The dopamine D3 receptor partial agonist CJB 090 inhibits the discriminative stimulus but not the reinforcing or priming effects of cocaine in squirrel monkeys

Abstract

Rationale: Dopamine D3 receptor mechanisms have been implicated in the abuse-related behavioral effects of cocaine.

Objectives: The purpose of this study was to investigate the effects of the D3 receptor partial agonist CJB 090 on the discriminative stimulus, reinforcing and priming effects of cocaine in squirrel monkeys. Complementary studies were conducted to compare CJB 090's effects on food-maintained behavior and species-typical unconditioned behaviors.

Methods: Monkeys were trained to: (1) discriminate cocaine from saline using a two-lever choice procedure, (2) self-administer cocaine on a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection, or (3) self-administer food on a comparable second-order schedule of food delivery. A final group of monkeys served in quantitative observational studies of unconditioned behaviors.

Results: In cocaine discrimination studies, pretreatment with CJB 090 significantly attenuated cocaine's discriminative stimulus effects. CJB 090 also significantly attenuated the partial cocaine-like stimulus effects of the preferential D3 receptor agonist PD 128907 but not the preferential D2 receptor agonist sumanirole. CJB 090 did not attenuate either self-administration of cocaine or cocaine-induced reinstatement of extinguished drug-seeking at a dose that reduced responding maintained by food. CJB 090 did not induce scratching or biting (species-typical effects of D2/3 receptor agonists) or catalepsy (typical effect of D2/3 receptor antagonists).

Conclusions: The results provide no evidence that CJB 090 reduced either the reinforcing or priming effects of cocaine but do suggest that CJB 090, acting via a D3 receptor mechanism, antagonized the discriminative stimulus effects of cocaine at a dose that did not induce adverse side effects.

Figure 1

Percentage of responses on the cocaine lever (top) and response rate (bottom) as a function of cumulative dosing of cocaine or CJB 090 in squirrel monkeys trained to discriminate cocaine from vehicle. Points are means ± SEM (n=6). Points above V show effects of vehicle.

Figure 2

Effects of A) cocaine, B) PD 128907, and C) sumanirole after 5 min i.m. pretreatment with vehicle or CJB 090 (17.8 mg/kg) in monkeys trained to discriminate cocaine from vehicle. Points are means ± SEM (n=5 or 6). * p<0.05 comparing percentage of cocaine lever responding after vehicle treatment, Bonferroni t-test.

Figure 3

Effects of repeated pretreatment with CJB 090 (17.8 mg/kg) or vehicle on response rate under the second-order schedule of i.v. cocaine injections. Right panel: Comparison of response rates after pretreatments during sequential components of cocaine (0.10 or 0.30 mg/kg/inj) self-administration. Data are means ± SEM (n=5).

Figure 4

Comparison of mean response rates across 5 days of pretreatment with CJB 090 (17.8 mg/kg) or vehicle during the availability of A) 0.1 mg/kg/inj of cocaine (n=5) or B) sucrose pellets (n=4). * p<0.05 comparing mean response rates on the corresponding day after vehicle treatment. ⁺ p<0.05 comparing mean response rates after CJB 090 treatment on day 1.

Figure 5

Effects of CJB 090 on reinstatement of drug-seeking induced by cocaine priming and the presentation of a cocaine cue. Point above SA: response rate during cocaine SA. Point above EXT: response rate during extinction of cocaine-seeking behavior. Right panel: Comparison of response rates after pretreatments during sequential components after priming with 0.30 or 1.0 mg/kg cocaine. * p<0.05 comparing response rates for the corresponding component after vehicle treatment (n=6), Bonferroni t-test.