Preclinical Modeling of Primal Emotional Affects (SEEKING, PANIC and PLAY): Gateways to the Development of New Treatments for Depression

Home , Jaak Panksepp, Psychological pain

Psychopathology Received: May 9, 2014 DOI: 10.1159/000366208 Accepted after revision: July 31, 2014 Published online: October 22, 2014

a b Jaak Panksepp Yoram Yovell a Department of Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State b University, Pullman, Wash. , USA; Institute for the Study of Affective Neuroscience, University of Haifa, Haifa , Israel

Key Words tics – (i) low-dose buprenorphine to counteract depression Depression · Preclinical models · Brain · Affective and suicidal ideation emanating from too much psychic pain neuroscience · PANIC system · SEEKING system · PLAY (PANIC overarousal), (ii) direct stimulation of the SEEKING sys- system · Deep brain stimulation · GLYX-13 tem to counteract amotivational dysphoria, and (iii) the discovery and initial clinical testing of social-joy-promoting mol- ecules derived from the analysis of the PLAY system. Abstract © 2014 S. Karger AG, Basel Mammalian brains contain at least 7 primal emotional systems – SEEKING, RAGE, FEAR, LUST, CARE, PANIC and PLAY (capitalization reflects a proposed primary-process terminol- A premise of affective neuroscience [1, 2] is that stud- ogy, to minimize semantic confusions and mereological falla- ies of the primal emotional feelings of other animals – cies). These systems help organisms feel affectively balanced namely preclinical models where detailed neuroscien- (e.g. euthymic) and unbalanced (e.g. depressive, irritable, tific inquiries may be conducted – can provide impor- manic), providing novel insights for understanding human tant basic information about imbalances in the psychopathologies. Three systems are especially important underlying affective circuits that promote psychiatric for understanding depression: The separation distress (PAN- disorders, with the possibility of developing more spe- IC) system mediates the psychic pain of separation distress cific and effective psychiatric treatments. The affective (i.e. excessive sadness and grief ), which can be counteracted neuroscience strategy takes animal emotional feelings by minimizing PANIC arousals (as with low-dose opioids). De- seriously, yielding empirical findings about affective pressive dysphoria also arises from reduced brain reward- states that cannot be collected in humans. Of course, we seeking and related play urges (namely diminished enthusi- recognize that emotional feelings in animals is a concept asm (SEEKING) and joyful exuberance (PLAY) which promote that has yet to be universally embraced, with many sustained amotivational states). We describe how an under- prominent investigators still claiming that we cannot standing of these fundamental emotional circuits can pro- ever study emotionally valenced states of mind in other mote the development of novel antidepressive therapeu- animals [3] or that they simply may not exist [4] . We be-

© 2014 S. Karger AG, Basel Jaak Panksepp, PhD 0254–4962/14/0000–0000$39.50/0 Department of Integrative Physiology and Neuroscience College of Veterinary Medicine, Washington State University E-Mail [email protected] PO Box 647620, Pullman, WA 99164-7620 (USA) www.karger.com/psp E-Mail jpanksepp @ vetmed.wsu.edu Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM lieve such skeptical perspectives overlook critical infor- allowed to make free ‘choices’ eagerly turn on DBS, with- mation, such as the fact that we can evoke coherent emo- in what we call the SEEKING, LUST, CARE and PLAY tional action tendencies with deep-brain stimulation systems; they turn off DBS that evokes RAGE, FEAR and (DBS) in homologous neural regions in all mammals PANIC (namely social distress) types of behavioral re- that have been tested [1, 5, 6] , and that such state shifts sponses. These effects are obtained by DBS applied only are demonstrably rewarding and punishing to animals, to subcortical brain systems, where homologous evolu- in the sense that animals ‘willingly’ turn them on or off, tionary brain organization patterns abound, namely respectively, which is the decisive empirical evidence for midline thalamic and mesencephalic, and most especial- affective states, namely valenced experiences, in non- ly hypothalamic, brain regions [1, 5, 6] . Importantly, speaking animals [7–9] . abundant validation is available for comparable DBS ma- Credible arguments against such interpretations of nipulations in humans [13, 14] , who can report their af- objective data for emotion-related affective states in ani- fective experiences verbally in real time as well as reflec- mals remain to be provided by those who assert that af- tively. Perhaps the most striking example in the literature fective states cannot be scientifically studied in animal is of a patient who received DBS to the periaqueductal models [3, 4]. There are only stipulative claims that ‘We gray, where various primal emotional systems converge, will never know what an animal feels’ [ 3 , p. 666] (our em- especially FEAR: a dramatic affective shift was observed, phasis). We think this mindset, reaffirming classical be- with the patient exclaiming suddenly that he was ‘scared haviorist dogma, overlooks abundant evidence, namely to death’ [14]. There are many comparable reports for that artificial (e.g. DBS) arousal of brain emotional cir- other emotional states, evoked in humans by DBS to the cuits in animals provides objective measures of positively same brain regions from which DBS in animals leads to (rewarding) and negatively (punishing) valenced feelings the distinct corresponding emotional behaviors [for a re- [1, 2]. Such replicable findings support our evidence- view, see 13 ]. based conclusion that all other mammals do experience Since such positively and negatively valenced effects their emotional arousals, and that a more detailed study (arising from evolutionarily related emotional network of such brain systems may provide unique opportunities arousals) generalize across species, we would suggest that for decoding which emotions, and which of their regula- DBS studies in animals provide a much underutilized way tory neurochemistries, may be involved in particular psy- to understand specific emotional systems that control hu- chiatric disorders [10, 11], hopefully providing novel man moods relevant for understanding and treatment of ideas for clinical therapeutics. Here we discuss how such human psychopathology. Again, since this point seems a strategy is currently impacting our search for evidence- not to have received adequate attention in the preclinical based new treatments for depression [for a more exten- modeling of psychiatric disorders, most of which remains sive discussion of relevant details, see 12 ]. resolutely behavioristic, we emphasize that empirical evi- This only seems like a radical new approach because dence for affective changes in animals is provided by the of an outdated behaviorist tradition (of ultimate skepti- rewarding and punishing properties of the above types of cism with the possibility that science can ever illuminate DBS. This interpretation is congruent with the fact that internally experienced psychological states in animals), humans have neither rewards nor punishments that they which still governs much of animal behavior research, do not experience in positive or negative valenced/affec- where discussions of the internal feelings of other ani- tive ways. We thus work from the premise that affective mals was consistently discouraged during the 20th cen- phenomenal forms of consciousness (valenced emotion- tury. We think this bias is outdated since it is counter- al, homeostatic and sensory qualia) may have been the acted by concrete evidence for 7 primary emotional pro- first forms of experience to have emerged in brain evolu- cesses – SEEKING, RAGE, FEAR, LUST, CARE, PANIC/ tion. We do not mean that these valence effects necessar- GRIEF and PLAY (capitalization reflects a proposed pri- ily imply ‘awareness’, which is an intrinsically ambiguous mary-process terminology , to minimize semantic confu- word in consciousness studies, suggesting ‘knowledge of sions and mereological fallacies), namely neural circuits one’s experiences’. Our position is simply that other ani- that evolution built into mammalian brains, with affect mals do have raw phenomenal experiences, namely affec- indexed by the capacity of localized subcortical DBS to tive qualia, which is advanced with the related proposal evoke coherent emotional action tendencies, which by that the neural circuits that produce such valenced expe- objective measures of reward and punishment are inter- riences are also critical for learning (e.g. the mechanisms preted to have affective contents. For instance, animals of ‘reinforcement’) [2] .

2 Psychopathology Panksepp /Yovell DOI: 10.1159/000366208

Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM Evolutionary Levels of Control in Mammalian Brains Two-way or ‘circular’ causation

In pursuing such issues, we focus on the evolutionary ‘Reward prediction error’ ‘layering’ that is evident in brain organization which, for Tertiary-process cognitions Largely neocortical didactic convenience, can be divided into ‘primary’ (e.g. deeply subcortical unconditional/instinctual emotional Top-down cognitive Bottom-up influences on ruminations and thoughts response systems), ‘secondary’ (intermediary learning regulation and memory mediated by the basal ganglia) and ‘tertiary’ ‘Wanting’

(neocortical) cognitively rich brain processes that may Secondary-process learning mediate higher-order syntactic thoughts in Edmund Largely upper limbic Rolls’s [4] intriguing hypothesis. Obviously, the lower affective brain functions (which deserve a distinct nomen- Top-down clature) are more capable of being empirically studied learned Bottom-up learning and development responses than any higher-order syntactic thoughts, which current- SEEKING ly remain empirically impenetrable in nonspeaking ani- Primary-process emotions mals; see figure 1 for the kinds of terminologies that are Primal affects deeply subcortical widely used in current discussions of the traditionally la- beled ‘brain reward system’, discovered over 60 years ago. Nested brain-mind hierarchies (ancestral origins of mind) Most contemporary investigators agree that this system does not mediate feelings of sensory-type pleasures, but Fig. 1. Nested hierarchies of psychobehavioral control within the instead, something very different; we think a proper af- brain – a summary of the hierarchical bottom-up and top-down fective descriptor for this evoked state is exuberance , for (circular) causation that is proposed to operate in every primal that is the state that accompanies enthusiastic foraging/ emotional system of the brain. The schematic summarizes the hy- exploration in humans, and those are the explicit behav- pothesis that in order for higher brain/mind functions to mature iors evoked by DBS of the medial forebrain bundle (MFB), and function (via bottom-up control), they have to be integrated with the lower brain/mind functions, with primary processes be- the neural substrate for SEEKING, which has only recent- ing depicted as squares (the SEEKING level), secondary-process ly been described in humans with modern in vivo imag- learning as circles (the ‘wanting’ level of analysis – as developed by ing tools (see Coenen et al. [15], with extensive neuroana- Kent Berridge et al. [71, 72] and tertiary processes by rectangles tomical descriptions) that have suggested immediate (e.g. the ‘reward prediction error’ level of analysis, as proposed by clinical implications [16, 17] . Schultz [73] ). For relevant additional discussion, see Ikemoto and Panksepp [74] , Wright and Panksepp [75] and Panksepp and In sum, it is much easier to study the valenced evolu- Wright [76] (especially fig. 1, p. 60) as well as Northoff et al. [77] tionarily constructed subcortical experiential functions and Haber and Knutson [78]. This schematic aims to convey the in animals than to study developmentally constructed manner in which bottom-up evolution of nested hierarchies can higher brain functions (e.g. cognitive higher-order syn- integrate lower brain functions with higher brain functions to tactic thoughts). Further, we postulate that it is currently eventually exert top-down regulatory control, with distinctly la- beled levels of control. Bottom-up controls prevail in early-infancy more important to fathom the lower affective functions and early-childhood development. Top-down control is optimized of mammalian brains for generating treatment-relevant in adolescence and especially in adulthood. Each emotional system understandings of human psychopathologies than are at- has abundant descending and ascending coordinated components tempts to understand higher brain functions in animals, to generate various instinctual emotional behaviors as well as the since their ‘thoughts’, if they exist, are surely nonverbal raw feelings normally associated with those behaviors. (perhaps visual) and currently empirically impenetrable. We admit that our conceptual position may be only an empirical/ontological approximation, especially when contrasted to affective qualia in humans (e.g. the qualita- rapidly than simply focusing on behavioral processes in tive feel of emotions in different animals may be as differ- animals. In sum, we propose that the neglect of affect in ent as their homologous body structures, most especially preclinical psychiatric modeling may be a major reason when raw feelings are blended with cognitions), but it is why no truly new psychiatric medicinal treatments have at least a workable empirical approach that remains much arisen from behavior-only preclinical modeling so far underutilized. Here we advance the view that such affec- [18] . To support this view, we will describe 3 new experi- tive modeling can yield new medical treatments more mental treatments for depression that we have helped de-

Preclinical Modeling of Primal Emotional Psychopathology 3 Affects DOI: 10.1159/000366208 Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM velop and implement, based on cross-species affective been sporadic open studies demonstrating that very low neuroscience thinking – a strategy that claims to have doses of buprenorphine can have robust and rapid anti- provided a preliminary characterization of the primal depressant effects [25, 26] . emotional underpinnings of human depressive disorders Accordingly, we designed a double-blind, placebo- by modeling relevant affective processes in animals, controlled pilot study of the effects of low-dose buprenor- namely the 3 described below. phine on depressed, nonpsychotic individuals with sustained thoughts about committing suicide. The study assessed their depressive and suicidal symptomatology at Three Key Emotional Systems Implicated in weekly intervals with scales noted in figure 2. Namely, the Depression severity of depressive symptoms and suicidality was measured with the respective Beck scales at 3 time points: im- Here we focus on only 3 primal emotional systems – mediately before, 1 week after and 2 weeks after the onset namely SEEKING, PANIC and PLAY – that we propose of sublingual buprenorphine or placebo treatment (initial are critically important for understanding depression-re- dose = 0.2 mg/day, gradually increased to 1.6 mg/day in lated affective changes. As such, they may presumably be divided doses). The study drug was given as an adjunct to modulated by new medications and perhaps old ones, like the treatment that the study participants were already re- opioids (e.g. buprenorphine), used at very low/safe doses. ceiving upon their recruitment to the trial. This prelimi- Throughout this discussion, because of space limitations, nary feasibility study indicated that 2 weeks after the on- we will not discuss the role of classical biogenic amine set of treatment, buprenorphine was distinctly more ef- systems, such as norepinephrine or serotonin imbalanc- fective than placebo in reducing depressive symptoms as es, in depression; biogenic amines modulate multiple (in- well as suicidal urges and ideation (fig. 2 ). deed all ) affective functions, including emotional ones. Despite such encouraging findings, this pilot study Indeed, they were the first to be implicated in the genesis suffered from several limitations. First, by design, the of depression (for a detailed summary of such data, see study population consisted of depressed and personality- Watt and Panksepp [19] ). disordered outpatients who were recruited into the study shortly after they had made a suicide attempt/gesture, namely at a time of crisis in their lives. This resulted in First Hypothesis: Overactivity of the PANIC System high noncompliance and dropout rates that reduced the Might Promote Depressive Feelings by Promoting number of our pilot study completers (n = 4 and n = 6 for ‘Psychological Pain’ the buprenorphine and placebo groups, respectively). Second, the small number of study completers, as well as Ever since the theoretical work of John Bowlby [20] , it the fact that for ethical reasons all study participants con- has been known that excessive early separation experi- tinued to receive ongoing treatments, including antide- ences, and poor parental bonding, increase the suscepti- pressant medications at the discretion of their treating bility to future depression. Using this logic, and knowing clinicians, resulted in significant demographic and base- how powerful opioids are in reducing separation distress line clinical differences between the treatment and pla- in all species ever tested [1, 9, 21] , we postulated that cebo groups, which in addition took the study medication pharmaceuticals that are very effective in reducing sepa- (buprenorphine or placebo) in a double-blind design. ration distress (i.e. PANIC arousal) might be novel anti- The small size and the heterogeneous nature of the study depressants. population precluded any assessment of the statistical sig- Recently investigators are increasingly entertaining nificance of these findings. Third, the placebo-controlled the possibility of using such ‘safe opioids’ for the treat- effects of buprenorphine on depression and suicidality ment of depression, as well as the chronic ‘psychological were only apparent after 2 weeks of treatment, but it was pain’ that often promotes suicidal ideation [22]. To be a unclear whether they might diminish or increase further ‘safe opioid’, the analgesic effects and the lethal (respira- with time. Still, since the treatments (buprenorphine or tory depression) effects of a particular opioid ligand need placebo) were administered in a double-blind fashion, we to be dissociated. Buprenorphine, a partial agonist at decided to proceed to a more extensive study. μ-opioid receptors (i.e. stimulating opioid receptors at In light of the encouraging findings as well as the lim- low doses, but blocking them at high doses), is just such itations of the pilot study, a larger, 4-week, multicenter, a drug [23, 24]. Indeed, across the past 30 years there have double-blind, placebo-controlled phase 3 clinical trial of

4 Psychopathology Panksepp /Yovell DOI: 10.1159/000366208

Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM 45 30 40 25 35 Placebo 30 20 Placebo 25 Color version available online 15 20 Mean BSI Mean BDI-II 15 10 Buprenorphine Buprenorphine 10 5 5 0 0 a Baseline Week 1 Week 2 b Baseline Week 1 Week 2

Fig. 2. Results of a small double-blind, placebo-controlled pilot (BDI)-II [79] . b Two weeks after the onset of treatment, buprenor- study that assessed the severity of depressive symptomatology and phine also appeared to be more effective than placebo in reducing suicidal urges of depressed, acutely suicidal, nonpsychotic indi- suicidal urges and ideation, as measured by the Beck Scale for Sui- viduals at 3 time points: immediately before, 1 week after and 2 cide Ideation (BSI) [80]. However, the small number of study com- weeks after the onset of sublingual buprenorphine or placebo pleters (n = 4 and n = 6 for the buprenorphine and placebo groups, treatment (initial dose = 0.2 mg/day, gradually increased to 1.6 mg/ respectively) and the heterogeneous nature of the study population day in divided doses). a Two weeks after the onset of treatment, do not allow assessment of the statistical significance of these find- buprenorphine was more effective than placebo in reducing de- ings. A larger 4-week study has been under way. pressive symptoms as measured by the Beck Depression Inventory

buprenorphine as an adjunctive treatment for depressive known to man seems remote. Based on ethological and suicidal psychopathology was designed; recruitment changes during relevant animal DBS studies, namely in- is currently completed (with n = 40 and n = 20 study com- duction of intense exploration and foraging, accompa- pleters in the buprenorphine and placebo groups, respec- nied by forward locomotion and sniffing, we have called tively). this massive, affectively positive ‘brain reward’ emotion circuitry the SEEKING system to better convey the affect of ‘enthusiasm-exuberance’ that this system probably Second Hypothesis: Reduced SEEKING Activity Can mediates [1, 2] . Diminish Enthusiasm for Life There has been abundant evidence for the obvious hypothesis that this system mediates affective feelings or- The ‘brain reward system’ concept has been with us ganisms have when they energetically engage their envi- since 1954, ever since James Olds and Peter Milner [27] ronments in the search for all kinds of resources [1, 2, 5, found self-stimulation behavior for self-administered 6]. Still, the old ‘brain reward’ nomenclature is still most DBS in animals. The most robust effects were obtained commonly used, although newer concepts have been from the MFB that courses upward from the ventral teg- emerging for a long time [see fig. 1 , for 3 major proposals, mental area situated at the base of the brain at the mid- which may be good descriptors of primary (SEEKING), brain-hypothalamic transition, distributing neural influ- secondary-learning (‘wanting’) and tertiary-cognitive ences, especially dopamine release, to various terminal (‘reward prediction error’) levels of neuronal processing]. regions such as the nucleus accumbens and further up It has also long been known that damage to this system medial frontal cortical regions, long implicated in emo- produces a global depressive type of behavioral change, tional processing [for anatomical summaries, see 1, 15 ]. where animals stop exploring their environments and The evoked feeling from MFB-DBS has been presumed stop self-grooming. They often stop eating and drinking, to be in a vaguely defined ‘pleasure’ category, but the pos- and may die if not carefully nursed back toward self- sibility that the feeling resembles any sensory pleasure maintenance. However, the traditional ‘pleasure/reward

Preclinical Modeling of Primal Emotional Psychopathology 5 Affects DOI: 10.1159/000366208 Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM system’ interpretation for MFB arousal [28] – which a few cluding the nucleus accumbens, which Schlaepfer et al. others, beside ourselves [1, 2, 5, 6, 29] , are beginning to [32] pioneered as a target for DBS treatment of depres- critique as basically incorrect, especially after the ‘para- sion. Our interpretation is that facilitation of the SEEK- doxical’ findings of Berridge and Valenstein [30] – still ING/enthusiasm urge is able to counteract the psycho- remains the commonly preferred historical label (for a logical pain engendered by sustained overactivity of the full discussion of various current schools of thought, see PANIC/separation distress system [19, 29, 31, 33] . Panksepp and Moskal [31] ). In any event, the ethological behavior patterns provoked by DBS of this circuitry do not closely resemble the ‘consummatory reward’ phase of Third Hypothesis: Depression May Often Reflect appetitive behavior, but rather the natural exploratory- Chronically Diminished Capacity for Social Joy foraging phases of motivated behavior that is so ubiqui- tous before any consummation can take place. Thus, the As our final example of the affective neuroscience accompanying state of mind is more likely to be akin to strategy for the identification of potential new antide- intense ‘interest’ or ‘enthusiasm’, with ‘exuberance’, even pressant therapies, congruent with the previous hypoth- ‘mania’, being reasonable descriptors of intense (even at eses, we postulated that increased PANIC, along with di- time pathological) arousal – namely the spectrum of feel- minished SEEKING and PLAY arousability, produces a ings that are depleted in depressed individuals. In short, dysphoric state in which individuals have a reduced ca- this system promotes a specific type of psychobehavioral pacity to experience social joy. Thus, we wondered wheth- ‘arousal’ (another excessively general term), allowing or- er we might be able to model such a potential antidepres- ganisms to energetically pursue all external rewards need- sive strategy in laboratory rats. Since we developed stan- ed for survival and reproduction, with an accompanying dardized procedures that anyone can use to study psychological state that is unlikely to reflect consumma- rough-and-tumble PLAY in laboratory rodents [34] , we tory ‘rewards’ (e.g. taste). eventually discovered vocal indicators of social play, akin Our guiding hypothesis has been that excessive and to the laughter of joy, in laboratory rats [35] , which were prolonged social loss, as reflected in affectively negative especially useful for addressing such affective questions. overarousal of the PANIC system, would diminish SEEK- Although by traditional behavioristic standards this ING system activity [11, 19], an effect that we preclin- may sound like an improbable discovery, it is currently cially modeled with considerable success [29] . Accord- generally agreed that rats have a fairly simple repertoire ingly, it was proposed that DBS of the MFB might be a of emotional vocalizations, mostly in the ultrasonic range robust antidepressant in treatment-resistant patients [15, (inaudible/undetectable to human hearing without spe- 16] . Since neither the MFB-based SEEKING system nor cialized equipment) that reflect positive and negative the separation-distress-evoking PANIC system had ever emotions [36, 37] . Positive ultrasonic vocalizations been adequately characterized in humans, diffusion ten- (USVs) in the 50-kHz (+ or – 20 kHz) range can be pro- sor imaging studies were conducted: as summarized in moted by a variety of positively valenced social activi- Coenen et al. [15] , putative trajectories of these systems ties – from the seeking of social or sexual companionship were readily defined, providing coordinates for potential to predictable joys such as daily feeding periods in hungry MFB-DBS studies in depressed humans. In other words, rats, or the receipt of rewarding brain stimulation or be- DBS-induced affective shifts might restore ‘enthusiasm’ ing tickled [38, 39] . As already noted, USVs that occur in depressed patients, and help them to again engage pos- around 50 kHz are emitted at particularly high rates dur- itively with the world, an interpretation that could be pre- ing social play [40] , preceding copulation [41] and in an- dicted from abundant preclinical work [1, 2, 5, 6, 31] . ticipation of or following the administration of cocaine or Results from the first 7 patients undergoing DBS at the amphetamine [42, 43] . Currently, abundant evidence University of Bonn medical center in Germany were pub- supports approximately 50-kHz vocalizations being used lished about a year ago [17] . The positive effects in 6 of as indicators of appetitive positive affect, specifically of the 7 patients were spectacular, with an antidepressant what we deem increased appetitive SEEKING system ac- effect in treatment-resistant individuals evident within tivity [44] – the fundamental substrate for appetitive en- the first day of treatment. These benefits were sustained thusiasm (which has inadequately been conceptualized as for as long as the patients have been followed so far (well ‘brain reward system’ activity) – appears to be underac- over a year), and psychiatric benefits were more rapid and tive in most animal models of depression [19, 29, 45] . In robust than alternative sites that have been studied, in- contrast, the 22-kHz ultrasonic ‘complaints’ of rats ap-

6 Psychopathology Panksepp /Yovell DOI: 10.1159/000366208

Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM pear to be a general indicator of negative mood states in- dices of gene expression profiles were harvested from the cluding PANIC (separation distress) alarm [29] . neocortices of animals that had experienced strictly posi- That 50-kHz chirps represent positive affect is dramat- tive play (no emission of 22-kHz USV complaints). Ex- ically supported by the finding that animals will self-stim- pression profiles for 1,200 genes were monitored 1 and ulate sites in the brain shown to reliably increase 50-kHz 6 h after the end of such play sessions; about one third of vocalizations [44] , and that these calls are abolished with the genes exhibited significantly changed expression pat- all aversive stimuli while being increased by cues that pre- terns in frontal executive-motor and posterior sensory- dict a variety of rewards [for overviews, see 37, 39 ]. Evi- perceptual projection regions of the neocortex [51, 52] . dence that 50-kHz calls represent a general appetitive Indeed, we have found that infusions of insulin-like state includes experiments demonstrating that such calls growth factor-I (one of the most intensely expressed are emitted in anticipation of all positive rewards, from genes) into the ventricular system of rats elevated 50-kHz play to rewarding brain stimulation and drugs of abuse chirping, whereas chemical blockade of the insulin-like [37, 43, 44, 46]. In addition, appetitive approach behav- growth factor-I receptor system reduced this index of iors have been recorded in response to playback of 50- positive affect [53] . kHz calls [47, 48] . Further, tickling animals, one of the A second candidate antidepressive neurochemical best behavioral ways to evoke 50-kHz calls under full ex- pathway (based on strong gene expression) was a receptor perimental control [37, 39], can robustly increase neuro- for the NR2B subunit of the glutamate-glycine receptor genesis in the hippocampus, a well-established neural ef- complex. Through a series of experiments at the Falk fect of antidepressants [49] . Center for Molecular Therapeutics described elsewhere The power of 50-kHz vocalizations as a measure of [51, 52], potential medicinal agents were constructed that positive affect comes most dramatically from knowledge might interact in therapeutic ways with glycine receptors, about the underlying neural system necessary for their in both facilitatory (agonist) ways at low doses and in- production: lesions to either the dopamine-rich neuronal hibitory (antagonist) ways at higher doses. A potentially fields of the ventral tegmental area or the MFB (through useful medicinal vector was identified, code-named which all monoamine systems, namely dopamine, nor- GLYX-13 (a tetrapeptide with the sequence threonine- epinephrine and serotonin, ascend from their cell bodies proline-proline-threonine), which is a partial agonist for that are located lower in the brainstem) produce an amo- glycine sites on N-methyl-D -aspartate receptors, promot- tivational syndrome resembling severe depression. Such ing glutamate transmission in low doses and blocking it lesions also dramatically reduce 50-kHz USVs, particu- in high doses. Fortunately, this positive social affect-facil- larly the frequency-modulated type chirps, which are the itating medicinal agent sailed smoothly through animal best indicators of positive affect [44] . and human toxicology trials and is currently in the FDA- All positive social situations reliably elevate positive- approved phase 2B of clinical testing, passing phase 2A affect indicative chirps. Likewise, manual human tickling with effect sizes considerably larger than those of selective reliably evokes robust chirping calls in young rats and can serotonin reuptake inhibitors [Moskal et al., unpubl. be continued into adulthood with stable response rates data]. GLYX-13 represents a totally novel antidepressant [35, 49, 50] , especially in animals that had received abun- concept. If it proceeds through the whole gamut of FDA dant tickling during adolescence. This tickling procedure, testing, namely the remaining phase 3 double-blind, pla- systematically used ( fig. 3 ), has provided the first ‘psycho- cebo-controlled evaluation, it may be the first novel anti- assay’ for positive social affect that is easy to implement depressant that has arisen from preclinical research. using short 2-min assays, in which 15-second no-tickling Again, the key affective neuroscience finding was that periods are followed by 15-second tickling periods [37, PLAY elevates relevant gene expressions in the brain, and 39] . that a resulting medicinal agent, GLYX-13, promotes Indeed, natural play has now been effectively used to positive affective 50-kHz USVs in rats during social play, screen for brain factors that may increase appetitive pos- which can be simulated by tickling rats and thereby indi- itive affect, as a way to guide discovery of brain neuro- rectly activating the SEEKING system [39, 51] . chemical systems that may yield antidepressant effects. In fact, our novel tickling technique (easily learned) is Panels of brain chemical candidates were derived using the first rigorous preclinical ‘psychoassay’ (fig. 3 ) for pos- genetic microarray technologies by screening which mo- itive social feelings that may be effectively used to iden- lecular pathways were significantly modulated by consis- tify not only depressogenic states in animals, but also new tently happy social play. Oligonucleotide microarray in- antidepressant factors. Further, we use the assay routine-

Preclinical Modeling of Primal Emotional Psychopathology 7 Affects DOI: 10.1159/000366208 Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM 75

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0 0 Off On Off On Off On Off On

a 0.2 s b

Fig. 3. a Characteristic data for a typical tickle-induced sonogram of periods correspond to 15-second intervals where rats receive tick- a frequency-modulated 50-kHz USV. b The 50-kHz response dur- ling during which rats are manually tickled starting quickly at the ing the standard tickle paradigm (n = 12: 6 males, 6 females; col- nape of their necks and turning the animals playfully on their backs lapsed across sexes, since no gender effects were present). An indi- while continuing to tickle their ventral surface and then releasing vidual rat is placed in a box; the ‘off’ periods correspond to 15-sec- them, which is repeated quickly 4–5 times during each 15-second ond intervals where no tickle is administered, whereas the ‘on’ tickling period. Data adapted from Wright and Panksepp [29] . ly to analyze individual phenotypic variability in outbred puffs to the nape of the neck [59] . Recently, one group of rats for their resistance to depression. It is known that the investigators used this method successfully to analyze af- level of responsivity to tickling is a stable affective pheno- fective changes resulting from heroin or alcohol with- type [54] with animals exhibiting high levels of chirps drawal; they found that besides increased immobility in generally being resistant to depressogenic stressors, and the forced swim test, withdrawal from either heroin or animals that exhibit low levels of chirping tending to be ethanol led to high rates of 22-kHz vocalizations, whereas depression prone. Indeed, these phenotypic differences controls produced hardly any such calls [60] . can be easily bred [53, 55–57] . Parenthetically, another method that we are actively pursuing is to create a simple assay to measure ‘spontaneous’ 50-kHz calls when ani- Contextual Issues mals are placed into a neutral, nonstimulating test envi- ronment. Such tests may be especially sensitive to tem- Because of space limitation, we have not discussed the peramental differences in positive affect, without any im- many other animal/preclinical models in this vast field of posed stimulation. research. They include various inescapable shock/stress On the negative side of the affective spectrum, there procedures, often with supposedly unfelt ‘fear’ measures are reasons to believe investigators could use 22-kHz such as unconditional freezing (as well as associated USVs in rats to index negative affect that may be relevant changes in fear-related memories), swimming test (Por- for understanding depression. Unlike 50-kHz calls, these solt test), sucrose intake as an index of anhedonia, and vocalizations are related to affectively negative brain re- many others. Perhaps the most robust brain-manipula- gions, such as the dorsal periaqueductal gray, where stim- tion-based model of depression is olfactory bulbectomy ulation produces strong aversive states accompanied of- in rodents. We note that detailed coverage of most of ten by 22-kHz USVs [29] . Indeed, animals that are simply these other models, widely used, is available in a special allowed to listen to playbacks of 22-kHz USVs show neu- issue of Neuroscience and Biobehavioral Reviews edited by ral activity in the periaqueductal gray [58] . Another sim- Markou [61] . Of course, we also use behavioral, especial- ple assay that may be implemented to evaluate sensitivity ly ethological, techniques to study depression, but what is to this kind of negative affect is the use of repeated air new in our approach is a direct focus on specific affective

8 Psychopathology Panksepp /Yovell DOI: 10.1159/000366208

Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM circuits to evoke depression as well as to monitor the de- ment of new therapeutics, through a better use of pre- pressive cascade. This distinguishing feature has perhaps clinical models, than has been typical during the past 60 allowed us more success in novel treatment development years of intensive animal research on affective disorders than has been typical in the field. [18] . In our coverage here we have not focused on traditional therapies, many of which also modulate the brain reward SEEKING circuitry, which is heavily influenced Conclusion by all the biogenic amines – e.g. dopamine, norepinephrine and serotonin [for a full summary, see 19 ], as also We have described extensive preclinical as well as pre- highlighted by antidepressant dopamine agonists and liminary clinical evidence in support of 3 hypotheses that reuptake inhibitors such as bupropion [62]. Further the attempt to bridge the gap between animal models of de- discovery of a glycine receptor partial agonist (GLYX-13), pression and human psychopathology: currently in human testing, converges on the exciting (i) Reducing ‘psychic pain’ promoted by the PANIC work on brain changes in glutamatergic transmission that (separation distress) system with ‘safe opioids’ such as may underlie depression: As is well known, there is cur- buprenorphine may reduce depression and suicidal rently intense interest in drugs like ketamine to modulate thoughts. (ii) Facilitating enthusiasm with DBS of the N-methyl-D -aspartate transmission, which can yield rap- trans-diencephalic MFB situated SEEKING system can id antidepressant effects [63]. Indeed, in line with find- alleviate amotivational dysphoria in treatment-resistant ings with GLYX-13, an additional exciting breakthrough depressed people. Finally, (iii) the study of brain neuro- is the ability of glycine partial agonists such a D -cycloser- chemical pathways that facilitate the capacity for social ine to strengthen psychotherapeutic benefits through re- joy in animals, as monitored by hedonically positive 50- consolidation of problematic memories with less negative kHz ultrasonics, has yielded a novel neurochemical inter- affect, perhaps by amplifying the therapeutic effects of vention (GLYX-13, a partial agonist for glycine recep- positive affects during therapy (for a full coverage, with tors), which has produced antidepressant effects in treat- extensive commentaries, see the forthcoming discussion ment-resistant depressed humans (successful FDA phase with Lane et al. [64]). Of course, there is also an extensive 2A testing completed over 2 years ago). focus on brain neuropeptide imbalances that contribute These are only 3 examples of the potential contribu- to depression, with exciting possibilities in the reduction tion of affective animal models to the understanding and of stress-induced negative affect with corticotropin-re- treatment of human mood disorders. Of course, these leasing factor antagonists [65, 66] . findings are only a beginning, but we believe that by tak- Further, we have not considered the common comor- ing animal emotional feelings seriously, we can craft pow- bidities, such as anxiety, that often accompany depres- erful new strategies which, for historical reasons, have sion. This has long been widely recognized, and the use been neglected. By developing objective measures to of benzodiazepine antianxiety agents is often highly ben- study relevant feeling processes in animals, as cross-spe- eficial during the first weeks of antidepressant treatment cies affective neuroscience aspires to do, we may deepen [67, 68]. For a fuller discussion of many of these issues, our understanding of human psychopathologies, and especially the vast neurochemical complexities, see Watt thereby facilitate the discovery of more effective treat- and Panksepp [19] . However, as emphasized in that re- ments for various psychiatric disorders where new treat- view, as well as elsewhere [69, 70] , we believe that a key ments are clearly needed. issue that has been neglected are the actual evolved affective/emotional systems in all mammalian brains that are the ultimate mediators of affective states in humans. Neu- Acknowledgment roscience has done a superb job of revealing the vast neurochemistries and brain anatomies that contribute to de- The research summarized in this paper was supported by grants from the Hope for Depression Research Foundation to J.P. pression, while concurrently largely neglecting the pri- and Y.Y., as well as the Institute for the Study of Affective Neuro- mary-process affective systems of mammalian brains as science (Haifa, Israel) to Y.Y. and a Neuropsychoanalytic Founda- targets of inquiry. We feel the time is ripe to make a read- tion Grant to J.P. justment in priorities: by actually focusing on the nature of the diverse negative and positive affects of the brain, perhaps we will make more rapid progress in develop-

Preclinical Modeling of Primal Emotional Psychopathology 9 Affects DOI: 10.1159/000366208 Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM References

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Preclinical Modeling of Primal Emotional Psychopathology 11 Affects DOI: 10.1159/000366208 Downloaded by: Verlag S. KARGER AG, BASEL 172.16.6.96 - 10/23/2014 9:35:00 AM