Pharmacological Reviews, Vol 17, 1-25, Copyright © 1965 by the American Society for Pharmacology and Experimental Therapeutics

BIOCHEMICAL ASPECTS OF THE ACTIONS OF PSYCHOTOMIMETIC DRUGS

¹ Departments of Pharmacology and Psychiatry, Yale University, School of Medicine, New Haven, Connecticut

A wide variety of chemuical structures is grouped generically under the classification of psychotomimetic drugs. Such a global grouping has little justification in terms of either somatic or behavioral effects, amid there is little likelihood of discovering a umiitary explamiation of the mechanismn of action of these drugs. Some subgroupings are based on common pharmacologic effects. In termits of cross-tolerance, effects on temperature amid effects on amine levels, the indolealkylamines and substituted phenethylamines appear to be related (52); and the piperidyl glycollates and other cholinolytic compounds may similarly be grouped according to effects on brain acetylcholine (71). Yet if progress is to be made in linking biochemical changes to psychotomimetic effects, a focus on neural sites of action and accessibility of drugs to those sites is required. Dose-dependent correlations with discrete and different autonomic, electroencephalographic and behavioral effects also are important to advances in this area. With LSD, for example, dose-depemident, centrally mediated effects (129), such as pyrexia, mydriasis, EEG alerting, hind limb ataxia, and certain behavioral effects (in rat) and mental effects (in man) show tolerance, while salivation and bradycardia do not (55, 56). Furthermore, effects can be elicited by low doses of LSD in rat (94), cat (99), and mami (79), for which either biochemical or neurophysiological correlates are lacking. In addition, neurophysiological studies have served to identify different sites of action for 5-HT throughout the brain (100, 118), but these as yet have not been correlated with associated biochemical effects of LSD.

Studies of the metabolism of psychotomimetic drugs have shed little light on their modes of action. Intriguing avenues of research have been opened by Szara in his investigations of the 6-hydroxylation of psychotomimetic N-alkyl indolealkylamines (and their effects on brain 5-HT), and his study of the 13-hydroxylation of LSD, and by Friedhoff and Van Winkle in their reports of mescaline-like derivatives, arising possibly from dopamine, in the urine of schizophrenic patients. Other interesting leads have come from Gessner et al. in the possible barmualine-like metabolite of melatonin, and from Brune and Himwich (30) in their observation that acute exacerbations in chronic schizophrenic patients are associated with marked increases in urinary excretion of tryptamine, and smaller increases in the excretion of other tryptophan metabolites. It has been emphasized, however, that all of these studies are fraught with methodologic problems and rigorous proof of each hypothesis is lacking.

Few investigators in this area will argue against the proposition that biogenic amines, and related neurochemical substances, play an as yet undefined role in brain function and behavior. Some very compelling correlations between druginduced behavioral change and the factors governing binding and release of 5-HT and norepinephrine have been made with the onset and recovery from stressimtduced changes in psychophysiologic condition (13). Yet if binding and release of amines from central storage sites and interaction with critical central receptors are envisaged as mechanisms significant to the action of psychotomimetic drugs, more than regional brain analyses are required. Relevant physicochemical means of measurement of binding and release have not been satisfactorily devised (see review by Green, 78). New methodologies—as, for example, fluorescence microscopy, which may provide morphological correlates of neurochemical changes measured in broken-cell preparations, and pertinent neuropharmacological investigation at the level of single units (e.g., by the micro-iontophoretic technique of drug application)—could contribute to specifying interactions with brain arnines. In addition, pharmacological analysis (and eventually chemical characterization) of various types of receptors which engage monoamines, such as tryptamine receptors (153, 159) will provide important information.