On the role of A(2A) and D(2) receptors in control of cocaine and food-seeking behaviors in rats

Recent studies indicate that adenosine may influence dopamine neurotransmission via A(2A) receptors which antagonistically interact with D(2) receptor-mediated signaling in the brain. We examined the effects of selective A(2A) receptor ligands such as the agonist CGS 21680 and the antagonists KW 6002 or SCH 58261 as well as of the D(2)-like receptor antagonist raclopride on reinstatement of cocaine seeking induced by cocaine, the cocaine-conditioned cue, or the D(2)-like receptor agonist quinpirole in rats. For comparison, effects of the A(2A) receptor ligands on reinstatement of food seeking were also studied. CGS 21680 significantly attenuated the reinstatement of cocaine (ip) seeking, and even more potently it reduced quinpirole (ip) or the cue-induced relapse of cocaine seeking as well as cue-induced food seeking. A potent reduction toward the cocaine-, quinpirole-, or cue-induced reinstatement of cocaine seeking was seen with raclopride. Pretreatment with KW 6002 or SCH 58261 reinstated cocaine seeking, and such increases were blocked by raclopride. In the higher doses, KW 6002 or SCH 58261 evoked food-seeking. In combination with the subthreshold dose of cocaine (2.5 mg/kg) or with the cue, low doses of KW 6002 but not SCH 58261 reinstated cocaine-seeking behavior, while none of the A(2A) receptor antagonists affected the cue-induced food-seeking behavior. The results indicate that A(2A) activation and D(2)-like receptor blockade counteract cocaine and food relapse. It is proposed that A(2A) receptor- and D(2) receptor-mediated adenosine and dopamine signaling antagonistically interact in the striato-pallidal GABA neurons to regulate cocaine and food-seeking behavior.