Psychosis model

Several diverse, potent, and selective GlyT-1 inhibitors have appeared in the literature and many are reported to be efficacious in animal psychosis models. Several of these have advanced into Phase I and Phase II clinical studies. Recent Phase II results from a double-blind, 320-patient study with the investigational GlyT-1 inhibitor RG1678 (33) [17] demonstrated that the compound improved negative symptoms and social functioning of stable patients currently on atypical antipsychotic therapy and was well tolerated at all doses tested [18]. 

Since then, several potent and selective sarcosine-based inhibitors have been reported in the literature. Representative examples include 5 (LY2365109) [37,38], 6 ((R)-N[3-phenyl-3-(4 -(4-toluoyl)phenoxy)-propyl] sarcosine or (R)-NPTS) [39,40], 7 [41], 8 [42], 9 (JNJ-17305600) [43], and 10 [44]. Members of these series have demonstrated efficacy in several psychosis models [38,40] and JNJ-17305600 is reportedly in Phase I clinical trials for schizophrenia (data not available) [23]. 

SSR-504734 is a potent, selective, and reversible inhibitor (IC50 = 18 nM) that is competitive with glycine [47,51]. The inhibitor rapidly and reversibly blocked the uptake of [14C]glycine in mouse cortical homogenates, which was sustained for up to 7 h. Complete cessation of blockade and return to glycine basal levels occurred prior to 24 h, which is in stark contrast to NFPS (>24 h). SSR-504734 potentiated a nearly twofold increase of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices and produced an increase in contralateral rotations in mice when microinjected into the striatum. Microdialysis experiments indicated that the inhibitor induced a rapid and sustained increase in extracellular glycine levels in the PFC of freely moving rats [51]. The compound also demonstrated efficacy in a variety of psychosis models [51-53]. SSR-504734 was reportedly in clinical trials for schizophrenia but discontinued after Phase I (data not disclosed) [54]. 

Although many of the examples of mGluR2 PAMs in the literature have been centered on anxiety and psychosis models, given that this target is intimately tied to the modulation of glutamate neurotransmission, we expect mGluR2 modulators to also have broad application in the treatment of neurodegenerative diseases. 

Ellinwood EH Jr, Sudilovsky A, Nelson LM Evolving behavior in the clinical and experimental amphetamine (model) psychosis. Am J Psychiatry 130 1088—1093, 1973... 

Somoza EC, Winhusen TM, Bridge TP, et al An open-label pilot study of methylpheni-date in the treatment of cocaine-dependent patients with adult attention deficit/ hyperactivity disorder. J Addict Dis 23 77—92, 2004 Sora 1, Wichems C, Takahashi N, et al Cocaine reward models conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95 7699-7704, 1998 Soral, Hall FS, Andrews AM, etal Molecular mechanisms of cocaine reward combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Nad Acad Sci U S A 98 5300-5305, 2001 Spear J, Alderton D Psychosis associated with prescribed dexamphetamine use 0etter). 

Robinson, T.E., and Becker, J.B. Enduring changes in brain and behavior produced by chronic amphetamine administration A review and evaluation of animal models of amphetamine psychosis. Brain Res 11 157-198, 1986. 

Ellinwood, E.H., Jr., and Kilbey. M.M. Chronic stimulant intoxication models of psychosis. In Hanin, I., and Usdin, E., eds. Animal Models in Psychiatry and Neurology. New York Pergamon Press, 1977. pp. 61-74. 

The close resemblance between schizophrenia and PCP-induced psychosis suggests that the behavioral effects produced by PCP might be useful as a model of psychosis. On this basis, most animal studies have examined the ability of various agents to modify PCP-induced hyperactivity and stereotypy. While some studies suggest that neuroleptics such as haloperidol (Castellani and Adams 1981 Garey et al. 1980), chlorpromazine, or clozapine (Freed et al. 

Glutamate systems have long been implicated in the pathophysiology of schizophrenia. Strong if circumstantial evidence comes from the psychosis associated with phencyclidine (PGP) administration PGP blocks of the ion channel the glutamate/NMDA receptor. Psychosis due to PGP and other noncompetitive NMDA antagonists includes the development of negative as well as positive symptoms and therefore is considered a better model of schizophre-... 

Inhibition of conditioned (but not unconditioned) avoidance behavior is one of the most predictive tests of antipsychotic action. Another is the inhibition of amphetamine- or apomorphine-induced stereotyped behavior. Other tests that may predict antipsychotic action are reduction of exploratory behavior without undue sedation, induction of a cataleptic state, inhibition of intracranial self-stimulation of reward areas, and prevention of apomorphine-induced vomiting. Most of these tests are difficult to relate to any model of clinical psychosis. 

In the case of schizophrenia it is dopamine, another neuromodulator not apparently involved in dream generation, whose overactivity results in psychosis and whose blockade by neuroleptics effects antipsychosis. We do not yet see how to fit dopamine and schizophrenic psychosis into the universal model, but hints as to how that might occur are already on the horizon. As the link between motor control and thought becomes better appreciated and the interaction of serotonin, norepinephrine, and dopamine is better understood, we will see, I predict, a seamless continuity among these control systems and their effects on consciousness. 

We find that the models of stimulant-induced and schizophrenic psychosis share three important elements (1) facilitation of the limbic system, (2) reciprocal disfacilitation of the prefrontal cortex, and (3) orchestration of these reciprocal changes by aminergic neuromodulatory systems. As it is item (3) that is causal in both models, we need to examine similarities and differences in the neuromodulatory mechanisms of the three classes of psychosis under scrutiny here. 

This possibility could provide a strong foundation for a unified model that says that psychosis may result in waking if either acetylcholine is blocked (atropine delirium) or dopamine is enhanced (amphetamine, manic, and schizophrenic psychosis) and/or if both acetylcholine and dopamine are enhanced but noradrenergic and/or serotonergic drives are reduced (depression and dream psychoses). 

Newcomer, J. W., Farber, N. B., Jevtovic-Todorovic, V., Selke, G., Melson, A. K., Hershey, T., Craft, S., Olney, J. W. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis, Neuropsychopharmacol. 1999, 20, 106-118. 

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