Lysergic acid diethylamide (LSD), a serotonin 5-HT(2A) receptor agonist, enhances Pavlovian eyeblink conditioning in rabbits. Acute injections of LSD, whether given parenterally or directly into the dorsal hippocampus, produced a 5-HT(2A)-mediated head-bob behavior. Chronic administration of LSD (3 or 10 nmol per side) during conditioning increased conditioned responses compared to vehicle controls. After repeated LSD infusions, subsequent infusion of another hallucinogen (DOI) elicited fewer head bobs, indicating desensitization of the 5-HT(2A) receptor. The slight, short-lived learning enhancement appears to result from this receptor desensitization within the hippocampus.
Lysergic acid diethylamide (LSD) at a dose of 30 nmol/kg enhances the acquisition of classically conditioned nictitating membrane responses in rabbits. Three experiments showed that LSD specifically improves learning, not performance, by increasing the frequency of conditioned responses and lowering the threshold for the conditioned stimulus intensity. LSD did not alter unconditioned response amplitude or the sensory processing of the unconditioned stimulus. The drug's enhancement of conditioned stimulus sensory processing is proposed to facilitate conditioning through both learning and performance mechanisms.
The hallucinogens DOI and LSD both require activation of serotonin 2A (5-HT2A) and dopamine D1 receptors to produce head-bob behavior in rabbits, while serotonin 2B/2C receptors are not involved. In vitro, LSD and the antagonist ritanserin bound to frontocortical 5-HT2A receptors pseudo-irreversibly, whereas DOI and ketanserin bound reversibly. LSD showed modest D1 receptor binding affinity, but DOI had negligible affinity for D1 receptors. Despite these differences in binding properties, activation of both 5-HT2A and D1 receptors is a common mechanism for the behavioral effects of these hallucinogens.