RATIONALE: Schizophrenia is a major mental disorder. Dissociative anesthetics such as phencyclidine (PCP) produce a syndrome in humans that is clinically indistinguishable from schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors in brain are modulated by the amino acid glycine (GLY), which reverses neurochemical and behavioral effects of PCP in rodents. The present study investigates GLY effects on PCP-induced behavior in primates. OBJECTIVES: In primates, PCP induces characteristic behavioral symptoms that can be used to model positive and negative symptoms of schizophrenia. This study investigated the effects of GLY treatment in ten socially housed monkeys receiving chronically infused PCP. METHODS: Ten monkeys received escalating then stable doses of continuously infused PCP through a series of subcutaneously implanted osmotic minipumps. During a segment of the highest PCP dose period, monkeys were concurrently treated with glycine (2 g kg(-1) day(-1) bid p.o.). Behavioral observations were recorded during baseline and treatment periods. RESULTS: Chronic PCP treatment was associated with a progressive decrease in stereotyped pacing and a progressive increase in scanning behavior. Eight of ten animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. GLY treatment significantly reversed the effects of PCP on stereotyped pacing but had no effect on scanning. CONCLUSIONS: The results support GLY treatment as beneficial for negative symptoms of schizophrenia. Although further validation is needed, the results also indicate that chronic PCP in primates may be an appropriate model system for development of drugs targeting positive and negative symptoms of schizophrenia.
RATIONALE: Schizophrenia is a major mental disorder. Dissociative anesthetics such as phencyclidine (PCP) produce a syndrome in humans that is clinically indistinguishable from schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors in brain are modulated by the amino acid glycine (GLY), which reverses neurochemical and behavioral effects of PCP in rodents. The present study investigates GLY effects on PCP-induced behavior in primates. OBJECTIVES: In primates, PCP induces characteristic behavioral symptoms that can be used to model positive and negative symptoms of schizophrenia. This study investigated the effects of GLY treatment in ten socially housed monkeys receiving chronically infused PCP. METHODS: Ten monkeys received escalating then stable doses of continuously infused PCP through a series of subcutaneously implanted osmotic minipumps. During a segment of the highest PCP dose period, monkeys were concurrently treated with glycine (2 g kg(-1) day(-1) bid p.o.). Behavioral observations were recorded during baseline and treatment periods. RESULTS: Chronic PCP treatment was associated with a progressive decrease in stereotyped pacing and a progressive increase in scanning behavior. Eight of ten animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. GLY treatment significantly reversed the effects of PCP on stereotyped pacing but had no effect on scanning. CONCLUSIONS: The results support GLY treatment as beneficial for negative symptoms of schizophrenia. Although further validation is needed, the results also indicate that chronic PCP in primates may be an appropriate model system for development of drugs targeting positive and negative symptoms of schizophrenia.
Authors: M Steffens; B Becker; C Neumann; A M Kasparbauer; I Meyhöfer; B Weber; M A Mehta; R Hurlemann; U Ettinger Journal: Hum Brain Mapp Date: 2016-11 Impact factor: 5.038