Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property.

Autor:	Higgins GA; InterVivo Solutions Inc., Fergus, ON, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada., Carroll NK; InterVivo Solutions Inc., Fergus, ON, Canada., Brown M; InterVivo Solutions Inc., Fergus, ON, Canada., MacMillan C; InterVivo Solutions Inc., Fergus, ON, Canada., Silenieks LB; InterVivo Solutions Inc., Fergus, ON, Canada., Thevarkunnel S; InterVivo Solutions Inc., Fergus, ON, Canada., Izhakova J; InterVivo Solutions Inc., Mississauga, ON, Canada., Magomedova L; InterVivo Solutions Inc., Mississauga, ON, Canada., DeLannoy I; InterVivo Solutions Inc., Mississauga, ON, Canada.; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada., Sellers EM; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.; DL Global Partners Inc., Toronto, ON, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2021 Feb 26; Vol. 12, pp. 640241. Date of Electronic Publication: 2021 Feb 26 (Print Publication: 2021).
DOI:	10.3389/fphar.2021.640241
Abstrakt:	Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. The high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports of these drugs being used at what are colloquially referred to as "micro" doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. In the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3-3 mg/kg [10-73 ng/ml]) and psilocybin/psilocin (0.05-0.1 mg/kg [7-12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. Tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male Long Evans rats trained in two food motivated tasks: a progressive ratio (PR) and serial 5-choice (5-CSRT) task. Both acute doses of ketamine (1-3 mg/kg IP) and psilocybin (0.05-0.1 mg/kg SC) pretreatment increased break point for food (PR task), and improved attentional accuracy and a measure of impulsive action (5-CSRT task). In each case, effect size was modest and largely restricted to test subjects characterized as "low performing". Furthermore, both drugs showed a similar pattern of effect across both tests. The present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility. Competing Interests: ES receives advisory fees from Diamond Therapeutics Inc. GAH, NC, MB, CM, LBS, ST, JI, LM, IDeL are all employees of InterVivo Solutions Inc (IVS). IVS is a contract research organization specializing in the use of clinically relevant animal models of CNS disease and drug disposition for BioPharma research. All work conducted by IVS employees was in the course of their regular duties. IVS received funding from Diamond Therapeutics to conduct the psilocybin studies. (Copyright © 2021 Higgins, Carroll, Brown, MacMillan, Silenieks, Thevarkunnel, Izhakova, Magomedova, DeLannoy and Sellers.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu