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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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Figure 1. Human iPS cells derived from human newborn fibroblasts by direct protein delivery. (a) These protein-induced human iPS colony shows a typical human ES cell morphology. (b) They can differentiate into all three germ layers including neuroectodermal lineage cells such as nestin-positive neural precursors (red) and Tuj1-positive neurons (green). Nuclei were stained with DAPI (blue).

somatic cells by retroviral transduc- lar, and molecular mechanisms under- transgenes may trigger altered cell tion of four transcription factors lying the disease process, which may physiology and/or abnormal differen- (ie, Oct4, Sox2, Klf4, and c-Myc) lead to ideal platforms for drug tiation properties. To address these (Takahashi and Yamanaka, 2006). screening. This new approach may be issues, recent studies used non-integrat- Furthermore, 1 year later, several especially important to advances in ing vectors (eg, adenovirus or episomal groups showed that human iPS cells psychiatry because (1) the underlying vectors) or excisable vectors (eg, could be generated from human pathogenic mechanisms of mental dis- piggyBac transposon and Cre-recombi- tissues by similar methods, paving orders are largely unknown, (2) cel- nase excisable viruses (Yamanaka, the way to generate disease- and lular models for disease mechanism 2009)). As these DNA vector-based patient-specific iPS cells (Takahashi study are extremely limited, and (3) manipulations are not completely free et al, 2007; Yu et al, 2007; Park et al, rational treatments are lacking in from potential chromosomal disrup- 2008). Until these advances, the bio- most cases. tion, we recently developed a new logical dogma was that the develop- Several major obstacles must be method to generate human iPS cells mental process is unidirectional in overcome for iPS cell technology to by direct protein delivery without the that a totipotent zygote becomes more make a full impact in psychiatric use of virus or DNA transfection and more restricted until terminally disease research. First, most iPS cells (Kim et al, 2009). These transgene- differentiated tissues are generated. have been derived by retroviral or andDNA-freeiPScells(Figure1) These new breakthrough studies lentiviral introduction of reprogram- could be useful not only for disease showed that epigenetic reprogram- ming factor-encoding genes, resulting mechanism study, but also for future ming by defined factors could reverse in multiple chromosomal disruptions, customized cell therapy of neuropsy- this process. any of which may cause genetic chiatric disorders. iPS cell technology is a tantalizing dysfunction and/or tumor formation. Kwang-Soo Kim1 new method of generating genetically This could be particularly problematic 1Department of Psychiatry and Program in Neuro- matched pluripotent stem cells in vitro. in psychiatric diseases that may have science, Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, MA, USA Unlike conventional methods that relatively subtle pathogenic mechan- E-mail: [email protected] generate embryonic stem cells from isms. Secondly, reprogramming trans- zygotic embryos, it does not require genes (in particular, c-Myc and Klf4) DISCLOSURE killing of embryos, thus avoiding the are closely associated with oncogen- The author has no conflicts of interest related to the material presented in this paper. This work was associated ethical dilemma. These iPS esis, raising the possibility that iPS partially supported by National Institutes of Health cells provide useful tools to study the cells generated by these factors may be Grants MH048866 and DC006501. molecular and cellular mechanisms of prone to tumor formation. Currently, development and differentiation, par- most iPS cells contain the reprogram- ...... ticularly early human development. ming transgenes in their chromo- Hyman SE (2008). A glimmer of light for neuropsy- Furthermore, iPS cells derived from somes although their expression is chiatric disorders. Nature 455: 890–893. Kim D, Kim CH, Moon JI, Chung YG, Chang MY, patients could be extremely useful for mostly silenced. Reactivation and/or Han BS et al (2009). Generation of human investigating the physiological, cellu- residual leaky expression of these induced pluripotent stem cells by direct delivery

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of reprogramming proteins. Cell Stem Cell 4: tion following stress or dopaminergic (that is, prodromal phase, initial 472–476. drugs. Indeed, the most replicated episode, and subsequent relapses), Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA et al (2008). Reprogramming of human somatic finding so far in schizophrenia dopaminergic neurons may be hyper- cells to pluripotency with defined factors. Nature positron emission tomography (PET) responsive to environmental stimuli, 451: 141–146. research has been an increased DA and exposure to even moderate Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007). Induction of pluripotent stem release after the administration of levels of stress (or DA drugs) produces cells from adult human fibroblasts by defined factors. amphetamine, and this DA increase excessive DA release, precipitating Cell 131:861–872. has been associated with positive illness in vulnerable individuals Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and psychotic symptoms and active stages and relapse in those with schizo- adult fibroblast cultures by defined factors. Cell of the illness. As increased stimulant- phrenia. 126: 663–676. induced DA release is a hallmark The phenomenon of DA sensitiza- Yamanaka S (2009). A fresh look at iPS cells. Cell 137: 13–17. of sensitization, several pieces of tion to psychostimulants is subjected Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz- evidence support the view that schizo- to cross-sensitization with stress. It is Bourget J, Frane JL, Tian S et al (2007). phrenia is associated with a process of well established that repeated stress Induced pluripotent stem cell lines derived from human somatic cells. Science 318: dopamine sensitization (Laruelle and (maternal separation, social-defeat 1917–1920. Abi-Dargham, 1999). stress, foot shock, tail pinch, restraint) Neuropsychopharmacology Reviews (2010) 35, Psychosis sufferers themselves often induces heightened sensitivity to low 346–348; doi:10.1038/npp.2009.108 cite a link between the experience of doses of dopaminergic drugs; and stress and psychotic symptoms. The conversely, repeated dopaminergic stress-vulnerability model suggests drug exposure increases the stress that an endogenous, organic dia- response in animals. Consistent with thesis or vulnerability interacts with these findings, prenatal and postnatal Advances in PET internal or external stressors in the stress is associated with increased development of psychotic disorders. drug-induced DA release, and differ- analyses of stress and However, the underlying neurobiolo- ent types of acute and repeated stress dopamine gical condition/event that results in an increase DA release (Abercrombie exaggerated response to stressors is et al, 1989; Kalivas et al, 1986). A deregulation of the stress response unknown. One proposed mechanism Similarly, recent studies in humans is a potential etiological factor in the is neurochemical sensitization of the using PET have shown increased development and relapse of dopamine DA systemFdopamine sensitiza- DA release after either a psychosocial (DA)-related human disorders, inclu- tionF, whereby repeated exposure or a metabolic stress task (Adler ding addiction, drug-induced psycho- to sensitizing life stressors (or DA et al, 2000; Pruessner et al, 2004). sis, and schizophrenia. Schizophrenia drugs) progresses into increased However, this finding was not repli- is characterized by a chronic relapsing stress-associated DA release. Hence, cated in another study, which used a nature and vulnerability to exacerba- during active periods of the illness different stress paradigm, with no

Healthy CHR BP = 5

Baseline: Non-Stress

Stress

BP = 0 Z = -8 Y = 2 Z = -8 Y = 2

11 Figure 1. Representative figure showing decreased [ C]-( + )-PHNO BPND in CHR following stress suggesting increased DA displacement, as compared with HV.

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