Neurophysiological effects of hallucinogens on serotonergic neuronal systems

Low intravenous doses of the hallucinogen d-lysergic acid diethylamide (LSD) markedly suppress the discharge of serotonin (5-HT)-containing neurons in the dorsal raphe nucleus of the rat. Microiontophoretically applied LSD also inhibits the firing of 5-HT neurons, indicating that the inhibitory effect is mediated directing on 5-HT neurons. Forebrain neurons receiving a major serotonergic input are relatively insensitive to LSD. Other indole hallucinogens (i.e., psilocin, dimethyltryptamine, and 5-methoxydimethyltryptamine) also preferentially inhibit raphe firing as compared to postsynaptic forebrain neurons. These observations led to the hypothesis that hallucinogens produce their psychoactive effects by acting preferentially upon 5-HT autoreceptors in the dorsal raphe allowing postsynaptic neurons to escape from the tonic inhibitory action of 5-HT neurons. However, problems exist with the concept that hallucinogens produce their psychoactive effects by disinhibiting postsynaptic neurons. First, the time course of the behavioral and neuronal effects of LSD do not correlate. Second, 5-HT neurons do not become tolerant to the inhibitory actions of LSD. Third, the hallucinogen mescaline fails to directly inhibit 5-HT neurons. Finally, the nonhallucinogen lisuride markedly suppresses the discharges of 5-HT neurons. These observations suggest that postsynaptic actions of hallucinogens may be of prime importance in producing their psychedelic effects. Evidence is presented to suggest that the hallucinogens may act postsynaptically to sensitize both serotonergic and noradrenergic receptors. It is suggested that a mechanism of receptor sensitization, in distinction to disinhibition, might account for the altered perceptual reactivity produced by these drugs.