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

Abstract

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.Results The pharmacological basis for stimulus control by LSD and hallucinogenic phenethylamines and tryptamines is serotonergic in nature. The 5-HT 2A receptor appears to be the primary site of action with significant modulation by other serotonergic sites including 5-HT 2C and 5-HT 1A receptors. Interactions with other neurotransmitters, especially glutamate and dopamine, are under active investigation. Most studies to date have been conducted in the rat but transgenic mice offer interesting possibilities. Conclusions Hallucinogen-induced stimulus control provides a unique behavioral tool for the prediction of subjective effects in man and for the elucidation of the pharmacological mechanisms of the action of these agents.

Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects

“…1). LSD and MDMA do not generalize to the discriminative stimulus effects of PCP in rats (7). The discriminative stimulus effects of PCP were diminished by combination with LSD or MDMA in rats, presumably due to masking effects (7).…”

“…Previous studies have indicated that the activation of 5-HT 2 receptors plays a role in the discriminative stimulus effects of U50,488H, PCP, MDMA, and LSD in animals (7,34). Even though these hallucinogenic drugs in some cases induce similar behavioral phenotypes, each type of drug exerts different discriminative stimulus effects by regulating different receptors and signals (Fig.…”

“…LSD and MDMA do not generalize to the discriminative stimulus effects of PCP in rats (7). The discriminative stimulus effects of PCP were diminished by combination with LSD or MDMA in rats, presumably due to masking effects (7). A recent study showed that MDMA can regulate the endogenous κ-opioid system mediated by the activation of 5-HT 2 receptors (35).…”

The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties

“…Our molecular and behavioral studies demonstrate that efavirenz has pharmacological properties predictive of psychoactive effects in humans. Although efavirenz interacts with several receptors within a similar range of concentration, several lines of evidence suggest that the psychoactive effects of efavirenz are predominately mediated by activation of the serotonin 5-HT 2A receptor similar to the psychoactive effects of LSD and other related hallucinogens (Fiorella et al, 1995;Winter, 2009). First, efavirenz has partial agonist properties at cloned serotonin 5-HT 2A receptors, which are blocked by antagonists of this receptor.…”

Assessment of Potential Long Term Health Effects on Army Human Test Subjects of Relevant Biological and Chemical Agents, Drugs, Medications and Substances

“…Additionally, the expression of pro-apoptotic Bax, cytochrome-c and caspase-9 were upregulated at the mRNA and protein level after ICG exposure. 374 ICG-related damage to the retina has long been thought to result in lower visual acuity than expected after surgery. 375,376 For example, a study from Korea showed that indocyanine greenrelated RPE atrophy in an elderly woman resulted in best-corrected visual acuity of 20/63 in the right eye and 20/125 in the left eye.…”