Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines

J. C. Winter 0 ) Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo , 102 Farber Hall, Buffalo, NY 14214-3000, USA Background Although man's first encounters with hallucinogens predate written history, it was not until the rise of the sister disciplines of organic chemistry and pharmacology in the nineteenth century that scientific studies became possible. Mescaline was the first to be isolated and its chemical structure determined. Since then, additional drugs have been recovered from their natural sources and synthetic chemists have contributed many more. Given their profound effects upon human behavior and the need for verbal communication to access many of these effects, some see humans as ideal subjects for study of hallucinogens. However, if we are to determine the mechanisms of action of these agents, establish hypotheses testable in human subjects, and explore the mechanistic links between hallucinogens and such apparently disparate topics as idiopathic psychosis, transcendental states, drug abuse, stress disorders, and cognitive dysfunction, studies in animals are essential. Stimulus control by hallucinogens has provided an intuitively attractive approach to the study of these agents in nonverbal species. Objective The intent of this review is to provide a brief account of events from the time of the first demonstration of hallucinogen-induced stimulus control to the present. In general, the review is limited to lysergic acid diethylamide (LSD) and the hallucinogenic derivatives of phenethylamine and tryptamine. - Hallucinogens, most often in the form of crude botanical extracts, have been known to man for thousands of years (Schultes and Hofmann 1980). However, scientific investigation of these drugs awaited the rise, in the nineteenth century, of organic chemistry and experimental pharmacology. Indeed, it was not until Heffters (1896) isolation of mescaline in 1896 from the cactus, Lophophora williamsii, and the determination of its chemical structure (3,4,5trimethoxyphenylethylamine) by Spath (1919) that a welldefined substance could be said to produce hallucinations. In view of the remarkable alterations in thought and perception produced by hallucinogens and because of the essentially subjective nature of a major portion of the effects of these drugs, it is not surprising that selfexperimentation played a prominent role in the initial investigation of drugs such as mescaline (Heffter 1897), 3,4-methylenedioxy-alpha-methylphenylethylamine (Alles 1959), lysergic acid diethylamide (LSD; Hofmann 1959), N,N-dimethyltryptamine (DMT; Szara 1956, 1957), and psilocybin (Hofmann 1968). No account of the selfadministration of psychoactive drugs would be complete without reference to Ann Shulgin and Alexander Shulgin (1991, 1997), whose personal experiences with an extensive series of tryptamines and phenethylamines are compiled in two volumes. However, even in those instances when adequate experimental designs have been employed in clinical studies (e.g., Gouzoulis-Mayfrank et al. 2005, 2006; Griffiths et al. 2006; Hollister et al. 1968, 1969a, b; Isbell et al. 1961, 1967; Snyder et al. 1968; Vollenweider et al. 1996, 1998a; Wolbach et al. 1962a, b), ethical considerations have placed significant constraints on the type of experiments undertaken. Thus, in seeking what the late Leo Hollister called the Holy Grail of pharmacology, the mechanism of action of drugs, investigators have often turned to infrahuman species. In so doing, certain ethical and legal problems are avoided and a wider range of experimental manipulation becomes permissible but, then, there arise questions of interpretation and extrapolation. It is generally assumed that the biological events that precede and accompany chemically induced hallucinations in man have some counterpart in lower species. Early infrahuman studies of hallucinogens employed what Peter Dews, the founder of behavioral pharmacology, referred to as isolated bits of dying tissue. These usually took the form of a section of smooth muscle situated in a tissue bath so that contraction and relaxation might be quantified (e.g., Wooley and Shaw 1954; Winter and Gessner 1968). While studies such as these provided valuable insights into the possible mechanisms of the action of hallucinogens, including a role for serotonin (Gaddum 1953), it was natural to seek behavioral correlates of human hallucinogenesis in animals. In a typical series of experiments, a profile of hallucinogenic activity was drawn using, it sometimes seemed, whatever behavior was at hand. The dependent variables ranged from neuropharmacological indices (Corne and Pickering 1967; Martin and Eades 1970; Silva and Calil 1975) to nonconditioned behavior (Dixon 1968; Schneider and Chenoweth 1970; Silva and Calil 1975) to operant behavior (Smythies and Sykes 1964; Uyeno 1969; Uyeno and Mitoma 1969; Silva and Calil 1975). Consensus as to the predictive ability of these approaches was achieved seldom if ever. It was propitious therefore that Ira Hirschhorn, as a part of his Ph.D. thesis research, successfully trained both LSD and mescaline as discriminative stimuli in the rat (Hirschhorn and Winter 1971). The technique of hallucinogen-induced stimulus control was then transferred, first by Hirschhorns colleague, Martin Schechter, and then by Hirschhorn himself, to the laboratory of John Rosecrans where it flourished (Glennon et al. 1979; Hirschhorn and Rosecrans 1974; Rosecrans and Glennon 1979; Schechter and Rosecrans 1972) On a purely intuitive basis, the study of the stimulus properties of hallucinogens is more attractive than, for example, analysis of LSD-impaired rope-climbing ability (Winter and Flataker 1956). Scope of this review A dictionary definition of hallucination seems simple enough: a perception of objects with no reality (Webster 1993). That apparent simplicity belies the range of potentially hallucinogenic chemicals and the complexity of human responses to those agents. In deference to that range and to that complexity, this review is restricted to the stimulus effects of LSD, tryptamines, and phenethylamines. Only passing mention will be made of anticholinergics, cannabinoids, exotic agents such as salvinorin, and all those other drugs which properly lay claim to the title hallucinogen. It is true that some attention will be paid to the noncompetitive N-methyl-D-aspartate (NMDA) antagonists as represented by phencyclidine (PCP) but only with respect to their possible commonalities with the objects of this review. I have made no attempt to be encyclopedic in my coverage but would direct the interested reader to the comprehensive list of stimulus control studies provided by the Drug Discrimination Bibliographic Database (Stolerman and Kamien 2004), to earlier reviews of hallucinogen-induced stimulus control (Winter 1974; Appel et al. 1982; Glennon 1999; Winter et al. 1999), and (...truncated)