Suppression of cocaine relapse-like behaviors upon pimavanserin and lorcaserin co-administration

Abstract

Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT_2A receptor (5-HT_2AR) and 5-HT_2C receptor (5-HT_2CR), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT_2AR antagonist/inverse agonist pimavanserin, selective 5-HT_2CR agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Keywords: 5-HT(2A) receptor; 5-HT(2C) receptor; Cocaine; Drug-seeking behavior; Lorcaserin; Pimavanserin.

Fig. 1.. Acute administration of pimavanserin plus lorcaserin does not suppress cocaine self-administration.

(A) Effects of acute pimavanserin (0.3, 1, 3 mg/ kg) on total cocaine infusions (mean ± SEM) are presented (n.s. vs. control). (B) Effects of acute lorcaserin (0.25, 0.5, 1 mg/kg) to alter total cocaine infusions (mean ± SEM) are presented. Lorcaserin (1.0 mg/kg) suppresses cocaine intake relative to control (*p < 0.05 vs. control; left panel); this effect is prevented by the selective 5-HT_2CR antagonist SB242084 (right panel). (C) Effects of subthreshold doses of pimavanserin (PIM; 0.5 mg/kg) plus lorcaserin (LOR; 0.5 mg/kg) on total cocaine infusions (mean ± SEM) are presented (n.s. vs. control).

Fig. 2.. Acute and repeated administration of pimavanserin plus lorcaserin suppress cocaine-seeking behavior during abstinence.

(A) Effects of acute and repeated pimavanserin (3 mg/kg) on cue-reinforced or inactive lever presses (mean ± SEM) on FA 10 are presented (*p < 0.05 vs. control). (B) Effects of acute and repeated lorcaserin (1 mg/kg) on cue-reinforced or inactive lever presses (mean ± SEM) are presented (*p < 0.05 vs. control cue-reinforced; ^p < 0.05 vs. control inactive). (C) Effects of acute and repeated combination of pimavanserin (0.5 mg/kg) plus lorcaserin (0.5 mg/kg) on cue-reinforced or inactive lever presses (mean ± SEM) on FA 10 are presented (*p < 0.05 vs. control cue-reinforced).