Polygenic psychiatric disorders, such as schizophrenia, will likely require systems-modulating therapeutics given the observation that hundreds to thousands of susceptibility genes exist. These therapeutics are difficult to identify without complex in vivo readouts. The most effective antipsychotic drugs bind to many receptors in the nervous system, and unlike ‘magic bullet’ drugs (including many antibiotics and some chemotherapeutics that act on single molecular targets) most antipsychotics are thought to act via poly-pharmacology on many targets simultaneously [Roth, B. L., Sheffler, D. J. & Kroeze, W. K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3, 353-359 (2004)]. The prototypes of most antipsychotic drugs, including chlorpromazine, haloperidol, and clozapine were originally discovered through their behavioral phenotypes in vivo [Kokel, D. & Peterson, R. T. Chemobehavioural phenomics and behaviour-based psychiatric drug discovery in the zebrafish. Brief Funct Genomic Proteomic 7, 483-490 (2008)]. Novel antipsychotics and other multi-target drugs have been difficult to identify—but not impossible [Besnard, J. et al. Automated design of ligands to polypharmacological profiles. Nature 492, 215-220 (2012)]—using traditional target based assays that focus on isolated receptors in vitro [Paul, S. M. et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov 9, 203-214 (2010)].
Given that there are no known biomarkers for most psychiatric disorders, behavior modification is another attractive endpoint for central nervous systems (CNS) drug screens. Freezing in response to aversive stimuli is an instinctive behavior common to most animals, including humans and fish. The ability to choose an appropriate defense response during a threatening situation can be essential for survival, but can also have consequences for psychiatric health [Hartley, C. A. & Phelps, E. A. Anxiety and decision-making. Biological psychiatry 72, 113-118, doi:10.1016/j.biopsych.2011.12.027 (2012)]. Altered responses to threatening stimuli and breakdown in limbic control are thought to be fundamental characteristics of several psychiatric disorders including schizophrenia [Laviolette, S. R. Dopamine modulation of emotional processing in cortical and subcortical neural circuits: evidence for a final common pathway in schizophrenia? Schizophrenia bulletin 33, 971-981, doi:10.1093/schbul/sbm048 (2007); Williams, L. M. et al. Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. The American journal of psychiatry 161, 480-489 (2004); Paradiso, S. et al. Emotions in unmedicated patients with schizophrenia during evaluation with positron emission tomography. The American journal of psychiatry 160, 1775-1783 (2003)] and post-traumatic stress disorder [Brewin, C. R. What is it that a neurobiological model of PTSD must explain? Progress in brain research 167, 217-228, doi:10.1016/s0079-6123(07)67015-0 (2008)].
However the time, space, and financial resources required for high-throughput (HT) behavioral screening for schizophrenia drug discovery have been prohibitive using traditional animal models. Target- and cell-based CNS discovery platforms facilitate rapid drug screening but are generally too simple to replicate the integrated networks required for complex brain processes [Hyman, S. E. Revolution stalled. Science translational medicine 4, 155cm111, doi:10.1126/scitranslmed.3003142 (2012)]. Conversely, rodent models offer sufficient biological complexity to study threat responses and other behaviors, but they are too large and unwieldy for high-throughput discovery.