Serotonin and hallucinogens

This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as partial agonists at 5-HT 2A and other 5-HT 2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HT The accidental discovery in 1943 of the hallucinogenic properties of the synthetic ergoline compound LSD (dlysergic acid diethylamide) by the chemist Albert Hoffman is well known. Five years later, in 1948, serotonin (later determined to be 5-hydroxytryptamine or 5-HT) was found in bovine blood serum NEURONAL ACTIONS OF HALLUCINOGENIC DRUGS Effects of Hallucinogens on 5-HT Neurons of the Raphe Nuclei The identification of 5-HT as a neurotransmitter was not achieved until the mid-1960s, when monoaminergic neuronal pathways in the brain were discovered and mapped by histochemical fluorescence methods (Dähl-strom and Fuxe 1964). These maps, which revealed that 5-HT neuronal cell bodies were clustered in the raphe nuclei of the brainstem, provided the basis for singlecell electrophysiological recordings from identified 5-HT neurons. LSD was found to have a potent inhibitory effect upon the tonically firing 5-HT neurons of the dorsal raphe nucleus In subsequent years, the delineation of multiple 5-HT receptor subtypes by radiolabeled ligand binding and molecular methods (see Affinity for 5-HT 2 Receptors Correlates with Hallucinogenic Potency Glennon, Titeler, and their colleagues showed that there is an excellent correlation between the affinity of both indoleamine and phenethylamine hallucinogens for 5-HT 2 receptors and hallucinogenic potency in humans Actions at 5-HT 2C receptors, which have been associated with anxiogenic responses Hallucinogens Enhance Sensory Responses in the Locus Coeruleus via 5-HT 2A Receptors The locus coeruleus (LC) consists of two dense clusters of noradrenergic neurons located bilaterally in the upper pons at the lateral border of the 4th ventricle. The LC, which projects diffusely to virtually all regions of the neuraxis, receives an extraordinary convergence of somatic, visceral, and other sensory inputs from all regions of the body, has been likened to a novelty detector for salient external stimuli (Aston-Jones and Bloom 1981; Cedarbaum and Aghajanian 1978). In this context, it is of interest that the systemic administration of LSD, mescaline, or other psychedelic hallucinogens in anesthetized rats, although decreasing spontaneous activity, produces a paradoxical facilitation of the activation of LC neurons by sensory stimuli (Aghajanian 1980; Rasmussen and Aghajanian 1986); this effect is not through a direct action on LC cell bodies, because it cannot be mimicked by the local, microiontophoretic application of the drugs. The effects of hallucinogens on LC neurons can be reversed by low intravenous doses of selective 5-HT 2 antagonists, such as ritanserin (Rasmussen and Aghajanian 1986). Antipsychotic drugs are also able to reverse the actions of hallucinogens in the locus coeruleus at doses correlating with their affinity for 5-HT 2A but not dopamine and adrenergic receptors Because the effects of systemically administered hallucinogens are through an activation of afferent inputs rather than through a direct action upon LC cell bodies, the LC itself cannot be used as a model for studying the direct cellular actions of hallucinogens. Nevertheless, the effects of the hallucinogens upon the LC are of interest, because this nucleus receives such an extraordinarily widespread convergence of sensory information, both somatosensory and visceral, relaying this information to virtually all other parts of the neuraxis, including the cerebral cortex. 5-HT 2A Receptors Enhance Glutamate Release in Neocortex The ubiquitous effects of hallucinogens on such complex processes as cognition, perception, and mood suggest the involvement of the cerebral cortex. The direct, postsynaptic effect of 5-HT in the cortex are variable: depolarization, hyperpolarization, or no change, depending upon whether the effects of excitatory 5-HT 2 receptors or inhibitory 5-HT 1A receptors are predominant in any given layer V pyramidal cell Whole-cell patch clamp recordings have demonstrated that 5-HT induces a small, but significant, increase in the amplitude of spontaneous EPSCs, an effect that may involve a postsynaptic amplification mechanism (Aghajanian and Marek 1997). Such a postsynaptic effect is consistent with the finding of a high density of 5-HT 2A receptor immunoreactivity in the apical dendrites of cortical pyramidal cells (Jakab and GoldmanRakic 1998; A Focal Mechanism for 5-HT 2A -Induced Glutamate Release onto Apical Dendrites of Layer V Pyramidal Cells A novel mechanism, independent of impulse flow, seems to be involved in the increase in glutamate release induced by 5-HT 2A receptor activation. Blockade of 5-HT-induced EPSCs by bath application of the fast sodium channel blocker tetrodotoxin (TTX) or perfusion of the slice with a solution containing no added calcium ("0" calcium) would generally suggest that 5-HT had activated glutamatergic cells in the slice, leading to an impulse-flow-dependent release of glutamate. Several lines of evidence argue against this conventional interpretation. First, we rarely found any neurons induced to fire by bath application of 5-HT (unlike our experience in the piriform cortex, where we readily found GABAergic interneurons excited by 5-HT). Second, none of the pyramidal cells (a potential source of intracortical excitatory inputs) in our sample were depolarized by 5-HT sufficiently to reach threshold for firing. Third, EPSCs could be induced by the microiontophoresis of 5-HT onto the apical dendrites of layer V pyramidal cells, but no cell firing was detected while recording extracellularly through the microiontophoretic electrod