Role of adenosine A2 receptors in brain stimulation reward under baseline conditions and during cocaine withdrawal in rats

Abstract

The present experiments tested the hypothesis that adenosine A2 receptors are involved in central reward function. Adenosine receptor agonists or antagonists were administered to animals that had been trained to self-stimulate in a rate-free brain stimulation reward (BSR) task that provides current thresholds as a measure of reward. The adenosine A(2A) receptor-selective agonists 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680) (0.1-1.0 mg/kg) and 2-[(2-aminoethylamino)carbonylethyl phenylethylamino]-5'-N-ethylcarboxamido adenosine (APEC) (0.003-0.03 mg/kg) elevated reward thresholds without increasing response latencies, a measure of performance. Specifically, CGS 21680 had no effect on response latency, whereas APEC shortened latencies. Bilateral infusion of CGS 21680 (3, 10, and 30 ng/side), directly into the nucleus accumbens, elevated thresholds but shortened latencies. The highly selective A(2A) antagonist 8-(3-chlorostyryl)caffeine (0.01-10.0 mg/kg) and the A2-preferring antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (0.3-10.0 mg/kg) did not alter thresholds or latencies, but DMPX (1.0, 10.0 mg/kg) blocked the threshold-elevating effect of APEC (0.03 mg/kg). In another study, repeated administration of cocaine (eight cocaine injections of 15 mg/kg, i.p., administered over 9 hr) produced elevations in thresholds at 4, 8, and 12 hr after cocaine. DMPX (3 and 10 mg/kg), administered before both the 8 and 12 hr post-cocaine self-stimulation tests, reversed the threshold elevation produced by cocaine withdrawal. These results indicate that stimulating adenosine A(2A) receptors diminishes BSR without producing performance deficits, whereas blocking adenosine receptors reverses the reward impairment produced by cocaine withdrawal or by an A(2A) agonist. These findings indicate that adenosine, via A(2A) receptors, may inhibit central reward processes, particularly during the neuroadaptations associated with chronic drug-induced neuronal activation.

Fig. 1.

Data are presented as mean percentage change from baseline threshold or latency (see Results). Error bars represent one SEM. A, Effects of the adenosine A_2A receptor agonist CGS 21680 on brain stimulation reward thresholds and response latencies. *p < 0.05, different from vehicle. B, Effects of the adenosine A_2A receptor agonist APEC on brain stimulation reward thresholds and response latencies. *p < 0.05, different from vehicle; #p < 0.05, different from 0.003 mg/kg.

Fig. 2.

Top, Effect of CGS 21680 injected into the nucleus accumbens on brain stimulation reward thresholds (A, B) and response latencies (C, D). Error bars indicate one SEM. *p < 0.05, different from all other values obtained in the nucleus accumbens site at both time points;⁺p < 0.05, different from 0 ng/side at 0–30 and 60–90 min; #p < 0.05, different from 3 ng/side at 0–30 min; ^ap < 0.05, different from vehicle [with regard to data collapsed across the two time points (see Results)]. Bottom, Placements of nucleus accumbens injectors (E) and medial forebrain bundle– lateral hypothalamus electrodes (F). Sections are arranged in rostrocaudal order;numbers indicate distance from bregma in millimeters.Filled ovals represent injector or electrode tips. Bilateral accumbens placements are shown only on one side for clarity. The left–right placement of the unilateral electrodes alternated among animals; again, placements are shown on one side for the sake of clarity. Figures were adapted from the atlas of Pellegrino et al. (1979).

Fig. 3.

A, Effects of the adenosine A_2A receptor antagonist CSC or the A2 receptor-preferring antagonist DMPX on brain stimulation reward thresholds and response latencies. CSC was tested in two dose ranges in separate groups of rats: a low-dose range (open squares) and a high-dose range (filled squares). Data are presented as mean percentage change from baseline threshold or latency (see Results). Error bars represent one SEM.

Fig. 4.

Interaction between DMPX and APEC on brain stimulation reward thresholds and response latencies. Data are presented as mean percent change from baseline threshold (see Results). Error bars represent one SEM. *p< 0.05, different from corresponding DMPX–APEC 0 combination; #p < 0.05, different from DMPX 10–APEC 0.03; +p < 0.05, different from DMPX 1.0–APEC 0.03. For additional comparisons, see Results.

Fig. 5.

Effects of withdrawal from five consecutive regimens of intraperitoneal cocaine injections (see Results) on reward thresholds (A) and response latencies (B). Animals were tested at 4, 8, 12, and 24 hr after treatment. Error bars indicate one SEM. *p < 0.05, different from corresponding saline value.

Fig. 6.

Effects of DMPX during cocaine withdrawal at 8 hr (A) and 12 hr (B) after cocaine or saline treatment. Graphs depict effects on reward thresholds; insets depict effects on response latency. Error bars indicate one SEM. *p < 0.05, different from all other means at 8 hr time point; #p < 0.05, different from post-saline–DMPX 0 at 8 hr time point;^ap < 0.05, different corresponding group given 3 mg/kg DMPX. For additional comparisons, see Results.