Effects of pimavanserin and lorcaserin on alcohol self-administration and reinstatement in male and female rats

Paul J Fletcher; Zhaoxia Li; Xiaodong Ji; Guy A Higgins; Douglas Funk; A D Lê

doi:10.1016/j.neuropharm.2022.109150

Effects of pimavanserin and lorcaserin on alcohol self-administration and reinstatement in male and female rats

Neuropharmacology. 2022 Sep 1:215:109150. doi: 10.1016/j.neuropharm.2022.109150. Epub 2022 May 27.

Authors

Paul J Fletcher¹, Zhaoxia Li², Xiaodong Ji², Guy A Higgins³, Douglas Funk², A D Lê⁴

Affiliations

¹ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychology, University of Toronto, Toronto, Ontario, Canada. Electronic address: paul.fletcher@camh.ca.
² Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
³ Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; InterVivo Solutions Inc, Fergus, Ontario, Canada.
⁴ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.

PMID: 35644487
DOI: 10.1016/j.neuropharm.2022.109150

Abstract

The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) modulates fundamental motivational processes, and the neurochemical and behavioural effects of drugs of abuse. Recently, attention has focused on the role of 5-HT acting via 5-HT_2A and 5-HT_2C receptor sub-types in this regard. We examined the impact of manipulating 5-HT_2A and 5-HT_2C receptor mediated function on several aspects of alcohol self-administration and alcohol-seeking behaviour in male and female rats. Specifically, experiments investigated the effect of the 5-HT_2A inverse agonist/antagonist pimavanserin, and the 5-HT_2C receptor agonist lorcaserin on these behaviours. In male and female rats trained to respond for alcohol reinforcement on fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement pimavanserin (0.3, 1 and 3 mg/kg) had no consistent effect on responding. Lorcaserin (0.25, 0.5 and 1 mg/kg) reduced these behaviours in both sexes. Following extinction of responding for alcohol, alcohol-seeking was reinstated by cues previously paired with alcohol. Pimavanserin (1 mg/kg) and lorcaserin (0.5 mg/kg) significantly reduced this reinstatement. In a two-bottle 24 h intermittent access procedure pimavanserin had no significant effects, but lorcaserin reduced alcohol consumption in both sexes at 1, 4 and 24 h after access to alcohol was allowed. Finally, as determined using in vivo microdialysis, alcohol increased, and lorcaserin (0.5 mg/kg) reduced, extracellular levels of DA in the NAc in male rats. In rats treated with lorcaserin prior to alcohol injection the net effect was that DA levels were not changed compared to those measured in control rats. These results suggest that blocking 5-HT_2A receptor activity has a very limited action to reduce alcohol-seeking. Activating 5-HT_2C receptors had a broader behavioural profile to reduce alcohol self-administration, alcohol drinking and alcohol seeking. These effects may partly result from a blunting of the effect of alcohol on mesolimbic DA release.

Keywords: Alcohol; Dopamine; Lorcaserin; Pimavanserin; Rat; Serotonin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzazepines
Dose-Response Relationship, Drug
Female
Male
Piperidines
Rats
Receptor, Serotonin, 5-HT2C
Self Administration
Serotonin 5-HT2 Receptor Agonists* / pharmacology
Serotonin*
Urea / analogs & derivatives

Substances

Benzazepines
Piperidines
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
Serotonin
lorcaserin
Urea
pimavanserin

Grants and funding

PJT165886/CIHR/Canada