STUDIES ON THE CONCURRENT BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF PSYCHOACTIVE DRUGS USING THE PUSH-PULL CANNULA

¹ Department of Pharmacology and Psychiatry Research Unit, Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota

Intraventricular infusions of ³H-norepinephrine or ¹⁴C-serotonin were given 1 hour or 30 minutes, respectively, before rats had their lateral ventricles perfused with artificial cerebrospinal fluid through chronic-indwelling push-pull cannulas while responding for food on a fixed-ratio 30 schedule of reinforcement. Twelve to 15 minutes into the session, they were injected i.p. with d-amphetamine (1.0, 2.5 or 5.0 mg/kg). mescaline (10, 15 or 20 mg/kg), d-lysergic acid diethylamide (LSD) (0.4 mg/kg) or 0.5 ml of isotonic NaCl. Only d-amphetamine produced a dose-dependent increase of tritium in the perfusate after injection, in addition to dose-related shortening of latencies to behavioral disruption. Thin-layer chromatographic analysis of the perfusate, taken during the 5.0 mg of d-amphetamine per kg session, revealed increased concentrations of radioactivity in segments having R_f values of authentic norepinephrine and normetanephrine. Mescaline produced similar effects on behavior, but produced dose-dependent increases only in ¹⁴C-radioactivity soon after drug administration. Thin-layer chromatographic separation of the perfusate after administration of 20 mg of mescaline per kg revealed apparent increased proportions of ¹⁴C-5-hydroxyindoleacetic acid. LSD (0.4 mg/kg) disrupted fixed-ratio responding in a manner similar to the high doses of mescaline and d-amphetamine but produced a significant decrease in ¹⁴C released without altering the metabolic disposition of 5-hydroxytryptamine or its acid metabolite. These data suggest that mescaline andd-amphetamine may act presynaptically to produce the release and/or block the reuptake of serotonin and norepinephrine, respectively. LSD, on the other hand, produces an apparent inhibition of release of 5-hydroxytryptamine, perhaps via a presynaptic action or through postsynaptic feedback inhibition.