Antagonism of a PCP drug discrimination by hallucinogens and related drugs

Drugs such as PCP and MK-801 can cause psychotic li reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cor tical neurons and may be one mechanism underlying neurodegenerative disease s, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, po ssibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamergic projections to the retrosplenial and cing ulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg ) from saline and were then given a series of antagonist tests. It was foun d that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg ), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, D OM, and, less effectively, DMT and LHM can block the behavio ral as well as the neurotoxic effects of NMDA antagonists most likely through actions at 5-HT2 receptors. (C) 2000 American College of Neuropsychopharmacology. Publ ished by Elsevier Science Inc.