D C Javitt1, A Balla, H Sershen, A Lajtha. 1. Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatry Research, Orangeburg, New York 10962, USA.
Abstract
BACKGROUND: Phencycline (PCP, "angel dust") and other noncompetitive antagonists of N-methyl-D-aspartate (NMDA)-type glutamatergic neurotransmission induce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rodents are reversed by glycine (GLY) and other NMDA augmenting agents. In rodents, behavioral effects of PCP are mediated, in part, by secondary dysregulation of subcortical dopaminergic neurotransmission. This study evaluates effects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. METHODS: Two separate experiments were performed. In the first, effects of GLY on PCP-induced stimulation of dopaminergic neurotransmission in nucleus accumbens were evaluated using in vivo microdialysis in awake animals. In the second, effects of a series of GLY transport antagonists were evaluated for potency in inhibiting PCP-induced hyperactivity. RESULTS: In microdialysis studies, GLY significantly inhibited PCP-induced stimulation of subcortical DA release in a dose-dependent fashion. In behavioral studies, the potency of a series of GLY transport antagonists for inhibiting PCP-induced hyperactivity in vivo correlated significantly with their potency in antagonizing GLY transport in vitro. CONCLUSIONS: These findings suggest, first, that GLY reverses not only the behavioral, but also the neurochemical, effects of PCP in rodents. Second, the findings suggest that GLY transport antagonists may induce similar effects to GLY, and may therefore represent an appropriate site for targeted drug development.
BACKGROUND:Phencycline (PCP, "angel dust") and other noncompetitive antagonists of N-methyl-D-aspartate (NMDA)-type glutamatergic neurotransmission induce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rodents are reversed by glycine (GLY) and other NMDA augmenting agents. In rodents, behavioral effects of PCP are mediated, in part, by secondary dysregulation of subcortical dopaminergic neurotransmission. This study evaluates effects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. METHODS: Two separate experiments were performed. In the first, effects of GLY on PCP-induced stimulation of dopaminergic neurotransmission in nucleus accumbens were evaluated using in vivo microdialysis in awake animals. In the second, effects of a series of GLY transport antagonists were evaluated for potency in inhibiting PCP-induced hyperactivity. RESULTS: In microdialysis studies, GLY significantly inhibited PCP-induced stimulation of subcortical DA release in a dose-dependent fashion. In behavioral studies, the potency of a series of GLY transport antagonists for inhibiting PCP-induced hyperactivity in vivo correlated significantly with their potency in antagonizing GLY transport in vitro. CONCLUSIONS: These findings suggest, first, that GLY reverses not only the behavioral, but also the neurochemical, effects of PCP in rodents. Second, the findings suggest that GLY transport antagonists may induce similar effects to GLY, and may therefore represent an appropriate site for targeted drug development.
Authors: Daniel C Javitt; Darryle Schoepp; Peter W Kalivas; Nora D Volkow; Carlos Zarate; Kalpana Merchant; Mark F Bear; Daniel Umbricht; Mihaly Hajos; William Z Potter; Chi-Ming Lee Journal: Sci Transl Med Date: 2011-09-28 Impact factor: 17.956