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

Abstract

Rationale: Dopamine D(2)-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 pramipexole-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 D(2)- (L: -741,626) and D(3)-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. D(2) and D(3) 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.

Figure 1

Top Panel) Responding maintained by pramipexole (0.01, 0.032, 0.1, or 0.32 mg/kg/inj), or saline under an FR1TO5.5-sec:FR1TO5.5-sec schedule of reinforcement during a 7-day substitution from cocaine (0.56 mg/kg/inj). Data represent the mean (± S.E.M.), n=6, number of nosepoke responses that resulted in cocaine injections paired with stimuli, or pramipexole injections paired with the stimuli that were previously paired with cocaine delivery (CS) during daily 90 min sessions. #, p<0.05; *, p<0.05; **, p<0.01; ***,p<0.001; +++, p<0.001. Significant differences in nosepoke responding maintained by pramipexole [0.01(#), 0.1(*), or 0.32(+) mg/kg/inj] and saline were determined by two-way ANOVA with post-hoc Bonferroni tests. Middle Panel) Dose-response curve for pramipexole-maintained responding. Data represent the mean (± S.E.M.), n=6, number of reinforced responses made during the 7th day of substitution from cocaine (0.56 mg/kg/inj). **, p<0.01; ***,p<0.001. Significant differences in nosepoke responding from saline were determined by one-way ANOVA with post-hoc Newman-Keuls tests. Bottom Panel) Responding maintained by 0.1 mg/kg/inj pramipexole during a 13-day substitution from 0.56 mg/kg/inj cocaine. Filled symbols represent nosepoke responses (filled circles) that resulted in the delivery of pramipexole in conjunction with presentation of the CS and lever presses (filled squares) that resulted in presentation of the NvlS. Open symbols represent nosepoke responses (open circles) that resulted in the delivery of pramipexole and an un-signaled 5.5-sec TO, and lever presses (open squares) that resulted in an un-signaled 5.5-sec TO. **, p<0.01; ***,p<0.001; ++, p<0.01; +++,p<0.001. Significant differences in nosepoke (*) or lever (+) responding as compared with nosepoke or lever responding during day 3 of the substitution were determined by one-way ANOVA with post-hoc Newman-Keuls tests.

Figure 2

Effects of pretreatments with saline or pramipexole (0.032, 0.1, 0.32, and 1.0 mg/kg; SC) on nosepoke responding (gray circles) for the presentation of stimuli that were previously paired with 0.56 mg/kg/inj cocaine reinforcement (CS), and lever pressing (gray squares) for a set of novel stimuli (NvlS). The effects of 0.32 mg/kg dose of pramipexole on nosepoke responses that failed to produce the CS (open circles), and lever presses failed to produce the NvlS (open squares) are also shown. Data represent the mean (± S.E.M.), n=6, number of responses that resulted in ratio completion during the final session for each pretreatment dose. *, p<0.05; **, p<0.01. Significant increases in responding for CS or NvlS presentation were determined by one-way repeated measures ANOVA with post-hoc Newman-Keuls tests. +, p<0.05. Significant differences between the amounts of responding observed during sessions in which nosepoke and lever responding resulted in the presentation of the CS and NvlS, and sessions in which CS and NvlS presentations were omitted were determined by two-tailed t-tests.

Figure 3

Effects of pretreatment with saline or pramipexole (0.032, 0.1, 0.32, and 1.0 mg/kg; SC) prior to sessions in which nosepoke responding was reinforced under a progressive ratio (PR) schedule of reinforcement by presentation of the previously cocaine-paired stimuli (CS). Black symbols represent the mean ± SEM, n=6, of each endpoint during the last day of PR responding for 0.56 mg/kg/inj cocaine for each endpoint. The total number of CS-reinforced nosepoke responses (gray circles) and inactive lever responses (open squares) are shown on the left y-axis, and represent the mean ± SEM, n=6, number of responses emitted during the final session for each pretreatment dose. The final ratio completed (open triangles) are shown on the right y-axis, and represent the mean ± SEM, n=6, value of the final ratio that was completed prior to session termination due to the 45-min limited hold, or 240-min session limit, whichever came first. +++,p<0.001; ***,p<0.001. Significant differences in each endpoint compared to saline pretreatment (*) or 0.56 mg/kg/inj cocaine-reinforced responding (+) were determined by one-way repeated measures ANOVA with post-hoc Newman-Keuls tests.

Figure 4

Effects of pretreatment with 0.32 mg/kg pramipexole on PR responding under four distinct stimulus conditions: CS^D-CS^R -- both the CS^D (yellow light inside the nosepoke aperture) and CS^R (green LED + house light) were scheduled, No Stim -- neither the CS^D, nor the CS^R were scheduled, CS^D -- only the CS^D was scheduled, and CS^R -- only the CS^R was scheduled. Data represent the mean ± SEM, n=6, for each endpoint during the final session that each condition was in place. Total nosepoke responses (black bars) are shown on the left y-axis and represent the mean ± SEM, n=6, number of nosepoke responses that resulted in ratio completion. The final ratio completed (gray bars) is shown on the right y-axis and represent the mean ± SEM, n=6, value of the final ratio that was completed prior to session termination due to the 45-min limited hold, or 240-min session limit, whichever came first. The session duration (open bars) is shown on the right y-axis and represents the mean ± SEM, n=6, time in minutes that elapsed prior to session termination due to the 45-min limited hold, or 240-min session limit, whichever came first. **,p<0.01; ***,p<0.001; ++,p<0.01; +++,p<0.001. Significant differences from CS^R-CS^D (*) and No Stim (+) as determined by one-way repeated measures ANOVA with post-hoc Newman-Keuls tests.

Figure 5

Effects of the pretreatment with the D2-preferring antagonist L-741,626 (1.0 mg/kg; SC), or the D3-selective antagonist PG01037 (32.0 mg/kg; SC) on the response-inducing effects of pramipexole (0.1, 0.32, 1.0, and 3.2 mg/kg; SC) or saline. Data represent the final ratio completed during sessions in which nosepoke responding was reinforced under a progressive ratio (PR) schedule of reinforcement by presentation of the stimuli that were previously paired with 0.56 mg/kg/inj cocaine reinforcement (CS). Saline data (gray circles) represent the mean ± SEM, n=6, of final ratios completed for sessions in which saline was administered 30-min prior to the administration of pramipexole (or saline). The effects of 1.0 ,g/kg L-741,626 (open inverted triangles) and 32.0 mg/kg PG01037 (open diamonds) represent the mean ± SEM, n=6, final ratio completed during sessions in which antagonists were administered 30-min prior to the administration of pramipexole (or saline). *,p<0.05; ***,p<0.001. Significant differences in the final ratio completed during sessions that were preceded by antagonist pretreatment as compared to those that were preceded by saline were determined by two-way repeated measures ANOVA with post-hoc Bonferroni tests.