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

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 and 5-HT receptor sub-types in this regard. We examined the impact of manipulating 5-HT and 5-HT 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 inverse agonist/antagonist pimavanserin, and the 5-HT 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 receptor activity has a very limited action to reduce alcohol-seeking. Activating 5-HT 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.