Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats.

The classic hallucinogens LSD, mescaline, and psilocybin, classified as Schedule 1 drugs, were tested in rats using intracranial self-stimulation (ICSS), a procedure that detects abuse-related effects of other drugs. In acute tests, all three drugs predominantly depressed ICSS, with weak and inconsistent evidence of abuse-related facilitation. Repeated LSD treatment did not alter its own depressant effects or the abuse-related effects of methamphetamine, but it did attenuate ICSS depression caused by the kappa opioid receptor agonist U69,593. These findings suggest that 5-HT2A agonist hallucinogens have weak abuse potential and provide evidence that repeated LSD may reduce depressant-like effects mediated by kappa opioid receptors.

Study at a glance

Abstract

The prototype 5-HT2A receptor agonist hallucinogens LSD, mescaline, and psilocybin are classified as Schedule 1 drugs of abuse by the U.S. Drug Enforcement Administration. Accumulating clinical evidence has also suggested that acute or repeated "microdosing" with these drugs may have utility for treatment of some mental health disorders, including drug abuse and depression. The goal of the present study was to evaluate LSD, mescaline, and psilocybin effects on intracranial self-stimulation (ICSS), a procedure that has been used to evaluate abuse-related effects of other classes of abused drugs. Effects of repeated LSD were also examined to evaluate potential changes in its own effects on ICSS or changes in effects produced by the abused psychostimulant methamphetamine or the prodepressant kappa opioid receptor (KOR) agonist U69,593. Male Sprague-Dawley rats were implanted with microelectrodes targeting the medial forebrain bundle and trained to respond under a "frequency-rate" ICSS procedure, in which many drugs of abuse increase (or "facilitate") ICSS. In acute dose-effect and time-course studies, evidence for abuse-related ICSS facilitation was weak and inconsistent; the predominant effect of all 3 drugs was dose- and time-dependent ICSS depression. Repeated LSD treatment failed to alter either its own ICSS depressant effects or the abuse-related effects of methamphetamine; however, repeated LSD did attenuate ICSS depression by U69,593. These results extend those of previous preclinical studies to suggest weak expression of abuse-related effects by 5-HT2A agonist hallucinogens and provide supportive evidence for therapeutic effects of repeated LSD dosing to attenuate KOR-mediated depressant effects but not abuse potential of psychostimulants. (PsycINFO Database Record (c) 2019 APA, all rights reserved).