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which continues to the end of the reach only up to 7–10 years of except for income received from their second decade, can, potentially, cause ageFtoo early to characterize long- primary employers, no financial sup- enduring, functionally significant term outcomes. port or compensation has been changes in neuronal circuitry. The Early-life experience and environ- received from any individual or cor- duration and timing of drug treatment mental factors are emerging as addi- porate entity over the past 3 years for are critical in determining long-term tional, important modulators of the research or professional service effects (Popa et al, 2008), owing to effects of psychotropic medications. and there are no personal financial developmental changes in the neural We recently showed that, in rats, some holdings that could be perceived as substrates on which the drugs act. of the enduring behavioral conse- constituting a potential conflict of Stress, which is associated with quences of fetal exposure to fluoxetine interest. affective disorders, adversely impacts do not occur if exposed infants are Douglas O Frost1, Robbin Gibb2 and neural development during fetal life subjected to behavioral testing, Bryan Kolb2 and postnatally, and is ameliorated by which, by its nature, provides supple- 1Department of Pharmacology and Experimental therapies that improve affect. Thus, mental sensory stimulation and Therapetics, Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA; potential, adverse, long-term effects of exercise (R Gibb, DO Frost and B 2Canadian Center for Behavioral Neuroscience, exposing the developing brain to Kolb, unpublished data). A provoca- University of Lethbridge, Lethbridge, AB, Canada medication must be weighed against tive, parallel finding has recently been E-mail: [email protected] the deleterious impact of stress eleva- reported in humans: In infants who ...... tion as a result of interrupted phar- are not breast fed, maternal SSRI use Ansorge MS, Morelli E, Gingrich JA (2008). Inhibition macotherapy of pregnant women, or during pregnancy is associated with of serotonin but not norepinephrine transport during development produces delayed, persistent not treating children or adolescents. altered hypothalamo–pituitary–adre- perturbations of emotional behaviors in mice. Human studies have revealed few nal (HPA) stress responses, whereas J Neurosci 28: 199–207. effects of fetal antidepressant drug breast feeding abolishes this effect of Depino AM, Tsetsenis T, Gross C (2008). GABA homeostasis contributes to the developmental (ADD) exposure that endure beyond fetal SSRI exposure by 3 months of age programming of anxiety-related behavior. Brain infancy. By contrast, adult rodents (Oberlander et al, 2008). The mode of Res 1210: 189–199. exposed to ADDs only during stages feeding seems to act epigenetically: Frost DO, Cercio Page S, Carroll C, Kolb B (2009). Early exposure to haloperidol or olanzapine in- corresponding to fetal life, childhood, breast-fed infants have lower methyla- duces long term alterations of dendritic form. or adolescence in humans exhibit a tion (and probably higher expression) Synapse (in press). spectrum of abnormalities, many of of the glucocorticoid receptor gene Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM (2008). Prenatal exposure to which are, surprisingly, components NR3C1 than nonbreast-fed infants maternal depression, neonatal methylation of of depression. Similar, long-term, (Oberlander et al, 2008). human glucocorticoid receptor gene (NR3C1) ‘mirror image’ effects (that is, Animal and human studies are and infant cortisol stress responses. Epigenetics 3: 97–106. drug-induced increases in disease consistent in demonstrating that Popa D, Lena C, Alexandre C, Adrien J components that are reduced by environment and experience during (2008). Lasting syndrome of depression pro- pharmacological treatment of adults) fetal and postnatal brain maturation duced by reduction in serotonin uptake dur- ing postnatal development: evidence from occur after early-life anxiolytic treat- interact with early-life psychotropic sleep, stress, and behavior. J Neurosci 28: ment (Depino et al, 2008). Early drug exposure to shape the ontogeny 3546–3554. exposure to atypical antipsychotic of behavior and neural circuitry. Zuo J, Liu Z, Ouyang X, Liu H, Hao Y, Xu L et al (2008). Distinct neurobehavioral consequences of drugs, used to treat bipolar disorder Epigenetic modulation of gene expres- prenatal exposure to sulpiride (SUL) and risper- in children and adolescents, induces sion appears to be one important idone (RIS) in rats. Prog Neuropsychopharmacol significant, long-lasting cognitive mediator of these effects. These find- Biol Psychiatry 32: 387–397. deficits (Zuo et al, 2008) and morpho- ings suggest possibilities for designing Neuropsychopharmacology Reviews (2010) 35, logical abnormalities (Frost et al, new therapeutic strategies that miti- 344–345; doi:10.1038/npp.2009.133 2009). gate the effects of early-life ADD Why do rodent and human data exposure. seem discrepant? In rodents, the behavioral syndromes induced by ACKNOWLEDGEMENTS early ADD (Ansorge et al, 2008) or Ligand functional anxiolytic (Depino et al, 2008) treat- This work was funded by 5R01 selectivity advances our ment are progressive and emerge fully MH074083 from the National Insti- understanding of drug only in early adulthood. This is tutes of Health, a Research Enhance- because early-life brain insults induce ment Award Program from the mechanisms and drug a cascade of effects over the course of Research Service of the US Depart- discovery development. Human studies of the ment of Veterans Affairs to DOF and effects on progeny of maternal ADD the Canadian Institutes of Health ‘Intrinsic efficacy’ (the concept that a treatment during pregnancy so far Research (BK). We declare that, drug acting at a single receptor is

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always an agonist, partial agonist, or differentiated side-effect profiles of the topic of this commentary. Except for his primary employment, Dr Vishakantha Murthy declares that no antagonist/inverse agonist) had been functional selectivity. compensation or support has been received from any accepted for a half-century. Two Of direct neuropsychopharmacolo- entity over the past three years for research or decades ago, it became clear that a gical relevance is the dopamine professional service. This work was supported by grants MH040537 and MH082441. single G protein-coupled receptor mechanism of action of aripiprazole...... (GPCR) could have promiscuous The most commonly disseminated Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC, G protein interactions. This suggested hypothesis is that aripiprazole causes Hanson BJ et al (2009). Parallel functional activity that some drugs might cause differ- ‘dopamine stabilization’ through D profiling reveals valvulopathogens are potent 2 5-HT2B receptor agonists: implications for drug ential effects on signaling via a single partial agonism. Conversely, other safety assessment. Mol Pharmacol Online July 1, receptor, and within a few years, there data have shown that aripiprazole, 2009; doi:10.1124/mol.109.058057. were data showing such ‘anomalous’ although sometimes a partial agonist, Kilts JD, Connery HS, Arrington EG, Lewis MM, F Lawler CP, Oxford GS et al (2002). Functional functional responses in the extreme, can also be a D2 pure antagonist or full selectivity of dopamine receptor agonists. II. a ligand acting at a single receptor agonist depending on the assay sys- Actions of dihydrexidine in D2L receptor-trans- being a full agonist at one function tem. As we have reviewed recently fected MN9D cells and pituitary lactotrophs. J Pharmacol Exp Ther 301: 1179–1189. and an antagonist at another (Kilts (Mailman, 2007), the original in vivo/ Mailman RB (2007). GPCR functional selectivity has et al, 2002). ex vivo data from the drug’s disco- therapeutic impact. Trends Pharmacol Sci 28: Strikingly, most laboratories engaged verers are consistent with D func- 390–396. 2 Neve KA (2009). Functional Selectivity of G Protein- with this phenomenon recognized its tional selectivity, but not with simple Coupled Receptor Ligands. Humana: New York. implications, each proffering a unique partial agonism. Functional selectivity Smith HP, Nichols DE, Mailman RB, Lawler CP name (eg, agonist-directed trafficking would thus predict that D ligands (1997). Locomotor inhibition, yawning and vacu- 2 ous chewing induced by a novel dopamine D2 of signaling, biased agonism, etc), with selected as partial agonists in a single post-synaptic receptor agonist. Eur J Pharmacol functional selectivity emerging as common functional assay may not be 323: 27–36. the apparent consensus. The naming similar clinically. From this perspec- Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H et al (2007). Func- quandary, the involved mechanisms, tive, the failure of preclamol or tional selectivity and classical concepts of quanti- the impact on understanding drug bifeprunox to have adequate antipsy- tative pharmacology. J Pharmacol Exp Ther 320: action, the relevance to drug discov- chotic efficacy may not be surprising. 1–13. ery, and even the implications for The level of complexity added by Neuropsychopharmacology Reviews (2010) 35, teaching have been reviewed recently functional selectivity also provides 345–346; doi:10.1038/npp.2009.117 (Urban et al, 2007), now including the opportunity. In the short term, it first book on the subject (Neve, 2009). permits a greater understanding of the It appears that this is a universal differential neuropsychopharmacology phenomenon for all GPCRs and other of drugs once thought to be function- drug targets, and that many drugs may ally similar, and may permit discrimi- Induced pluripotent cause such differential signaling. nation of potential drug candidates. stem (iPS) cells and their The question is whether functional In the long term, scientific advances selectivity is an interesting artifact for showing how individual signaling future in psychiatry the specialist, or a mechanism that pathways affect cellular function (and One of the most significant challenges affects psychoactive drug action and subsequent physiological responses) in neuroscience for the twenty-first drug discovery. The data suggest that will provide a mechanistic foundation century is to understand the molecular both are true (Kilts et al, 2002; Smith for the discovery of rationally chosen and cellular basis of neuropsychiatric et al, 1997). As an example, a recent functionally selective drugs. disorders. Despite extensive research, publication examined the impact of 1 the last several decades failed to yield functional selectivity on valvulopathy, Richard B Mailman and 1 clearly validated new drug targets or which was thought to be due to Vishakantha Murthy 1Departments of Pharmacology and Neurology and therapeutic mechanisms for major 5-HT2B agonist-induced mitogenic The Neuroscience Institute, Pennsylvania State Uni- psychiatric disorders (Hyman, 2008). action in the heart. Clinical drugs versity College of Medicine and Milton S. Hershey One important limitation is the lack were selected for their 5-HT agonist Medical Center, Hershey, PA, USA 2B E-mail: [email protected] of pathogenically and physiologically profile in traditional assays, and then reliable animal and cellular model functionally profiled. Of this group, DISCLOSURE systems of psychiatric disorders. This ropinirole was differentiated from the In addition to income from his primary employer, challenging situation is now changing other compounds by its signaling Dr Richard Mailman has an equity interest in Biovalve Technologies and Effipharma, which creates a through the advances that followed profile, possibly explaining why it potential conflict of interest that has been monitored Shinya Yamanaka and his colleagues’ has a decreased risk of valvulopathy by committees at his current and previous employer. successful generation of pluripotent In the past three years, Dr Mailman has also been (Huang et al, 2009). To our knowl- compensated for providing scientific opinions relevant stem cells in 2006, so called ‘induced’ edge, this is the first example for the to legal or public policy matters that are not related to pluripotent stem (iPS) cells, from

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