Dissociations between the effects of hallucinogens on behavior and raphe unit activity in behaving cats

The hypothesis that hallucinogenic drugs exert their behavioral effects by an action at pre- or postsynaptic serotonin receptors was evaluated by co-administering various drugs that possess either serotonin agonist or antagonist properties, while concurrently monitoring behavior and the electrophysiological activity of serotonin-containing dorsal and median raphe neurons in freely moving cats. Co-administration of the serotonin receptor blockers, metergoline or mianserin, with lysergic acid diethylamide (LSD) produced no change in the inhibitory effects of LSD on raphe neurons, but produced a dose-dependent blockade of the behavioral effects of LSD in the cat. The latter data suggest that perhaps LSD exerts its behavioral effects by an action at postsynaptic serotonin receptors. Co-administration of drugs that increase synaptic serotonin, L-5-hydroxytryptophan, tranylcypromine, fluoxetine or p-chloramphetamine with LSD greatly potentiated the inhibitory effect of LSD on raphe unit activity, but also produced dose-dependent decreases in these behavioral effects of LSD in the cat. Thus, both enhancing the activity at postsynaptic serotonin receptors and receptor antagonism blocked the behavioral effects of LSD. Co-administration of dopamine receptor blockers, haloperidol or chlorpromazine, produced no significant change in the response of raphe neurons to LSD, but these drugs also produced a dose-dependent blockade of the behavioral effects of LSD in the cat. Co-administration of the dopamine agonists, apomorphine or d-amphetamine, however, potentiated the behavioral effects of LSD, while producing a partial reversal of the inhibitory effects of LSD on raphe unit activity. The results are discussed in the context of using animal models to study the possible actions of hallucinogens in humans.