Some behavioral effects of hallucinogens are mediated by a postsynaptic serotonergic action: evidence from single...

Although central serotonergic systems appear to be linked importantly to the mechanism of action of a variety of hallucinogenic drugs, the nature of this interaction has remained unclear. In the present study, the question of whether the critical link is presynaptic or postsynaptic was examined in cats. Behaviorally inactive doses (1.0 mg/kg) of the serotonin receptor antagonists mianserin, ketanserin or metergoline effectively blocked behavior, as measured by the cat limb flick response, elicited by either LSD (50 micrograms/kg) or DOM (250 micrograms/kg) but not that resulting either from lisuride (50 micrograms/kg) or a high dose of apomorphine (4 mg/kg). Pretreatment with 1.0 mg/kg of mianserin, which completely attenuated LSD's behavioral effect, failed to alter LSD-induced depression of mesencephalic serotonergic neuron discharge. These results demonstrate that at least some of the behavioral effects of LSD can be blocked by pharmacological antagonism of postsynaptic serotonin receptors which leaves LSD's presynaptic effect unaffected. Thus, the behavioral, and possibly psychoactive, effects of hallucinogens appear to be attributable to an action at 5HT2 receptors, presumably located postsynaptically.