Adaptive changes in behavior after repeated administration of various psychoactive drugs.

Evidence has been presented that d-amphetamine interacts with various types of behavior in the context of a conditioning paradigm. Rats exposed simultaneously to a locomotor activity measurement and three dose levels of d-amphetamine on repeated occasions gradually developed dose-related enhancement of drug-stimulated activity, which persisted after discontinuation of the drug. Rats trained in FR-operant chambers with food reinforcement showed a decrease in the rate of lever pressing after administration of d-amphetamine. Tolerance to this effect required varying numbers of daily drug injections, according to the subject's degree of prior drug experience. In both situations the drug administrations were coupled with the behavioral measure to allow for conditioning effects. In a continuous avoidance procedure the initial dose of d-amphetamine did not enhance response rate, although subsequent doses did produce significant stimulation. Even when the initial doses were administered out of temporal phase with the avoidance measurement, the simultaneous administration of the drug and the behavioral procedure on a subsequent day resulted in a significant drug-induced stimulation of response rate. Thus, in this particular instance, the conditioning influence of the earlier doses was apparent whether or not the drug effect occurred in contiguity with the avoidance measurement. Other reports in the literature (16) suggest that hallucinogenic drug action may be characterized by the peculiar "pause" in an FR pattern of responding for food reinforcement. This proposal was substantiated and extended to a number of representative hallucinogenic agents. d-Amphetamine or chlorpormazine reduced the rate of FR responding without provoking an obvious pause. Examination of tolerance and cross-tolerance to the hallucinogenic pause in the FR pattern after LSD, mescaline, psilocybin, DOM, and DMT generally indicated interactions between the drugs, although this was not entirely consistent. It follows that the mechanisms of action of these drugs probably have elements in common, though they are not necessarily identical. In doses as small as 10 mg/kg, cinanserin, a serotonergic receptor-blocking agent, completely reversed the pause in FR pattern induced by the various hallucinogenic drugs.