Reversal of phencyclidine-induced effects by glycine and glycine transportinhibitors

Background: Phencycline (PCP, "angel dust") and other noncompetitive antago nists of N-methyl-D-aspartate (NMDA)-type glutamatergic neurotransmission i nduce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rode nts are reversed by glycine (GLY) and other NMDA augmenting agents. In rode nts, behavioral effects of PCP are mediated, in part, by secondary dysregul ation of subcortical dopaminergic neurotransmission. This study evaluates e ffects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. Methods: Two separate experiments were performed lit 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 behav ioral studies, the potency of a series of GLY transport antagonists for inh ibiting PCP-induced hyperactivity in vivo correlated significantly with the ir potency in antagonizing GLY transport in vitro. Conclusions: These findings suggest,first, that GLY reverses not only the b ehavioral, but also the neurochemical, effects of PCP in rodents. Second, t he findings suggest that GLY transport antagonists may induce similar effec ts to GLY, and may therefore represent an appropriate site for targeted dru g development. (C) 1999 Society of Biological Psychiatry.