labuschagne et al., 2010, overwhelmingly in normal subjects—continue to be generated. 2011; Zink and Meyer-Lindenberg, 2012). Regarding functional Some of these add to the body of support for therapeutic effects, imaging biomarkers, these techniques would be greatly aided by while others do the opposite, revealing a more complex role for technical advances, especially a radionucleotide for OTRs. The OT in human behavior, emotion, and cognition (De Dreu et al., development of such a tracer—invaluable in the study of clinically 2010, 2011). These complexity-revealing findings in particular relevant aspects of central dopaminergic (Seeman and Tallerico, have spurred some investigators to suggest that it is premature 1998; Volkow et al., 2001) and opiatergic systems (Greenwald to speculate about OT’s therapeutic potential for neuropsychi- et al., 2003; Mitchell et al., 2012)—would aid in characterizing atric disorders and opine that before we do clinical trials, the field the relationship between central OTR density, clinical pheno- needs more translational studies to elucidate OT’s complex role types, and treatment with OT. In vivo visualization of the human (e.g., Grillon et al., 2012; Miller, 2013). OTR would be particularly fascinating given that (1) in animal As active clinicians and translational researchers, we recognize species, OTR distribution is a significant determinant of behav- the value of translational research. Faced daily with individuals ior (Hammock and Young, 2006; Ross et al., 2009; Ophir et al., and families who have profound and often urgent need for bet- 2012); and (2) OTR density appears to vary dynamically during ter treatments, however, we also recognize its limitations. While phases of life (Bale et al., 2001; Meddle et al., 2007). As well, we agree that additional preclinical OT research in animals and functional imaging studies demonstrating the cortical effects of humans is vital, we do not believe these trials should be done IN OT (Figure 1)and(Bethlehem et al., 2012) are vital addi- at the expense of randomized controlled trials in clinical pop- tions to translational OT research, given the significant variability ulations. Instead, a stepwise, tandem progression is optimal. of cortical organization among different species, including those Translational research works best in a bi-directional mode, with most frequently used in OT research (Preuss, 2000). Though a few preclinical studies informing clinical trials and the results of clini- studies have examined post-mortem OTR binding in the human cal trials—in turn—helping identify which preclinical paradigms CNS (using the same radiolabeled peptide as in rodents) (Loup have the best predictive validity for a specific disorder and drug et al., 1989, 1991), synthesis of small-molecule radioligands for class. In this way, translational paradigms can be further leveraged the OTR (Smith et al., 2012), would greatly aid our understanding to conduct impactful preclinical research. Animal studies have the of the functional role of the OT system in human brain disorders ability to efficiently deliver clinically relevant information without and treatment. the expense, time, and risk-considerations inherent in human tri- To advance the therapeutic potential of OT, the abovemen- als. Similarly, preclinical human studies in which acute effects of tioned biomarkers need to be refined and applied to clinically drugs, like OT, are examined on symptom proxies such as func- ill patients. These studies would clarify several basic pharmaco- tional imaging changes in clinically relevant circuits or laboratory dynamics and pharmacokinetic questions surrounding OT (infra analogs of pathological conditions (e.g., CCK-induced panic) are supra), and—most importantly—could be used to predict ther- much easier, less expensive, and less risky than classic randomized apeutic response. Vitally, biomarker-guided clinical trials may clinical trials. However, at present, the predictive validity of both optimize the efficiency of future clinical trials, facilitating the these forms of preclinical drug research with regard to psychiatric

www.frontiersin.org March 2013 | Volume 7 | Article 35 | 13 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

disorders is far from perfect. Examples abound in which efficacy relevant measures may prompt research emphasis on wider dose or deleterious effects noted in clinical trials were not manifested ranging in phase-II studies of OT. Likewise, animal studies show- in preclinical studies and vice versa. Though clearly we sup- ing tolerance of clinically relevant preclinical effects after a certain port translational research and the ongoing search for reliable duration of treatment may prompt longer-duration trials to eval- biomarkers of clinical response in psychiatric illness, the sim- uate this effect in humans. Similarly, evidence of adverse effect ple facts are: rodents are not humans, and changes in functional in animals emerging at certain doses or durations may prompt imaging or laboratory tasks are not the same as changes in clinical incorporation of specific safety monitoring features into OT clin- symptoms. ical trials. This latter point is particularly important given that As one can see in the abovementioned review, there is cur- randomized controlled trials are costly and labor-intensive, and rently reasonably good evidence from animal and human pre- that negative results due to type-II errors (i.e., missing a signif- clinical trials that OT may have therapeutic benefit in at least icant therapeutic effect) for example, by infelicitous selection of three brain-based conditions: schizophrenia, anxiety, and autism. dose(s) or dosing frequency can be devastating to future studies. For the myriad reasons discussed above, we believe that addi- To this end, there is a definitely a need for more translational tional preclinical studies will not—by themselves—answer the research using animal models with validity—particularly predic- critical therapeutic questions that face clinicians in the field. tive validity—for the specific conditions for which OT is a can- Therefore, proof-of-concept clinical trials are warranted. As a didate treatment (e.g., autism, schizophrenia, anxiety, etc.). Such point of comparison, phase II studies—the kind that are now studies will help address the vital questions we have delineated needed to directly test the various hypotheses regarding OT’s in this paper. These animal studies should be complemented by therapeutic utility—have been carried out by industry on inves- translational human studies using single doses and non-symptom tigational agents with far less data supporting their efficacy and outcomes. Knowledge derived from both of these approaches will safety. These facts, together with (1) the profound impairments increase the likelihood of success of critical clinical trials. As men- imposed by brain-based disease; (2) the often-inadequate efficacy tioned above, the third element in the bench-to-beside arc are of extant treatment; and (3) a disheartening lack of promising, clinical trials using OT, which can reciprocally provide useful novel treatments in the pipeline, we believe, justifies cautious information to evaluate the predictive validity of various animal execution of clinical trials with OT in the abovementioned con- models and proxy-symptom human paradigms. ditions. In this regard it is noteworthy that—after a long period In light of these facts, and in light of the prodigious amount of gestation—the water seems to have broken on research directly of animal and human OT research, it is surprising how little testing OT’s clinical promise: several potentially seminal clinical effort has been specifically directed to address the translational studies of OT appear be underway in several top “target” disorders questions delineated above. For example, despite good evidence (www.clinicaltrials.gov). from preliminary clinical trials that OT has therapeutic benefit in However, OT will not be developed into a drug for any schizophrenia (MacDonald and Feifel, 2012a), at the time of this psychiatric indication with one, two, or even three investigator- writing, only three published studies have explored exogenous initiated clinical trials. These initial trials often produce neg- OT’s effects in animals models with predictive relevance specif- ative or weak therapeutic effects. Thus, concurrent preclinical ically for schizophrenia (Feifel and Reza, 1999; Lee et al., 2005; studies—both animal and human—are needed to advance the Feifel et al., 2012b). In order to help OT deliver on its therapeutic therapeutic development of OT. These additional preclinical stud- promise, there remains much work across the entire translational ies are needed to inform the design of the inevitable second spectrum. wave of clinical trials in the current “big three” indications, as well as initial proof-of-concept trials in other emerging candi- ACKNOWLEDGMENTS date OT-responsive disorders. For example, preclinical studies Thanks to Maribel Santos for help with the illustration and Tina, demonstrating dichotomous dose-dependent effects on clinically Kainoa, and Mataio MacDonald for editorial assistance.

REFERENCES the plasma and cerebrospinal but not in plasma of humans. autism spectrum disorders. Al-Ayadhi, L. Y. (2005). Altered oxy- fluid of lactating rhesus monkeys J. Clin. Endocrinol. Metab. 57, Proc. Natl. Acad. Sci. U.S.A. 107, tocin and vasopressin levels in autis- (Macaca mulatta): evidence for 947–951. 4389–4394. tic children in Central Saudi Arabia. functionally independent oxy- Anagnostou, E., Soorya, L., Chaplin, Anderson, G. M. (2006). Report of Neurosciences 10, 47–50. tocinergic pathways in primates. W.,Bartz,J.,Halpern,D., altered urinary oxytocin and AVP Albiston, A. L., Diwakarla, S., J. Clin. Endocrinol. Metab. 71, Wasserman, S., et al. (2012). excretion in neglected orphans Fernando, R. N., Mountford, S. 1531–1535. Intranasal oxytocin versus placebo should be reconsidered. J. Autism J.,Yeatman,H.R.,Morgan,B., Amico, J. A., Seif, S. M., and Robinson, in the treatment of adults with Dev. Disord. 36, 829–830. et al. (2011). Identification and A. G. (1981). Oxytocin in human autism spectrum disorders: a Ansseau, M., Legros, J. J., Mormont, development of specific inhibitors plasma: correlation with neuro- randomized controlled trial. C.,Cerfontaine,J.L.,Papart,P., for insulin-regulated aminopep- physin and stimulation with estro- Mol. Autism 3:16. doi: 10.1186/ Geenen, V., et al. (1987). Intranasal tidase as a new class of cognitive gen. J. Clin. Endocrinol. Metab. 52, 2040-2392-3-16 oxytocin in obsessive-compulsive enhancers. Br.J.Pharmacol.164, 988–993. Andari, E., Duhamel, J. R., Zalla, disorder. Psychoneuroendocrinology 37–47. Amico, J. A., Tenicela, R., Johnston, T., Herbrecht, E., Leboyer, 12, 231–236. Amico, J. A., Challinor, S. M., and J., and Robinson, A. G. (1983). M., and Sirigu, A. (2010). Averbeck,B.B.,Bobin,T.,Evans, Cameron, J. L. (1990). Pattern A time-dependent peak of oxy- Promoting social behavior with S., and Shergill, S. S. (2011). of oxytocin concentrations in tocin exists in cerebrospinal fluid oxytocin in high-functioning Emotion recognition and oxytocin

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 14 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

in patients with schizophrenia. Benedict, C., Hallschmid, M., Schmitz, Burri, A., Heinrichs, M., Schedlowski, Cho, M. M., DeVries, A. C., Williams, Psychol. Med. 1–8. doi: 10.1017/ K., Schultes, B., Ratter, F., Fehm, M., and Kruger, T. H. (2008). The J. R., and Carter, C. S. (1999). The S0033291711001413 H. L., et al. (2007). Intranasal acute effects of intranasal oxy- effects of oxytocin and vasopressin Bagdy, G., and Kalogeras, K. T. (1993). insulin improves memory in tocin administration on endocrine on partner preferences in male Stimulation of 5-HT1A and 5- humans: superiority of insulin and sexual function in males. and female prairie voles (Microtus HT2/5-HT1C receptors induce oxy- aspart. Neuropsychopharmacology Psychoneuroendocrinology 33, ochrogaster). Behav. Neurosci. 113, tocin release in the male rat. Brain 32, 239–243. 591–600. 1071–1079. Res. 611, 330–332. Bergeron, C., Kovacs, K., Ezrin, C., Cardoso, C., Ellenbogen, M. A., Choi, D. C., Rothbaum, B. O., Gerardi, Bailey,J.E.,Kendrick,A.,Diaper,A., and Mizzen, C. (1991). Hereditary and Linnen, A. M. (2012). Acute M., and Ressler, K. J. (2010). Potokar, J. P., and Nutt, D. J. (2007). diabetes insipidus: an immunohis- intranasal oxytocin improves Pharmacological enhancement A validation of the 7.5% CO2 tochemical study of the hypotha- positive self-perceptions of per- of behavioral therapy: focus on model of GAD using paroxetine lamus and pituitary gland. Acta sonality. Psychopharmacology 220, posttraumatic stress disorder. Curr. and lorazepam in healthy volun- Neuropathol. 81, 345–348. 741–749. Top. Behav. Neurosci. 2, 279–299. teers. J. Psychopharmacol. 21, 42–49. Bernatova, I., Rigatto, K. V., Key, Carmichael, M. S., Humbert, R., Dixen, Choleris, E., Devidze, N., Kavaliers, Bakharev, V. D., Tikhomirov, S. M. P., and Morris, M. (2004). J., Palmisano, G., Greenleaf, W., and M., and Pfaff, D. W. (2008). M., and Lozhkina, T. K. (1984). Stress-induced pressor and corti- Davidson, J. M. (1987). Plasma oxy- Steroidal/neuropeptide interactions Psychotropic properties of oxytocin. costerone responses in oxytocin- tocin increases in the human sexual in hypothalamus and amygdala Probl. Endokrinol. (Mosk) 30, 37–41. deficient mice. Exp. Physiol. 89, response. J. Clin. Endocrinol. Metab. related to social anxiety. Prog. Brain Bale,T.L.,Davis,A.M.,Auger,A.P., 549–557. 64, 27–31. Res. 170, 291–303. Dorsa,D.M.,andMcCarthy,M. Bethlehem, R. A. I., van Honk, J., Carter, C. S., Pournajafi-Nazarloo, H., Chou,H.H.,Twamley,E.,and M. (2001). CNS region-specific Auyeung, B., and Baron-Cohen, S. Kramer, K. M., Ziegler, T. E., Swerdlow, N. R. (2012). Towards oxytocin receptor expression: (2012). Oxytocin, brain physiology, White-Traut, R., Bello, D., et al. medication-enhancement of cogni- importance in regulation of anxiety and functional connectivity: a (2007). Oxytocin: behavioral asso- tive interventions in schizophrenia. and sex behavior. J. Neurosci. 21, review of intranasal oxytocin fMRI ciations and potential as a sali- Handb. Exp. Pharmacol. 213, 2546–2552. studies. Psychoneuroendocrinology. vary biomarker. Ann. N.Y. Acad. Sci. 81–111. Bales, K. L., and Carter, C. S. (2003). Availableonlineat:http://dx.doi. 1098, 312–322. Christensen, J., Kvistgaard, H., Sex differences and developmen- org/10.1016/j.psyneuen.2012.10.011 Chai, S. Y., Yeatman, H. R., Parker, M. Knudsen, J., Shaikh, G., Tolmie, J., tal effects of oxytocin on aggres- Birkett, M. A., Shinday, N. M., Kessler, W., Ascher, D. B., Thompson, Cooke, S., et al. (2013). A novel sion and social behavior in prairie E.J.,Meyer,J.S.,Ritchie,S., P.E.,Mulvey,H.T.,etal. deletion partly removing the AVP voles (Microtus ochrogaster). Horm. and Rowlett, J. K. (2011). Acute (2008). Development of cognitive gene causes autosomal recessive Behav. 44, 178–184. anxiogenic-like effects of selec- enhancers based on inhibition of inheritance of early-onset neurohy- Bales, K. L., and Perkeybile, A. M. tive serotonin reuptake inhibitors insulin-regulated aminopeptidase. pophyseal diabetes insipidus. Clin. (2012). Developmental experiences are attenuated by the benzodi- BMC Neurosci. 9(Suppl. 2):S14. doi: Genet. 83, 44–52. and the oxytocin receptor system. azepine diazepam in BALB/c mice. 10.1186/1471-2202-9-S2-S14 Churchland, P. S., and Winkielman, P. Horm. Behav. 61, 313–319. Pharmacol. Biochem. Behav. 98, Challinor,S.M.,Winters,S.J.,and (2012). Modulating social behavior Bales,K.L.,Plotsky,P.M.,Young,L. 544–551. Amico, J. A. (1994). Pattern of oxy- with oxytocin: how does it work? J.,Lim,M.M.,Grotte,N.,Ferrer, Born,J.,Lange,T.,Kern,W.,McGregor, tocin concentrations in the periph- What does it mean? Horm. Behav. E., et al. (2007a). Neonatal oxytocin G. P., Bickel, U., and Fehm, H. eral blood of healthy women and 61, 392–399. manipulations have long-lasting, L. (2002). Sniffing neuropep- men: effect of the menstrual cycle Cushing, B. S., and Carter, C. S. sexually dimorphic effects on vaso- tides: a transnasal approach to the and short-term fasting. Endocr. Res. (2000). Peripheral pulses of oxy- pressin receptors. Neuroscience 144, human brain. Nat. Neurosci. 5, 20, 117–125. tocin increase partner preferences in 38–45. 514–516. Chang, S. W., Barter, J. W., Ebitz, female, but not male, prairie voles. Bales, K. L., van Westerhuyzen, J. Bowen, M. T., Carson, D. S., Spiro, R. B., Watson, K. K., and Platt, Horm. Behav. 37, 49–56. A., Lewis-Reese, A. D., Grotte, N. A., Arnold, J. C., and McGregor, M. L. (2012). Inhaled oxytocin Dale, H. H. (1906). On some physiolog- D., Lanter, J. A., and Carter, C. I. S. (2011). Adolescent oxytocin amplifies both vicarious reinforce- ical actions of ergot. J. Physiol. 34, S. (2007b). Oxytocin has dose- exposure causes persistent reduc- ment and self reinforcement in rhe- 163–206. dependent developmental effects on tions in anxiety and alcohol con- sus macaques (Macaca mulatta). De Dreu, C. K., Greer, L. L., Handgraaf, pair-bonding and alloparental care sumption and enhances sociability Proc. Natl. Acad. Sci. U.S.A. 109, M. J., Shalvi, S., Van Kleef, G. in female prairie voles. Horm. Behav. in rats. PLoS ONE 6:e27237. doi: 959–964. A., Baas, M., et al. (2010). The 52, 274–279. 10.1371/journal.pone.0027237 Chapman, C. D., Frey, W. H. 2nd., neuropeptide oxytocin regulates Bartz, J., Simeon, D., Hamilton, H., Broadbear, J. H., Tunstall, B., and Craft, S., Danielyan, L., Hallschmid, parochial altruism in intergroup Kim, S., Crystal, S., Braun, A., et al. Beringer, K. (2011). Examining M., Schioth, H. B., et al. (2012). conflict among humans. Science (2011a). Oxytocin can hinder trust the role of oxytocin in the Intranasal treatment of central ner- 328, 1408–1411. and cooperation in borderline per- interoceptive effects of 3, 4- vous system dysfunction in humans. De Dreu, C. K., Greer, L. L., Van Kleef, sonality disorder. Soc. Cogn. Affect. methylenedioxymethamphetamine Pharm. Res. doi: 10.1007/s11095- G. A., Shalvi, S., and Handgraaf, Neurosci. 6, 556–563. (MDMA, ‘ecstasy’) using a drug 012-0915-1. [Epub ahead of print]. M. J. (2011). Oxytocin pro- Bartz, J. A., Zaki, J., Bolger, N., and discrimination paradigm in the rat. Chaviaras, S., Mak, P., Ralph, D., motes human ethnocentrism. Ochsner, K. N. (2011b). Social Addict. Biol. 16, 202–214. Krishnan, L., and Broadbear, Proc. Natl. Acad. Sci. U.S.A. 108, effects of oxytocin in humans: con- Bujanow, W. (1972). Hormones in the J. H. (2010). Assessing the 1262–1266. text and person matter. Trends Cogn. treatment of psychoses. Br. Med. J. antidepressant-like effects of Delville, Y., Mansour, K. M., and Sci. 15, 301–309. 4, 298. carbetocin, an oxytocin agonist, Ferris, C. F. (1996). Testosterone Baskaran, A., Milev, R., and McIntyre, Burghy, C. A., Stodola, D. E., Ruttle, using a modification of the forced facilitates aggression by modulat- R. S. (2012). The neurobiology of P.L.,Molloy,E.K.,Armstrong, swimming test. Psychopharmacology ing vasopressin receptors in the the EEG biomarker as a predictor J. M., Oler, J. A., et al. (2012). 210, 35–43. hypothalamus. Physiol. Behav. 60, of treatment response in depression. Developmental pathways to Chen, X. Q., Fawcett, J. R., Rahman, Y. 25–29. Neuropharmacology 63, 507–513. amygdala-prefrontal function E., Ala, T. A., and Frey, I. W. (1998). den Boer, J. A., and Westenberg, H. Belmaker, R. H., and Wald, D. (1977). and internalizing symptoms in Delivery of nerve growth factor to G. (1992). Oxytocin in obsessive Haloperidol in normals. Br. J. adolescence. Nat. Neurosci. 15, the brain via the olfactory pathway. compulsive disorder. Peptides 13, Psychiatry 131, 222–223. 1736–1741. J. Alzheimers Dis. 1, 35–44. 1083–1085.

www.frontiersin.org March 2013 | Volume 7 | Article 35 | 15 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

de Oliveira, D. C., Chagas, M. H., Epperson, C. N., McDougle, C. J., and neurohypophysial hormones in et al. (2012). Oxytocin plasma con- Garcia, L. V., Crippa, J. A., and Price, L. H. (1996a). Intranasal man: effect of age. Exp. Physiol. 83, centrations after single intranasal Zuardi, A. W. (2012a). Oxytocin oxytocin in obsessive-compulsive 409–418. oxytocin administration—A study interference in the effects induced disorder. Biol. Psychiatry 40, Frank, R., and Hargreaves, R. (2003). in healthy men. Neuropeptides 46, by inhalation of 7.5% CO2 547–549. Clinical biomarkers in drug dis- 211–215. in healthy volunteers. Hum. Epperson, C. N., McDougle, C. J., covery and development. Nat. Rev. Graugaard-Jensen, C., Hvistendahl, Psychopharmacol. 27, 378–385. and Price, L. H. (1996b). Intranasal Drug Discov. 2, 566–580. G. M., Frokiaer, J., Bie, P., and de Oliveira, D. C., Zuardi, A. W., Graeff, oxytocin in trichotillomania. Biol. Frey, W. H. (1991). WPTO,UC. Djurhuus, J. C. (2008). The influ- F.G.,Queiroz,R.H.,andCrippa, Psychiatry 40, 559–560. Corporation. ence of high and low levels of J. A. (2012b). Anxiolytic-like effect Fehm, H. L., Perras, B., Smolnik, R., Fu,C.H.,Mourao-Miranda,J., estrogen on diurnal urine regula- of oxytocin in the simulated pub- Kern, W., and Born, J. (2000). Costafreda, S. G., Khanna, A., tion in young women. BMC Urol. lic speaking test. J. Psychopharmacol. Manipulating neuropeptidergic Marquand, A. F., Williams, S. C., 8:16. doi: 10.1186/1471-2490-8-16 26, 497–504. pathways in humans: a novel et al. (2008). Pattern classification Greenwald, M. K., Johanson, C. de Vries, G. J. (2008). Sex differences approach to neuropharmacology? of sad facial processing: toward the E., Moody, D. E., Woods, J. H., in vasopressin and oxytocin inner- Eur. J. Pharmacol. 405, 43–54. development of neurobiological Kilbourn,M.R.,Koeppe,R.A.,etal. vation of the brain. Prog. Brain Res. Feifel, D., MacDonald, K., Cobb, P., and markers in depression. Biol. (2003). Effects of buprenorphine 170, 17–27. Minassian, A. (2012a). Adjunctive Psychiatry 63, 656–662. maintenance dose on mu-opioid Dhuria, S. V., Hanson, L. R., and intranasal oxytocin improves Fu, C. H., Williams, S. C., Brammer, receptor availability, plasma Frey, W. H. 2nd. (2010). Intranasal verbal memory in people with M. J., Suckling, J., Kim, J., Cleare, concentrations, and antagonist delivery to the central nervous sys- schizophrenia. Schizophr. Res. 139, A. J., et al. (2007). Neural responses blockade in heroin-dependent vol- tem: mechanisms and experimen- 207–210. to happy facial expressions in major unteers. Neuropsychopharmacology tal considerations. J. Pharm. Sci. 99, Feifel, D., Shilling, P. D., and Belcher, depression following antidepressant 28, 2000–2009. 1654–1673. A. M. (2012b). The effects of oxy- treatment. Am. J. Psychiatry 164, Grewen, K. M., Davenport, R. E., Ditzen, B., Schaer, M., Gabriel, B., tocin and its analog, carbetocin, on 599–607. and Light, K. C. (2010). An inves- Bodenmann, G., Ehlert, U., and genetic deficits in sensorimotor gat- Fuchs, A. R., Behrens, O., and Liu, tigation of plasma and salivary Heinrichs, M. (2009). Intranasal ing. Eur. Neuropsychopharmacol. 22, H. C. (1992). Correlation of noc- oxytocin responses in breast- and oxytocin increases positive commu- 374–378. turnal increase in plasma oxytocin formula-feeding mothers of infants. nication and reduces cortisol lev- Feifel, D., MacDonald, K., McKinney, with a decrease in plasma estra- Psychophysiology 47, 625–632. els during couple conflict. Biol. R.,Heisserer,N.,andSerrano, diol/progesterone ratio in late preg- Griebel, G., Beeske, S., and Stahl, S. Psychiatry 65, 728–731. V. (2011). A randomized, nancy. Am. J. Obstet. Gynecol. 167, M. (2012). The vasopressin V(1b) Domes,G.,Lischke,A.,Berger,C., placebo-controlled investigation of 1559–1563. receptor antagonist SSR149415 in Grossmann, A., Hauenstein, K., intranasal oxytocin in patients with Gimpl, G., and Fahrenholz, F. (2001). the treatment of major depressive Heinrichs, M., et al. (2010). anxiety. Neuropsychopharmacology The oxytocin receptor system: and generalized anxiety disor- Effects of intranasal oxytocin 36, S324–S449. structure, function, and regulation. ders: results from 4 randomized, on emotional face processing in Feifel, D., MacDonald, K., Nguyen, A., Physiol. Rev. 81, 629–683. double-blind, placebo-controlled women. Psychoneuroendocrinology Cobb, P., Warlan, H., Galangue, B., Gimpl, G., Postina, R., Fahrenholz, F., studies. J. Clin. Psychiatry 73, 35, 83–93. et al. (2010). Adjunctive intranasal and Reinheimer, T. (2005). Binding 1403–1411. Dumont,G.J.,deVisser,S.J.,Cohen, oxytocin reduces symptoms in domains of the oxytocin receptor Grillon,C.,Krimsky,M.,Charney, A. F., and van Gerven, J. M. schizophrenia patients. Biol. for the selective oxytocin recep- D.R.,Vytal,K.,Ernst,M.,and (2005). Biomarkers for the effects Psychiatry 68, 678–680. tor antagonist barusiban in com- Cornwell, B. (2012). Oxytocin of selective serotonin reuptake Feifel, D., and Reza, T. (1999). Oxytocin parison to the agonists oxytocin increases anxiety to unpre- inhibitors (SSRIs) in healthy sub- modulates psychotomimetic- and carbetocin. Eur. J. Pharmacol. dictable threat. Mol. Psychiatry. jects. Br. J. Clin. Pharmacol. 59, induced deficits in sensorimotor 510, 9–16. doi: 10.1038/mp.2012.156. [Epub 495–510. gating. Psychopharmacology 141, Goldman, M., Marlow-O’Connor, ahead of print]. Dumont, G. J., Sweep, F. C., van der 93–98. M.,Torres,I.,andCarter,C.S. Grimmelikhuijzen, C. J., and Hauser, F. Steen, R., Hermsen, R., Donders, Feldman, R. (2012). Oxytocin and (2008). Diminished plasma oxy- (2012). Mini-review: the evolution A. R., Touw, D. J., et al. (2009). social affiliation in humans. Horm. tocin in schizophrenic patients with of neuropeptide signaling. Regul. Increased oxytocin concentra- Behav. 61, 380–391. neuroendocrine dysfunction and Pept. 177(Suppl.), S6–S9. tions and prosocial feelings Feldman, R., Gordon, I., and Zagoory- emotional deficits. Schizophr. Res. Guastella, A. J., Einfeld, S. L., Gray, in humans after ecstasy (3,4- Sharon, O. (2011). Maternal and 98, 247–255. K. M., Rinehart, N. J., Tonge, B. methylenedioxymethamphetamine) paternal plasma, salivary, and uri- Goldman,M.B.,Gomes,A.M.,Carter, J., Lambert, T. J., et al. (2010). administration. Soc. Neurosci. 4, nary oxytocin and parent-infant C. S., and Lee, R. (2011). Divergent Intranasal oxytocin improves emo- 359–366. synchrony: considering stress and effects of two different doses of tion recognition for youth with Du Vigneaud, V. (1956). Trail of sulfur affiliation components of human intranasal oxytocin on facial affect autism spectrum disorders. Biol. research: from insulin to oxytocin. bonding. Dev. Sci. 14, 752–761. discrimination in schizophrenic Psychiatry 67, 692–694. Science 123, 967–974. Ferguson, J. N., Young, L. J., Hearn, patients with and without poly- Guastella,A.J.,Howard,A.L., Ebstein, R. P., Knafo, A., Mankuta, E. F., Matzuk, M. M., Insel, T. dipsia. Psychopharmacology 216, Dadds, M. R., Mitchell, P., and D., Chew, S. H., and Lai, P. S. R., and Winslow, J. T. (2000). 101–110. Carson, D. S. (2009). A random- (2012). The contributions of oxy- Social amnesia in mice lacking Gordon, I., Martin, C., Feldman, R., ized controlled trial of intranasal tocin and vasopressin pathway genes the oxytocin gene. Nat. Genet. 25, and Leckman, J. F. (2011). Oxytocin oxytocin as an adjunct to expo- to human behavior. Horm. Behav. 284–288. and social motivation. Dev. Cogn. sure therapy for social anxiety 61, 359–379. Fibiger, H. C. (2012). Psychiatry, Neurosci. 1, 471–493. disorder. Psychoneuroendocrinology Engstrom, T., Barth, T., Melin, P., the pharmaceutical industry, and Gordon, I., Zagoory-Sharon, O., 34, 917–923. and Vilhardt, H. (1998). Oxytocin the road to better therapeutics. Leckman, J. F., and Feldman, R. Guastella, A. J., and MacLeod, C. receptor binding and uterotonic Schizophr. Bull. 38, 649–650. (2010). Oxytocin and the develop- (2012). A critical review of the influ- activity of carbetocin and its Forsling,M.L.,Montgomery, ment of parenting in humans. Biol. ence of oxytocin nasal spray on metabolites following enzymatic H., Halpin, D., Windle, R. J., Psychiatry 68, 377–382. social cognition in humans: evi- degradation. Eur. J. Pharmacol. 355, and Treacher, D. F. (1998). Gossen, A., Hahn, A., Westphal, L., dence and future directions. Horm. 203–210. Daily patterns of secretion of Prinz, S., Schultz, R. T., Grunder, G., Behav. 61, 410–418.

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 16 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

Hall, S. S., Lightbody, A. A., McCarthy, M. H., et al. (2012). Plasma oxy- Illum, L. (2004). Is nose-to-brain trans- responsiveness and partner pref- B. E., Parker, K. J., and Reiss, A. tocin immunoreactive products and port of drugs in man a reality? erence formation as adults. Horm. L. (2012). Effects of intranasal response to trust in patients with J. Pharm. Pharmacol. 56, 3–17. Behav. 60, 498–504. oxytocin on social anxiety in social anxiety disorder. Depress. Israel, J. M., Le Masson, G., Theodosis, Kemp, A. H., Quintana, D. S., Kuhnert, males with fragile X syndrome. Anxiety 29, 924–930. D. T., and Poulain, D. A. (2003). R.L.,Griffiths,K.,Hickie,I.B., Psychoneuroendocrinology 37, Hoge, E. A., Pollack, M. H., Kaufman, Glutamatergic input governs and Guastella, A. J. (2012). Oxytocin 509–518. R.E.,Zak,P.J.,andSimon,N. periodicity and synchronization increases heart rate variability in Hammock,E.A.,andYoung,L.J. M. (2008). Oxytocin levels in social of bursting activity in oxytocin humans at rest: implications for (2006). Oxytocin, vasopressin and anxiety disorder. CNS Neurosci. neurons in hypothalamic organ- social approach-related motivation pair bonding: implications for Ther. 14, 165–170. otypic cultures. Eur. J. Neurosci. 17, and capacity for social engage- autism. Philos. Trans. R. Soc. Lond. Hollander, E., Bartz, J., Chaplin, W., 2619–2629. ment. PLoS ONE 7:e44014. doi: B Biol. Sci. 361, 2187–2198. Phillips, A., Sumner, J., Soorya, L., Ito, M., and Jameson, J. L. (1997). 10.1371/journal.pone.0044014 Harmer, C. J. (2008). Serotonin and et al. (2007). Oxytocin increases Molecular basis of autosomal dom- Kent,J.M.,Coplan,J.D.,andGorman, emotional processing: does it retention of social cognition inant neurohypophyseal diabetes J. M. (1998). Clinical utility of help explain antidepressant drug in autism. Biol. Psychiatry 61, insipidus. Cellular toxicity caused the selective serotonin reup- action? Neuropharmacology 55, 498–503. by the accumulation of mutant take inhibitors in the spectrum 1023–1028. Hollander, E., Novotny, S., Hanratty, vasopressin precursors within the of anxiety. Biol. Psychiatry 44, Harmer, C. J., Bhagwagar, Z., Perrett, M.,Yaffe,R.,DeCaria,C.M., endoplasmic reticulum. J. Clin. 812–824. D. I., Vollm, B. A., Cowen, P. J., and Aronowitz, B. R., et al. (2003). Invest. 99, 1897–1905. Keri, S., Kiss, I., and Kelemen, O. Goodwin, G. M. (2003). Acute SSRI Oxytocin infusion reduces repet- Jin,D.,Liu,H.X.,Hirai,H.,Torashima, (2009). Sharing secrets: oxytocin administration affects the process- itive behaviors in adults with T., Nagai, T., Lopatina, O., et al. and trust in schizophrenia. Soc. ing of social cues in healthy volun- autistic and Asperger’s disorders. (2007). CD38 is critical for social Neurosci. 4, 287–293. teers. Neuropsychopharmacology 28, Neuropsychopharmacology 28, behaviour by regulating oxytocin Kimura, T., Tanizawa, O., Mori, K., 148–152. 193–198. secretion. Nature 446, 41–45. Brownstein, M. J., and Okayama, H. Harmer, C. J., Goodwin, G. M., and Holma,K.M.,Holma,I.A.,Melartin, Johnson, A. E., Coirini, H., Insel, T. (1992). Structure and expression of Cowen, P. J. (2009a). Why do T.K.,Rytsala,H.J.,andIsometsa, R., and McEwen, B. S. (1991). a human oxytocin receptor. Nature antidepressants take so long to E. T. (2008). Long-term outcome of The regulation of oxytocin 356, 526–529. work? A cognitive neuropsycho- major depressive disorder in psy- receptor binding in the ventro- Kindt, M., Soeter, M., and Vervliet, B. logical model of antidepressant chiatric patients is variable. J. Clin. medial hypothalamic nucleus by (2009). Beyond extinction: erasing drug action. Br. J. Psychiatry 195, Psychiatry 69, 196–205. testosterone and its metabolites. human fear responses and prevent- 102–108. Holt-Lunstad, J., Birmingham, W., and Endocrinology 128, 891–896. ing the return of fear. Nat. Neurosci. Harmer, C. J., O’Sullivan, U., Favaron, Light, K. C. (2011). The influence Jonas, K., Johansson, L. M., Nissen, E., 12, 256–258. E., Massey-Chase, R., Ayres, R., of depressive symptomatology and Ejdeback, M., Ransjo-Arvidson, A. Kirsch, P., Esslinger, C., Chen, Q., Mier, Reinecke, A., et al. (2009b). Effect perceived stress on plasma and sali- B., and Uvnas-Moberg, K. (2009). D., Lis, S., Siddhanti, S., et al. of acute antidepressant administra- vary oxytocin before, during and Effects of intrapartum oxytocin (2005). Oxytocin modulates neural tion on negative affective bias in after a support enhancement inter- administration and epidural analge- circuitry for social cognition and depressed patients. Am. J. Psychiatry vention. Psychoneuroendocrinology sia on the concentration of plasma fear in humans. J. Neurosci. 25, 166, 1178–1184. 36, 1249–1256. oxytocin and prolactin, in response 11489–11493. Harmer, C. J., Heinzen, J., O’Sullivan, Horvat-Gordon, M., Granger, D. A., to suckling during the second day Knobloch, H. S., Charlet, A., U., Ayres, R. A., and Cowen, P. J. Schwartz,E.B.,Nelson,V.J.,and postpartum. Breastfeed. Med. 4, Hoffmann, L. C., Eliava, M., (2008). Dissociable effects of acute Kivlighan, K. T. (2005). Oxytocin is 71–82. Khrulev, S., Cetin, A. H., et al. antidepressant drug administration not a valid biomarker when mea- Jorgensen, H., Kjaer, A., Knigge, U., (2012). Evoked axonal oxytocin on subjective and emotional pro- sured in saliva by immunoassay. Moller, M., and Warberg, J. (2003a). release in the central amygdala cessing measures in healthy vol- Physiol. Behav. 84, 445–448. Serotonin stimulates hypothalamic attenuates fear response. Neuron 73, unteers. Psychopharmacology (Berl.) Huber, D., Veinante, P., and Stoop, R. mRNA expression and local release 553–566. 199, 495–502. (2005). Vasopressin and oxytocin of neurohypophysial peptides. Kosaka, H., Munesue, T., Ishitobi, M., Heinrichs, M., Baumgartner, T., excite distinct neuronal populations J. Neuroendocrinol. 15, 564–571. Asano,M.,Omori,M.,Sato,M., Kirschbaum, C., and Ehlert, U. in the central amygdala. Science 308, Jorgensen, H., Riis, M., Knigge, U., et al. (2012). Long-term oxytocin (2003). Social support and oxytocin 245–248. Kjaer, A., and Warberg, J. (2003b). administration improves social interact to suppress cortisol and Huffmeijer,R.,Alink,L.R.,Tops, Serotonin receptors involved in behaviors in a girl with autistic subjective responses to psychoso- M., Grewen, K. M., Light, K. C., vasopressin and oxytocin secre- disorder. BMC Psychiatry 12:110. cial stress. Biol. Psychiatry 54, Bakermans-Kranenburg, M. J., et al. tion. J. Neuroendocrinol. 15, doi: 10.1186/1471-244X-12-110 1389–1398. (2012). Salivary levels of oxytocin 242–249. Kostoglou-Athanassiou, I., Athanas- Hirosawa, T., Kikuchi, M., Higashida, remain elevated for more than Jourdain, P., Dupouy, B., Bonhomme, siou, P., Treacher, D. F., Wheeler, H.,Okumura,E.,Ueno,S., two hours after intranasal oxytocin R., Theodosis, D. T., Poulain, M. J., and Forsling, M. L. (1998). Shitamichi, K., et al. (2012). administration. Neuro Endocrinol. D. A., and Israel, J. M. (1998). Neurohypophysial hormone and Oxytocin attenuates feelings of Lett. 33, 21–25. Electrophysiological studies of melatonin secretion over the natu- hostility depending on emotional Hunter, D. J., Schulz, P., and Wassenaar, oxytocin neurons in organotypic ral and suppressed menstrual cycle context and individuals’ char- W. (1992). Effect of carbetocin, slice cultures. Adv. Exp. Med. Biol. in premenopausal women. Clin. acteristics. Sci. Rep. 2:384. doi: a long-acting oxytocin analog 449, 135–145. Endocrinol. 49, 209–216. 10.1038/srep00384 on the postpartum uterus. Clin. Kandel, E. R., and Squire, L. R. (1999). Kramer, K. M., Cushing, B. S., and Hoffman,E.R.,Brownley,K.A., Pharmacol. Ther. 52, 60–67. Memory: From Mind to Molecules. Carter, C. S. (2003). Developmental Hamer, R. M., and Bulik, C. M. Hurlemann, R., Patin, A., Onur, O. New York, NY: Henry Holt and effects of oxytocin on stress (2012). Plasma, salivary, and uri- A., Cohen, M. X., Baumgartner, T., Company. response: single versus repeated nary oxytocin in anorexia ner- Metzler, S., et al. (2010). Oxytocin Keebaugh,A.C.,andYoung,L.J. exposure. Physiol. Behav. 79, vosa: a pilot study. Eat. Behav. 13, enhances amygdala-dependent, (2011). Increasing oxytocin recep- 775–782. 256–259. socially reinforced learning and tor expression in the nucleus Krupitsky, E., Burakov, A., Romanova, Hoge,E.A.,Lawson,E.A.,Metcalf,C. emotional empathy in humans. accumbens of pre-pubertal female T., Dunaevsky, I., Strassman, R., A., Keshaviah, A., Zak, P. J., Pollack, J. Neurosci. 30, 4999–5007. prairie voles enhances alloparental and Grinenko, A. (2002). Ketamine

www.frontiersin.org March2013|Volume7|Article35| 17 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

psychotherapy for heroin addic- caused by chronic phencyclidine Liggins, G. C. (1963). Antidiuretic (2011b). Oxytocin improves tion: immediate effects and two- administration are reversed by oxy- effects of oxytocin, morphine and social cognition in patients with year follow-up. J. Subst. Abuse Treat. tocin. Neuropsychopharmacology 30, pethidine in pregnancy and labour. depression. Biol. Psychiatry 69, 23, 273–283. 1883–1894. Aust. N.Z. J. Obstet. Gynaecol. 3, 279S–280S. Kuboyama, T., Hashimoto, H., Legros, J. J. (2001). Inhibitory effect of 81–83. MacDonald, K., and Feifel, D. (2012a). Ueguchi, T., Yamaki, T., Hirakawa, oxytocin on corticotrope function Light, K. C., Grewen, K. M., and Amico, Oxytocin in schizophrenia: a review K., Noto, T., et al. (1988). Diurnal in humans: are vasopressin and J. A. (2005). More frequent part- of evidence for its therapeutic changes in vasopressin and oxytocin oxytocin ying-yang neurohor- ner hugs and higher oxytocin levels effects. Acta Neuropsychiatr. 24, levels in cerebrospinal fluid of post- mones? Psychoneuroendocrinology are linked to lower blood pressure 130–146. operative patients with intracranial 26, 649–655. and heart rate in premenopausal MacDonald, K., and Feifel, D. (2012b). aneurysms. Endocrinol. Jpn. 35, Legros, J. J., Chiodera, P., Geenen, V., women. Biol. Psychol. 69, 5–21. Dramatic improvement in sexual 249–254. Smitz, S., and von Frenckell, R. Lindow, S. W., Newham, A., Hendricks, function induced by intranasal oxy- Kumsta, R., and Heinrichs, M. (2013). (1984). Dose-response relationship M. S., Thompson, J. W., and tocin. J. Sex. Med. 9, 1407–1410. Oxytocin, stress and social behavior: between plasma oxytocin and van der Spuy, Z. M. (1996). The MacDonald, K., and MacDonald, neurogenetics of the human oxy- cortisol and adrenocorticotropin 24-hour rhythm of oxytocin and T. M. (2010). The peptide that tocin system. Curr. Opin. Neurobiol. concentrations during oxytocin beta-endorphin secretion in human binds: a systematic review of oxy- 23, 11–16. infusion in normal men. J. Clin. pregnancy. Clin. Endocrinol. 45, tocin and its prosocial effects in Kuwabara, Y., Takeda, S., Mizuno, M., Endocrinol. Metab. 58, 105–109. 443–446. humans. Harv. Rev. Psychiatry 18, and Sakamoto, S. (1987). Oxytocin Leknes, S., Wessberg, J., Ellingsen, D. Linnen, A. M., Ellenbogen, M. A., 1–21. levels in maternal and fetal plasma, M., Chelnokova, O., Olausson, H., Cardoso, C., and Joober, R. (2012). Mah, B. L., Van Ijzendoorn, M. amniotic fluid, and neonatal plasma and Laeng, B. (2012). Oxytocin Intranasal oxytocin and salivary H.,Smith,R.,andBakermans- and urine. Arch.Gynecol.Obstet. enhances pupil dilation and sen- cortisol concentrations during Kranenburg, M. J. (2013). Oxytocin 241, 13–23. sitivity to ‘hidden’ emotional social rejection in university in postnatally depressed moth- Labuschagne, I., Phan, K. L., Wood, A., expressions. Soc. Cogn. Affect. students. Stress 15, 393–402. ers: its influence on mood Angstadt, M., Chua, P., Heinrichs, Neurosci. doi: 10.1093/scan/nss062. Liu, J. C., Guastella, A. J., and Dadds, and expressed emotion. Prog. M., et al. (2010). Oxytocin atten- [Epub ahead of print]. M. R. (2012). Effects of oxytocin on Neuropsychopharmacol. Biol. uates amygdala reactivity to fear Leuchter, A. F., Cook, I. A., Hunter, A. human social approach measured Psychiatry 40, 267–272. in generalized social anxiety dis- M., Cai, C., and Horvath, S. (2012). using intimacy equilibriums. Horm. Mak, P., Broussard, C., Vacy, K., and order. Neuropsychopharmacology 35, Resting-state quantitative electroen- Behav. 62, 585–591. Broadbear, J. H. (2012). Modulation 2403–2413. cephalography reveals increased Loup, F., Tribollet, E., Dubois- of anxiety behavior in the elevated Labuschagne, I., Phan, K. L., Wood, A., neurophysiologic connectivity in Dauphin, M., and Dreifuss, J. J. plus maze using peptidic oxytocin Angstadt, M., Chua, P., Heinrichs, depression. PLoS ONE 7:e32508. (1991). Localization of high-affinity and vasopressin receptor ligands M., et al. (2011). Medial frontal doi: 10.1371/journal.pone.0032508 binding sites for oxytocin and in the rat. J. Psychopharmacol. 26, hyperactivity to sad faces in gen- Leuner, B., Caponiti, J. M., and Gould, vasopressin in the human brain. an 532–542. eralized social anxiety disorder and E. (2012). Oxytocin stimulates adult autoradiographic study. Brain Res. Manning, M., Misicka, A., Olma, A., modulation by oxytocin. Int. J. neurogenesis even under conditions 555, 220–232. Bankowski, K., Stoev, S., Chini, Neuropsychopharmacol. 1–14. doi: of stress and elevated glucocorti- Loup, F., Tribollet, E., Dubois- B., et al. (2012). Oxytocin and 10.1017/S1461145711001489 coids. Hippocampus 22, 861–868. Dauphin, M., Pizzolato, G., and vasopressin agonists and antago- Landgraf, R., Hacker, R., and Buhl, H. Levin, R., Heresco-Levy, U., Bachner- Dreifuss, J. J. (1989). Localization of nists as research tools and potential (1982). Plasma vasopressin and oxy- Melman, R., Israel, S., Shalev, I., and oxytocin binding sites in the human therapeutics. J. Neuroendocrinol. 24, tocin in response to exercise and Ebstein, R. P. (2009). Association brainstem and upper spinal cord: 609–628. during a day-night cycle in man. between arginine vasopressin 1a an autoradiographic study. Brain McCarthy, M. M., McDonald, C. H., Endokrinologie 79, 281–291. receptor (AVPR1a) promoter region Res. 500, 223–230. Brooks, P. J., and Goldman, D. Landgraf, R., and Neumann, I. D. polymorphisms and prepulse inhi- Lowbridge, J., Manning, M., Haldar, J., (1996). An anxiolytic action of (2004). Vasopressin and oxy- bition. Psychoneuroendocrinology and Sawyer, W. H. (1977). Synthesis oxytocin is enhanced by estrogen tocin release within the brain: 34, 901–908. and some pharmacological in the mouse. Physiol. Behav. 60, a dynamic concept of multiple Li, C., Bhatt, P. P., and Johnston, T. properties of [4-threonine 7- 1209–1215. and variable modes of neu- P. (1997). Transmucosal delivery of glycine]oxytocin, [1-(L-2-hydroxy- McEwen, B. B. (2004). Brain-fluid bar- ropeptide communication. Front. oxytocin to rabbits using a mucoad- 3-mercaptopropanoic acid), riers: relevance for theoretical con- Neuroendocrinol. 25, 150–176. doi: hesive buccal patch. Pharm. Dev. 4-threonine 7-glycine]oxytocin troversies regarding vasopressin and 10.1016/j.yfrne.2004.05.001 Technol. 2, 265–274. (hydroxy[Thr4, Gly7]oxytocin), oxytocin memory research. Adv. Lawson, E. A., Holsen, L. M., Santin, Li, C., Wang, W., Summer, S. N., and [7-Glycine]oxytocin, peptides Pharmacol. 50, 531–592, 655–708. M., Meenaghan, E., Eddy, K. Westfall, T. D., Brooks, D. P., Falk, S., with high oxytocic-antidiuretic McGonigle, P. (2012). Peptide ther- T., Becker, A. E., et al. (2012). et al. (2008). Molecular mechanisms selectivity. J. Med. Chem. 20, apeutics for CNS indications. Oxytocin secretion is associated of antidiuretic effect of oxytocin. 120–123. Biochem. Pharmacol. 83, 559–566. with severity of disordered eating J. Am. Soc. Nephrol. 19, 225–232. MacDonald, K. (2012). Sex, receptors, McGregor, I. S., and Bowen, M. T. psychopathology and insular cortex Lieberman, J. A., and Stroup, T. and attachment: a review of individ- (2012). Breaking the loop: oxy- hypoactivation in anorexia nervosa. S. (2011). The NIMH-CATIE ual factors influencing response to tocin as a potential treatment for J. Clin. Endocrinol. Metab. 97, schizophrenia study: what did oxytocin. Front. Neurosci. 6:194. doi: drug addiction. Horm. Behav. 61, E1898–E1908. we learn? Am. J. Psychiatry 168, 10.3389/fnins.2012.00194 331–339. Lee, H. J., Caldwell, H. K., Macbeth, A. 770–775. MacDonald, E., Dadds, M. R., Brennan, Meddle, S. L., Bishop, V. R., Gkoumassi, H., and Young, W. S., 3rd. (2008). Liedman, R., Hansson, S. R., Howe, D., J. L., Williams, K., Levy, F., and E., van Leeuwen, F. W., and Douglas, Behavioural studies using temporal Igidbashian, S., McLeod, A., Russell, Cauchi, A. J. (2011a). A review A. J. (2007). Dynamic changes in and spatial inactivation of the oxy- R. J., et al. (2008). Reproductive of safety, side-effects and subjec- oxytocin receptor expression and tocin receptor. Prog. Brain Res. 170, hormones in plasma over the tive reactions to intranasal oxy- activation at parturition in the 73–77. menstrual cycle in primary dys- tocin in human research. Psycho- rat brain. Endocrinology 148, Lee, P. R., Brady, D. L., Shapiro, R. menorrhea compared with healthy neuroendocrinology 36, 1114–1126. 5095–5104. A., Dorsa, D. M., and Koenig, J. subjects. Gynecol. Endocrinol. 24, MacDonald, K., MacDonald, T., Mens,W.B.,Witter,A.,andvan I. (2005). Social interaction deficits 508–513. Wilson,M.P.,andFeifel,D. Wimersma Greidanus, T. B. (1983).

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 18 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

Penetration of neurohypophyseal oxytocin receptors. Adv. Exp. Med. Ozsoy, S., Esel, E., and Kula, M. vasopressin and oxytocin on phys- hormones from plasma into cere- Biol. 395, 301–310. (2009). Serum oxytocin levels in iologic responding during personal brospinal fluid (CSF): half-times of Murphy, S. E., Norbury, R., O’Sullivan, patients with depression and the combat imagery in Vietnam veter- disappearance of these neuropep- U., Cowen, P. J., and Harmer, C. effects of gender and antidepres- ans with posttraumatic stress disor- tides from CSF. Brain Res. 262, J. (2009). Effect of a single dose sant treatment. Psychiatry Res. 169, der. Psychiatry Res 48, 107–117. 143–149. of citalopram on amygdala response 249–252. Pitt, G. R., Batt, A. R., Haigh, R. Meyer-Lindenberg, A., Kolachana, B., to emotional faces. Br. J. Psychiatry Parker, K. J., Buckmaster, C. L., M., Penson, A. M., Robson, P. A., Gold, B., Olsh, A., Nicodemus, 194, 535–540. Schatzberg,A.F.,andLyons,D. Rooker, D. P., et al. (2004). Non- K. K., Mattay, V., et al. (2009). Naber, F., van Ijzendoorn, M. H., M. (2005). Intranasal oxytocin peptide oxytocin agonists. Bioorg. Genetic variants in AVPR1A linked Deschamps, P., van Engeland, administration attenuates the Med. Chem. Lett. 14, 4585–4589. to autism predict amygdala acti- H., and Bakermans-Kranenburg, ACTH stress response in mon- Preuss, T. M. (2000). Taking the vation and personality traits in M. J. (2010). Intranasal oxy- keys. Psychoneuroendocrinology 30, measure of diversity: comparative healthy humans. Mol. Psychiatry 14, tocin increases fathers’ observed 924–929. alternatives to the model-animal 968–975. responsiveness during play Parker,K.J.,Kenna,H.A.,Zeitzer,J. paradigm in cortical neuroscience. Michopoulos, V., Checchi, M., Sharpe, with their children: a double- M.,Keller,J.,Blasey,C.M.,Amico, Brain Behav. Evol. 55, 287–299. D., and Wilson, M. E. (2011). blind within-subject experiment. J. A., et al. (2010). Preliminary evi- Prichard, Z. M., Mackinnon, A. J., Estradiol effects on behavior and Psychoneuroendocrinology 35, dence that plasma oxytocin levels Jorm, A. F., and Easteal, S. (2007). serum oxytocin are modified by 1583–1586. are elevated in major depression. AVPR1A and OXTR polymor- social status and polymorphisms Neumann, I., Douglas, A. J., Pittman, Psychiatry Res. 178, 359–362. phisms are associated with sexual in the serotonin transporter gene Q. J., Russell, J. A., and Landgraf, Parrott, A. C. (2007). The psychother- and reproductive behavioral pheno- in female rhesus monkeys. Horm. R. (1996). Oxytocin released within apeutic potential of MDMA (3, 4- types in humans. Mutation in brief Behav. 59, 528–535. the supraoptic nucleus of the rat methylenedioxymethamphetamine): no. 981. Online. Hum. Mutat. 28, Miller, G. (2013). Neuroscience. The brain by positive feedback action an evidence-based review. 1150. promise and perils of oxytocin. is involved in parturition-related Psychopharmacology (Berl.) 191, Quirin, M., Kuhl, J., and Dusing, R. Science 339, 267–269. events. J. Neuroendocrinol. 8, 181–193. (2011). Oxytocin buffers cortisol Mitchell, J. M., O’Neil, J. P., Janabi, 227–233. Patil, S. B., and Sawant, K. K. (2008). responses to stress in individuals M.,Marks,S.M.,Jagust,W. Neumann, I. D. (2007). Stimuli and Mucoadhesive microspheres: a with impaired emotion regulation J., and Fields, H. L. (2012). consequences of dendritic release of promising tool in drug delivery. abilities. Psychoneuroendocrinology Alcohol consumption induces oxytocin within the brain. Biochem. Curr. Drug Deliv. 5, 312–318. 36, 898–904. endogenous opioid release in Soc. Trans. 35(Pt 5), 1252–1257. Patisaul, H. B., Scordalakes, E. M., Raggenbass, M. (2008). Overview of the human orbitofrontal cor- Neumann, I. D., and Landgraf, R. Young, L. J., and Rissman, E. F. cellular electrophysiological actions tex and nucleus accumbens. (2012). Balance of brain oxytocin (2003). Oxytocin, but not oxytocin of vasopressin. Eur. J. Pharmacol. Sci. Transl. Med. 4:116ra6. doi: and vasopressin: implications for receptor, is regulated by oestrogen 583, 243–254. 10.1126/scitranslmed.3002902 anxiety, depression, and social receptor beta in the female mouse Renaud,L.P.,Day,T.A.,andFerguson, Mitchell, M. D., Haynes, P.J., Anderson, behaviors. Trends Neurosci. 35, hypothalamus. J. Neuroendocrinol. A. V. (1984). CNS regulation A. B., and Turnbull, A. C. (1981). 649–659. 15, 787–793. of reproduction: peptidergic Plasma oxytocin concentrations Nishimori, K., Takayanagi, Y., Yoshida, Pedersen,C.A.,Gibson,C.M.,Rau,S. mechanisms. Brain Res. Bull. 12, during the menstrual cycle. Eur. J. M., Kasahara, Y., Young, L. J., W.,Salimi,K.,Smedley,K.L.,Casey, 181–186. Obstet. Gynecol. Reprod. Biol. 12, and Kawamata, M. (2008). New R. L., et al. (2011). Intranasal oxy- Renner, D. B., Frey, W. H. 2nd., and 195–200. aspects of oxytocin receptor func- tocin reduces psychotic symptoms Hanson, L. R. (2012a). Intranasal Modabbernia, A., Rezaei, F., Salehi, B., tion revealed by knockout mice: and improves theory of mind and delivery of siRNA to the olfac- Jafarinia, M., Ashrafi, M., Tabrizi, sociosexual behaviour and control social perception in schizophrenia. tory bulbs of mice via the olfactory M., et al. (2013). Intranasal oxy- of energy balance. Prog. Brain Res. Schizophr. Res. 132, 50–53. nerve pathway. Neurosci. Lett. 513, tocinasanadjuncttorisperidone 170, 79–90. Pedersen, C. A., Smedley, K. L., 193–197. in patients with schizophrenia: an Nussey, S. S., Page, S. R., Ang, V. T., and Leserman, J., Jarskog, L. F., Rau, Renner, D. B., Svitak, A. L., Gallus, N. J., 8-week, randomized, double-blind, Jenkins, J. S. (1988). The response S. W., Kampov-Polevoi, A., et al. Ericson, M. E., Frey, W. H. 2nd., and placebo-controlled study. CNS of plasma oxytocin to surgical stress. (2013). Intranasal oxytocin blocks Hanson, L. R. (2012b). Intranasal Drugs 27, 57–65. Clin. Endocrinol. 28, 277–282. alcohol withdrawal in human delivery of insulin via the olfactory Modahl, C., Green, L., Fein, D., Morris, Ohlsson, B., Truedsson, M., Bengtsson, subjects. Alcohol. Clin. Exp. Res. 37, nerve pathway. J. Pharm. Pharmacol. M., Waterhouse, L., Feinstein, C., M., Torstenson, R., Sjolund, K., 484–489. 64, 1709–1714. et al. (1998). Plasma oxytocin levels Bjornsson, E. S., et al. (2005). Perry, A., Bentin, S., Shalev, I., Riekkinen, P., Legros, J. J., Sennef, in autistic children. Biol. Psychiatry Effects of long-term treatment with Israel, S., Uzefovsky, F., Bar- C.,Jolkkonen,J.,Smitz,S.,and 43, 270–277. oxytocin in chronic constipation; On, D., et al. (2010). Intranasal Soininen, H. (1987). Penetration Modi, M. E., and Young, L. J. (2012). a double blind, placebo-controlled oxytocin modulates EEG of DGAVP (Org 5667) across the The oxytocin system in drug discov- pilot trial. Neurogastroenterol. Motil. mu/alpha and beta rhythms blood-brain barrier in human sub- ery for autism: animal models and 17, 697–704. during perception of biological jects. Peptides 8, 261–265. novel therapeutic strategies. Horm. Ophir, A. G., Gessel, A., Zheng, D. J., motion. Psychoneuroendocrinology Riem, M. M., Bakermans-Kranenburg, Behav. 61, 340–350. and Phelps, S. M. (2012). Oxytocin 35, 1446–1453. M.J.,Pieper,S.,Tops,M.,Boksem, Morimoto, B., De Lannoy, I., Fox, receptor density is associated with Pincus, D., Kose, S., Arana, A., Johnson, M. A., Vermeiren, R. R., et al. A. W., Gozes, I., and Stewart, A. male mating tactics and social K., Morgan, P. S., Borckardt, J., (2011). Oxytocin modulates amyg- (2009). Davunetide: pharmacoki- monogamy. Horm. Behav. 61, et al. (2010). Inverse effects of dala, insula, and inferior frontal netics and distribution to brain after 445–453. oxytocin on attributing mental gyrus responses to infant crying: intravenous or intranasal admin- Otto,M.W.,Tolin,D.F.,Simon,N.M., activity to others in depressed a randomized controlled trial. Biol. istration to rat. Chem. Today 27, Pearlson, G. D., Basden, S., Meunier, and healthy subjects: a double- Psychiatry 70, 291–297. 16–20. S. A., et al. (2010). Efficacy of d- blind placebo controlled FMRI Riem,M.M.,van,I.M.H.,Tops, Mouillac, B., Chini, B., Balestre, M. N., cycloserine for enhancing response study. Front. Psychiatry 1:134. doi: M., Boksem, M. A., Rombouts, Jard, S., Barberis, C., Manning, M., to cognitive-behavior therapy for 10.3389/fpsyt.2010.00134 S. A., and Bakermans-Kranenburg, et al. (1995). Identification of ago- panic disorder. Biol. Psychiatry 67, Pitman,R.K.,Orr,S.P.,andLasko, M. J. (2012). No laughing matter: nist binding sites of vasopressin and 365–370. N. B. (1993). Effects of intranasal intranasal oxytocin administration

www.frontiersin.org March 2013 | Volume 7 | Article 35 | 19 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

changes functional brain connec- Sabatier, N. (2006). alpha-Melanocyte- receptor in the mouse. J. Neurosci. J. Neuropsychopharmacol. 16, tivity during exposure to infant stimulating hormone and oxytocin: 30, 8274–8284. 255–260. laughter. Neuropsychopharmacology a peptide signalling cascade in the Seeman, P., and Tallerico, T. (1998). Stankova, T., Eichhammer, P., 37, 1257–1266. hypothalamus. J. Neuroendocrinol. Antipsychotic drugs which elicit lit- Langguth,B.,andSand,P.G. Ring,R.H.,Malberg,J.E.,Potestio, 18, 703–710. tle or no parkinsonism bind more (2012). Sexually dimorphic effects L.,Ping,J.,Boikess,S.,Luo,B., Sala, M., Braida, D., Donzelli, A., loosely than dopamine to brain D2 of oxytocin receptor gene (OXTR) et al. (2006). Anxiolytic-like activ- Martucci, R., Busnelli, M., receptors, yet occupy high levels of variants on Harm Avoidance. Biol. ity of oxytocin in male mice: Bulgheroni, E., et al. (2013). these receptors. Mol. Psychiatry 3, Sex Differ. 3:17. doi: 10.1186/ behavioral and autonomic evi- Mice heterozygous for the oxytocin 123–134. 2042-6410-3-17 dence, therapeutic implications. receptor gene (Oxtr(+/−)) show Seifer, D. B., Sandberg, E. C., Ueland, Stock, S., Bremme, K., and Uvnas- Psychopharmacology (Berl.) 185, impaired social behaviour but not K., and Sladen, R. N. (1985). Moberg, K. (1991). Plasma levels 218–225. increased aggression or cognitive Water intoxication and hypona- of oxytocin during the menstrual Ring,R.H.,Schechter,L.E.,Leonard,S. inflexibility: evidence of a selective tremic encephalopathy from the cycle, pregnancy and following K.,Dwyer,J.M.,Platt,B.J.,Graf,R., haploinsufficiency gene effect. J. use of an oxytocin nasal spray. A treatment with HMG. Hum. et al. (2010). Receptor and behav- Neuroendocrinol. 25, 107–118. case report. J. Reprod. Med. 30, Reprod. 6, 1056–1062. ioral pharmacology of WAY-267464, Sala, M., Braida, D., Lentini, D., 225–228. Stoop, R. (2012). Neuromodulation by a non-peptide oxytocin receptor Busnelli, M., Bulgheroni, E., Seng, J., Miller, J., Sperlich, M., van de oxytocin and vasopressin. Neuron agonist. Neuropharmacology 58, Capurro, V., et al. (2011). Ven,C.J.,Brown,S.,Carter,C.S., 76, 142–159. 69–77. Pharmacologic rescue of impaired et al. (2013). Exploring dissociation Stratton, J. F., Stronge, J., and Boylan, Robertson, G. L. (1995). Diabetes cognitive flexibility, social deficits, and oxytocin as pathways between P. C. (1995). Hyponatraemia insipidus. Endocrinol. Metab. Clin. increased aggression, and seizure trauma exposure and trauma- and non-electrolyte solutions in North Am. 24, 549–572. susceptibility in oxytocin receptor related hyperemesis gravidarum: labouring primigravida. Eur. J. Rodrigues, S. M., Saslow, L. R., Garcia, null mice: a neurobehavioral model a test-of-concept pilot. J. Trauma Obstet. Gynecol. Reprod. Biol. 59, N., John, O. P., and Keltner, D. of autism. Biol. Psychiatry 69, Dissociation 14, 40–55. 149–151. (2009). Oxytocin receptor genetic 875–882. Shukovski, L., Healy, D. L., and Findlay, Swaab, D. F., Pool, C. W., and Nijveldt, variation relates to empathy Salonia, A., Nappi, R. E., Pontillo, M., J. K. (1989). Circulating immunore- F. (1975). Immunofluorescence and stress reactivity in humans. Daverio, R., Smeraldi, A., Briganti, active oxytocin during the human of vasopressin and oxytocin Proc. Natl. Acad. Sci. U.S.A. 106, A., et al. (2005). Menstrual cycle- menstrual cycle comes from the in the rat hypothalamo- 21437–21441. related changes in plasma oxy- pituitary and is estradiol depen- neurohypophypopseal system. Ross, H. E., Freeman, S. M., Spiegel, tocin are relevant to normal sexual dent. J. Clin. Endocrinol. Metab. 68, J. Neural Trans. 36, 195–215. L. L., Ren, X., Terwilliger, E. F., function in healthy women. Horm. 455–460. Szeto, A., McCabe, P. M., Nation, D. and Young, L. J. (2009). Variation Behav. 47, 164–169. Silber, M., Almkvist, O., Larsson, B., A.,Tabak,B.A.,Rossetti,M.A., in oxytocin receptor density in the Sanders, G., Freilicher, J., and Stock, S., and Uvnas-Moberg, K. McCullough, M. E., et al. (2011). nucleus accumbens has differen- Lightman, S. L. (1990). (1987). The effect of oral contra- Evaluation of enzyme immunoassay tial effects on affiliative behaviors Psychological stress of expo- ceptive pills on levels of oxytocin in and radioimmunoassay methods in monogamous and polygamous sure to uncontrollable plasma and on cognitive functions. for the measurement of plasma voles. J. Neurosci. 29, 1312–1318. noise increases plasma oxy- Contraception 36, 641–650. oxytocin. Psychosom. Med. 73, Ross, T. M., Martinez, P. M., Renner, tocin in high emotionality Simeon, D., Bartz, J., Hamilton, H., 393–400. J. C., Thorne, R. G., Hanson, L. women. Psychoneuroendocrinology Crystal, S., Braun, A., Ketay, S., et al. Thompson, M. R., Callaghan, P. D., R., and Frey, W. H., 2nd. (2004). 15, 47–58. (2011). Oxytocin administration Hunt,G.E.,Cornish,J.L.,and Intranasal administration of inter- Saphire-Bernstein, S., Way, B. M., attenuates stress reactivity in bor- McGregor, I. S. (2007). A role for feron beta bypasses the blood-brain Kim, H. S., Sherman, D. K., and derline personality disorder: a pilot oxytocin and 5-HT(1A) receptors barrier to target the central nervous Taylor, S. E. (2011). Oxytocin study. Psychoneuroendocrinology 36, in the prosocial effects of 3, 4 system and cervical lymph nodes: a receptor gene (OXTR) is related to 1418–1421. methylenedioxymethamphetamine non-invasive treatment strategy for psychological resources. Proc. Slattery, D. A., and Neumann, I. ("ecstasy"). Neuroscience 146, multiple sclerosis. J. Neuroimmunol. Natl. Acad. Sci. U.S.A. 108, (2010). Oxytocin and major 509–514. 151, 66–77. 15118–15122. depressive disorder: experimental Thorne, R. G., and Frey, W. H. 2nd. Rossoni, E., Feng, J., Tirozzi, B., Brown, Scantamburlo, G., Ansseau, M., and clinical evidence for links to (2001). Delivery of neurotrophic D., Leng, G., and Moos, F. (2008). Geenen, V., and Legros, J. J. (2011). aetiology and possible treatment. factors to the central nervous Emergent synchronous bursting of Intranasal oxytocin as an adjunct Pharmaceuticals 3, 702–724. system: pharmacokinetic consid- oxytocin neuronal network. PLoS to escitalopram in major depres- Smith, A. L., Freeman, S. M., erations. Clin. Pharmacokinet. 40, Comput. Biol. 4:e1000123. doi: sion. J. Neuropsychiatry Clin. Stehouwer, J. S., Inoue, K., Voll, 907–946. 10.1371/journal.pcbi.1000123 Neurosci. 23:E5. doi: 10.1176/appi. R. J., Young, L. J., et al. (2012). Thorne, R. G., Pronk, G. J., Rubin, L. H., Carter, C. S., Drogos, L., neuropsych.23.2.E5 Synthesis and evaluation of C-11, Padmanabhan, V., and Frey, W. Jamadar, R., Pournajafi-Nazarloo, Scantamburlo, G., Hansenne, M., F-18 and I-125 small molecule H. 2nd. (2004). Delivery of insulin- H., Sweeney, J. A., et al. (2011). Fuchs, S., Pitchot, W., Marechal, radioligands for detecting oxytocin like growth factor-I to the rat brain Sex-specific associations between P., Pequeux, C., et al. (2007). receptors. Bioorg. Med. Chem. 20, and spinal cord along olfactory peripheral oxytocin and emo- Plasma oxytocin levels and anxiety 2721–2738. and trigeminal pathways follow- tion perception in schizophrenia. in patients with major depres- Spigset, O. (1999). Adverse reactions ing intranasal administration. Schizophr. Res. 130, 266–270. sion. Psychoneuroendocrinology 32, of selective serotonin reuptake Neuroscience 127, 481–496. Rupp,H.A.,James,T.W.,Ketterson, 407–410. inhibitors: reports from a sponta- Tost, H., Kolachana, B., Hakimi, S., E. D., Sengelaub, D. R., Ditzen, B., Scharrer, E., and Scharrer, B. (1945). neous reporting system. Drug Saf. Lemaitre, H., Verchinski, B. A., and Heiman, J. R. (2012). Amygdala Neurosecretion. Physiol. Rev. 25, 20, 277–287. Mattay, V. S., et al. (2010). A response to negative images 171–181. Sripada, C. S., Phan, K. L., common allele in the oxytocin in postpartum vs. nulliparous Schorscher-Petcu, A., Sotocinal, S., Labuschagne, I., Welsh, R., Nathan, receptor gene (OXTR) impacts women and intranasal oxytocin. Ciura, S., Dupre, A., Ritchie, J., P. J., and Wood, A. G. (2013). prosocial temperament and human Soc. Cogn. Affect. Neurosci. doi: Sorge, R. E., et al. (2010). Oxytocin- Oxytocin enhances resting-state hypothalamic-limbic structure and 10.1093/scan/nss100. [Epub ahead induced analgesia and scratching connectivity between amygdala function. Proc. Natl. Acad. Sci. of print]. are mediated by the vasopressin-1A and medial frontal cortex. Int. U.S.A. 107, 13936–13941.

Frontiers in Neuroscience | Neuroendocrine Science March2013|Volume7|Article35| 20 MacDonald and Feifel Oxytocin-based therapeutics for brain disorders

Tranter, R., Bell, D., Gutting, P., Volkow,N.D.,Wang,G.,Fowler,J.S., Wigger, A., and Neumann, I. D. (2002). Young,W.S.,Li,J.,Wersinger,S.R., Harmer, C., Healy, D., and Logan, J., Gerasimov, M., Maynard, Endogenous opioid regulation of and Palkovits, M. (2006). The vaso- Anderson, I. M. (2009). The effect L., et al. (2001). Therapeutic stress-induced oxytocin release pressin 1b receptor is prominent in of serotonergic and noradrenergic doses of oral methylphenidate within the hypothalamic paraven- the hippocampal area CA2 where antidepressants on face emotion significantly increase extracellular tricular nucleus is reversed in late it is unaffected by restraint stress processing in depressed patients. dopamine in the human brain. pregnancy: a microdialysis study. or adrenalectomy. Neuroscience 143, J. Affect. Disord. 118, 87–93. J. Neurosci. 21, RC121. Neuroscience 112, 121–129. 1031–1039. Turner,R.A.,Altemus,M.,Yip,D. Walum, H., Lichtenstein, P., Williams, J. R., Insel, T. R., Harbaugh, Zhang, G., and Cai, D. (2011). Circadian N., Kupferman, E., Fletcher, D., Neiderhiser, J. M., Reiss, D., C. R., and Carter, C. S. (1994). intervention of obesity develop- Bostrom, A., et al. (2002). Effects of Ganiban, J. M., Spotts, E. L., Oxytocin administered centrally ment via resting-stage feeding emotion on oxytocin, prolactin, and et al. (2012). Variation in the facilitates formation of a part- manipulation or oxytocin treatment. ACTH in women. Stress 5, 269–276. oxytocin receptor gene is asso- ner preference in female prairie Am. J. Physiol. Endocrinol. Metab. Twamley, E. W., Vella, L., Burton, C. ciated with pair-bonding and voles (Microtus ochrogaster). 301, E1004–E1012. Z., Heaton, R. K., and Jeste, D. social behavior. Biol. Psychiatry 71, J. Neuroendocrinol. 6, 247–250. Zhong, S., Monakhov, M., Mok, H. V. (2012). Compensatory cognitive 419–426. Windle,R.J.,Gamble,L.E.,Kershaw, P.,Tong,T.,Lai,P.S.,Chew,S. training for psychosis: effects in a Walum, H., Westberg, L., Henningsson, Y. M., Wood, S. A., Lightman, H., et al. (2012). U-shaped rela- randomized controlled trial. J. Clin. S., Neiderhiser, J. M., Reiss, D., S. L., and Ingram, C. D. (2006). tion between plasma oxytocin lev- Psychiatry 73, 1212–1219. Igl, W., et al. (2008). Genetic vari- Gonadal steroid modulation of els and behavior in the trust game. Uvnas-Moberg, K., Sjogren, C., ation in the vasopressin receptor stress-induced hypothalamo- PLoS ONE 7:e51095. doi: 10.1371/ Westlin, L., Andersson, P. O., and 1a gene (AVPR1A) associates with pituitary-adrenal activity and journal.pone.0051095 Stock, S. (1989). Plasma levels of pair-bonding behavior in humans. anxiety behavior: role of cen- Zhu,J.,Jiang,Y.,Xu,G.,andLiu,X. gastrin, somatostatin, VIP, insulin Proc. Natl. Acad. Sci. U.S.A. 105, tral oxytocin. Endocrinology 147, (2012). Intranasal administration: and oxytocin during the menstrual 14153–14156. 2423–2431. a potential solution for cross-BBB cycle in women (with and without Wang,H.,Ward,A.R.,andMorris, Windle, R. J., Judah, J. M., and delivering neurotrophic factors. oral contraceptives). Acta Obstet. J. F. (1995). Oestradiol acutely Forsling, M. L. (1997). Effect of oxy- Histol. Histopathol. 27, 537–548. Gynecol. Scand. 68, 165–169. stimulates exocytosis of oxytocin tocin receptor antagonists on the Zink, C. F., and Meyer-Lindenberg, van Ijzendoorn, M., Bhandari, R., and vasopressin from dendrites and renal actions of oxytocin and vaso- A. (2012). Human neuroimaging van der Veen, R., Grewen, K., somata of hypothalamic magno- pressin in the rat. J. Endocrinol. 152, of oxytocin and vasopressin in and Bakermans-Kranenburg, M. J. cellular neurons. Neuroscience 68, 257–264. social cognition. Horm. Behav. 61, (2012). Elevated salivary levels of 1179–1188. Wotjak, C. T., Ganster, J., Kohl, G., 400–409. oxytocin persist more than seven Weisman, O., Zagoory-Sharon, Holsboer, F., Landgraf, R., and hours after intranasal administra- O., and Feldman, R. (2012a). Engelmann, M. (1998). Dissociated Conflict of Interest Statement: David tion. Front. Neurosci. 6:174. doi: Intranasal oxytocin administration central and peripheral release of Feifel is a named inventor on a method 10.3389/fnins.2012.00174 is reflected in human saliva. vasopressin, but not oxytocin, in of use patent for oxytocin submitted Veinante, P., and Freund-Mercier, M. J. Psychoneuroendocrinology 37, response to repeated swim stress: by UCSD. K. MacDonald declare that (1995). Histoautoradiographic 1582–1586. new insights into the secretory the research was conducted in the detection of oxytocin- and Weisman, O., Zagoory-Sharon, capacities of peptidergic neurons. absence of any commercial or financial vasopressin-binding sites in the O., and Feldman, R. (2012b). Neuroscience 85, 1209–1222. relationships that could be construed amygdala of the rat. Adv. Exp. Med. Oxytocin administration to parent Wu, N., Li, Z., and Su, Y. (2012). The as a potential conflict of interest. Biol. 395, 347–348. enhances infant physiological and association between oxytocin recep- Vinogradov, S., Fisher, M., and de behavioral readiness for social tor gene polymorphism (OXTR) Received: 06 December 2012; paper Villers-Sidani, E. (2012). Cognitive engagement. Biol. Psychiatry 72, and trait empathy. J. Affect. Disord. pending published: 08 January 2013; training for impaired neural sys- 982–989. 138, 468–472. accepted: 28 February 2013; published tems in neuropsychiatric illness. Weisman, O., Zagoory-Sharon, O., Yoshida, M., Takayanagi, Y., Inoue, K., online: 15 March 2013. Neuropsychopharmacology 37, Schneiderman, I., Gordon, I., Kimura,T.,Young,L.J.,Onaka,T., Citation: MacDonald K and Feifel D 43–76. and Feldman, R. (2012c). Plasma et al. (2009). Evidence that oxytocin (2013) Helping oxytocin deliver: consid- Viviani, D., Charlet, A., van den Burg, oxytocin distributions in a large exerts anxiolytic effects via oxytocin erations in the development of oxytocin- E., Robinet, C., Hurni, N., Abatis, cohort of women and men and their receptor expressed in serotonergic based therapeutics for brain disorders. M., et al. (2011). Oxytocin selec- gender-specific associations with neurons in mice. J. Neurosci. 29, Front. Neurosci. 7:35. doi: 10.3389/fnins. tively gates fear responses through anxiety. Psychoneuroendocrinology. 2259–2271. 2013.00035 distinct outputs from the central Availableonlineat:http://dx.doi. Young, S. N., and Anderson, G. N. This article was submitted to Frontiers amygdala. Science 333, 104–107. org/10.1016/j.psyneuen.2012.08.011 (2010). Bioanalytical inaccuracy: a in Neuroendocrine Science, a specialty of Viviani, D., and Stoop, R. (2008). White-Traut, R., Watanabe, K., threat to the integrity and efficiency Frontiers in Neuroscience. Opposite effects of oxytocin and Pournajafi-Nazarloo, H., Schwertz, of research. J. Psychiatry Neurosci. Copyright © 2013 MacDonald and vasopressin on the emotional D., Bell, A., and Carter, C. S. (2009). 35, 3–6. Feifel. This is an open-access article dis- expression of the fear response. Detection of salivary oxytocin levels Young, W. S. 3rd., Shepard, E., Amico, tributed under the terms of the Creative Prog. Brain Res. 170, 207–218. in lactating women. Dev. Psychobiol. J., Hennighausen, L., Wagner, K. Commons Attribution License,which Volkow, N. D., and Skolnick, P. (2012). 51, 367–373. U., LaMarca, M. E., et al. (1996). permits use, distribution and reproduc- New medications for substance use Wiedemann, K. (2011). Biomarkers Deficiency in mouse oxytocin pre- tion in other forums, provided the origi- disorders: challenges and oppor- in development of psychotropic vents milk ejection, but not fertility nal authors and source are credited and tunities. Neuropsychopharmacology drugs. Dialogues Clin. Neurosci. 13, or parturition. J. Neuroendocrinol. 8, subject to any copyright notices concern- 37, 290–292. 225–234. 847–853. ing any third-party graphics etc.

www.frontiersin.org March 2013 | Volume 7 | Article 35 | 21