Dopamine D3 and D2 receptor mechanisms in the abuse-related behavioral effects of cocaine: studies with preferential antagonists in squirrel monkeys

Abstract

Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferring antagonist PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin- 1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide HCl] and the D2-preferring antagonist L-741626 [3-[4-(4-chlorophenyl)-4- hydroxypiperidin-1-yl]methyl-1H-indole] attenuated several behavioral effects of cocaine in squirrel monkeys. Quantitative observational studies established doses of each antagonist that did not produce untoward effects, which were used in subsequent comparisons. In addition, the ability of the D3-preferring agonist PD128907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] and the D2-preferring agonist sumanirole [(R)-5,6-dihydro-5-(methylamino)-4H- imidazo[4,5,1-ij]quinolin-2(1H)-one(Z)-2-butenedioate] to reproduce cocaine's discriminative stimulus (DS) and priming effects were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine- and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine.

Fig. 1.

Effects of PG01037 and L-741626 on species-typical behaviors. Environment-directed behavior includes locomotion, object manipulation, and foraging. Catalepsy indicates static posture and muscle rigidity. ∗, p < 0.05 comparing scores after pretreatments with drug and vehicle, Bonferroni t test. Data are means ± S.E.M. (n = 4).

Fig. 2.

Percentage of responses on the cocaine lever as a function of cumulative dose of cocaine after intramuscular pretreatment with DA antagonists or their respective vehicles in squirrel monkeys trained to discriminate cocaine from vehicle. Points are means ± S.E.M. (n = 6). ∗, p < 0.05 comparing percentage of cocaine-lever responding after pretreatments with drug and vehicle, Bonferroni t test.

Fig. 3.

Percentage of responses on the cocaine lever as a function of cumulative dose of DA agonists PD128907 (A) or sumanirole (B) after intramuscular pretreatment with PG01037, L-741626, or their respective vehicles in squirrel monkeys trained to discriminate cocaine from vehicle. Points are means ± S.E.M. (n = 6). ∗, p < 0.05 comparing percentage of cocaine-lever responding after pretreatments with drug and vehicle, Bonferroni t test.

Fig. 4.

A, effects of pretreatment with DA antagonists on the overall rate of responding under the second-order schedule of intravenous cocaine self-administration as a function of cocaine dose. Data presented are averaged over the last 3 days of treatment. Points above Control indicate the rate of responding in the absence of cocaine injections. Inset, comparison of the effects of pretreatment with 100 mg/kg PG01037 versus vehicle during self-administration of cocaine (0.10 mg/kg/injection). ∗, p < 0.05 comparing response rates after pretreatments with drug and vehicle, Bonferroni t test. B, effects of pretreatment with L-741626 as a function of sequential components during the cocaine self-administration session; points above SR indicate overall session rates. Data are means ± S.E.M. (n = 4–5).

Fig. 5.

Comparison of the effects of DA antagonists on behavior maintained by self-administered cocaine (0.10 mg/kg/injection) (A) and food under a second-order schedule over a 5-day test period (B). Data are means ± S.E.M. (n = 5). ∗, p < 0.05 comparing response rates for the corresponding days after pretreatments with drug and vehicle, Bonferroni t test.

Fig. 6.

Rate of responding during reinstatement of extinguished drug-seeking behavior induced by priming with cocaine, PD128907 and sumanirole. Point above SA is the response rate during baseline cocaine self-administration; point above EXT is the response rate in the absence of cocaine and cocaine-paired stimulus. Data are means ± S.E.M. (n = 5). ∗, p < 0.05 comparing response rates induced by drug priming to response rate during extinction, Bonferroni t test.

Fig. 7.

Effects of DA antagonists on reinstatement of drug-seeking behavior induced by priming with cocaine (A), PD128907 (B), and sumanirole (C). Points above Veh indicate the effect of DA antagonists on reinstatement induced by the cocaine-paired stimulus after vehicle priming. Data are means ± S.E.M. (n = 5). ∗, p < 0.05 comparing response rates after pretreatments with drug and vehicle, Bonferroni t test.