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

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 KORmediated depressant effects but not abuse potential of psychostimulants. Public Health SignificanceHallucinogens are drugs of abuse but may also have therapeutic potential for some mental health disorders. The current study uses an intracranial self-stimulation procedure in rats to examine abuse-related effects and potential therapeutic effects of acute and repeated treatment with prototype hallucinogens.

Anxiety-like behavior induced by salicylate depends on age and can be prevented by a single dose of 5-MeO-DMT

“…But an important study showed that it can also modulate the sigma-1 receptor and therefore, indirectly affect Na + and K + channels (Fontanilla et al, 2009). Adding to the complexity of the mechanisms in which psychedelics affects the anxious brain, specific agonists of 5HT receptors do not seem to provide any beneficial effects in mood disorders (Sakloth et al, 2019).…”

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…Interestingly, the acute administration of LSD, psilocybin, and mescaline fails to produce reliable evidence of abuse (Sakloth et al, 2019). Moreover, the authors found that repeated LSD (at the highest doses tested, but not at low doses) tends to attenuate the rewarding effects of the psychostimulant methamphetamine and the depressant k-opioid receptor agonist U69,593, although only findings for the latter were statistically significant (Sakloth et al, 2019).…”

“…A rare case of physical dependence from, and tolerance to, LSD has recently been reported in the literature (Modak et al, 2019). One recent study investigated the abuse liability of low-and high-dose LSD, psilocybin, and mescaline and repeated LSD administration via the intracranial self-stimulation paradigm in rats, which is widely adopted to determine the abuse potential of a putative drug (Sakloth et al, 2019). Interestingly, the acute administration of LSD, psilocybin, and mescaline fails to produce reliable evidence of abuse (Sakloth et al, 2019).…”

“…One recent study investigated the abuse liability of low-and high-dose LSD, psilocybin, and mescaline and repeated LSD administration via the intracranial self-stimulation paradigm in rats, which is widely adopted to determine the abuse potential of a putative drug (Sakloth et al, 2019). Interestingly, the acute administration of LSD, psilocybin, and mescaline fails to produce reliable evidence of abuse (Sakloth et al, 2019). Moreover, the authors found that repeated LSD (at the highest doses tested, but not at low doses) tends to attenuate the rewarding effects of the psychostimulant methamphetamine and the depressant k-opioid receptor agonist U69,593, although only findings for the latter were statistically significant (Sakloth et al, 2019).…”

The therapeutic potential of microdosing psychedelics in depression

“… 1 , 4 , 6 Moreover, preliminary findings and anecdotal reports suggest that psychedelics even show therapeutic potential in substance use disorders. 1 , 7 , 8 In addition, current research is investigating therapeutic applications of these substances in psychiatric disorders, with a focus on affective disorders. 8 – 11 While the intensity or quality of the psychedelic experience seems to contribute to its therapeutic effect, 12 anecdotal evidence also suggests that repeated use of smaller doses without the psychedelic experience (‘microdosing’) is efficacious self-treatment for people suffering from affective disorders.…”