Effects of pramipexole on the reinforcing effectiveness of stimuli that were previously paired with cocaine reinforcement in rats

Abstract

Rationale Dopamine D2-like agonists maintain responding when substituted for cocaine in laboratory animals. However, these effects appear to be mediated by an interaction with stimuli that were previously paired with cocaine reinforcement (CS). Objectives To evaluate the extent to which the pramipexole-maintained and -induced responding are influenced by cocaine-paired stimuli. Methods Rats were trained to nosepoke for cocaine under fixed ratio 1 (FR1) or progressive ratio (PR) schedules of reinforcement. In FR1-trained rats, pramipexole was substituted for cocaine with injections either paired with CSs, or delivered in their absence. The capacity of experimenter-administered pramipexole to induce FR1 and PR responding for CS presentation was evaluated. The effects of altering stimulus conditions, as well as pretreatments with D2- (L-741,626) and D3-preferring (PG01037) antagonists on pramipexole-induced PR responding were also evaluated. Results When substituted for cocaine, pramipexole maintained responding at high rates when injections were paired with CSs, but low rates when CSs were omitted. Similarly, experimenter-administered pramipexole induced dose-dependent increases in FR1 or PR responding, with high rates of responding observed when the CS was presented, and low rates of responding when CS presentation was omitted. D2 and D3 antagonists differentially affected pramipexole-induced PR responding, with L-741,626 and PG01037 producing rightward, and downward shifts in the dose-response curve for CS-maintained responding, respectively. Conclusions These data indicate that pramipexole is capable of enhancing the reinforcing effectiveness of conditioned stimuli, and raise the possibility that similar mechanisms are responsible for the increased occurrence of impulse control disorders in patients being treated with pramipexole.

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development

“…Although D3R full agonists can reverse D3R dysregulation, they also have abuse potential (Collins et al, 2012b) and may impair “impulse control” (Ahlskog, 2011; Dagher and Robbins, 2009; Fenu et al, 2009). We reviewed findings that suggest that D3R partial agonists are promising candidates for capturing D3R agonists’ therapeutic effects with a more suitable side-effect profile.…”

“…SA of D3/D2R agonists when substituted for cocaine may be driven in part by the reinforcing or incentive motivational effects of drug-conditioned stimuli. For instance, intake of D3/D2R agonists is higher during substitution tests when cocaine-conditioned stimuli (CS+) are presented response-contingently compared to when the CS+ is omitted (Collins et al, 2012b; Collins and Woods, 2009). This effect is antagonized by a D3/D2R antagonist and to a lesser degree by a D3R-selective antagonist.…”

Dopamine D3 Receptors in the Basolateral Amygdala and the Lateral Habenula Modulate Cue-Induced Reinstatement of Nicotine Seeking

“…At least 2 days at extinction baseline separated each test with L741626. These doses were selected based on a previously published report (Collins et al, 2012).…”

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans

“…For example, in rodents, acute administration of pramipexole decreases self-administration of a high dose of cocaine, presumably by shifting the dose response curve leftward (Caine et al, 1997). Acute pramipexole has also been shown to increases the reinforcing efficacy of conditioned stimuli previously paired with cocaine (Collins et al, 2012). Yet, the D3-preferring partial agonist, BP 897, blocked cue-induced cocaine-seeking in a rodent model of relapse (Pilla et al, 1999).…”