ABSTRACT
Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate 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 found 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, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.
Subject(s)
Discrimination Learning/drug effects , Discrimination Learning/physiology , Phencyclidine/antagonists & inhibitors , DOM 2,5-Dimethoxy-4-Methylamphetamine/administration & dosage , Animals , Brain/drug effects , Dose-Response Relationship, Drug , Drug Combinations , Lisuride/administration & dosage , Lysergic Acid Diethylamide/administration & dosage , Male , N,N-Dimethyltryptamine/administration & dosage , Rats , Rats, Sprague-Dawley , Ritanserin/administration & dosage , Spiperone/administration & dosage , Time FactorsABSTRACT
In an attempt to increase the selectivity of drug discrimination, rats were trained to discriminate LSD (0.08 mg/kg) from a group of "other" compounds consisting of cocaine (10 mg/kg), pentobarbital (5 mg/kg), and saline. Acquisition of this LSD-other discrimination was rapid (31 days) in chambers equipped with retractable levers and did not differ significantly from that of a group of animals trained to discriminate LSD from saline (26 days). In substitution (generalization) tests, hallucinogens such as LSD, DMT, and DOM mimicked LSD in a dose-dependent manner in both groups. The designer drug (+/-)MDMA substituted for LSD in the LSD-other group (ED50 = 1.38) but did not substitute for the training drug in the LSD-ND group; neither (+) MDMA nor PCP mimicked LSD in either group. Most importantly, lisuride, quipazine, and yohimbine, drugs that have been described as "false positives," substituted for LSD in animals trained to discriminate LSD from saline (ED50s = 0.012, 1.662, 2.344, respectively), but not in animals trained to discriminate LSD from other drugs. Thus, the LSD-other training procedure can be described as more selective than the standard drug-ND procedure.
