Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A2A receptors during extinction training in rats

Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors. These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking. Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks. Following a 1-week withdrawal, the direct effects of adenosine receptor modulation were tested by administering the adenosine A(1) receptor agonist, N-6-cyclopentyladenosine (CPA, 0.03 and 0.1 mg/kg), the adenosine A(2A) agonist, CGS 21680 (0.03 and 0.1 mg/kg), the presynaptic adenosine A(2A) receptor antagonist, SCH 442416 (0.3, 1, and 3 mg/kg), or vehicle prior to each of six daily extinction sessions. The persistent effects of adenosine receptor modulation during extinction training were subsequently tested on reinstatement to cocaine seeking induced by cues, cocaine, and the dopamine D-2 receptor agonist, quinpirole. All doses of CPA and CGS 21680 impaired initial extinction responding; however, only CPA treatment during extinction produced persistent impairment in subsequent cocaine- and quinpirole-induced seeking. Dissociating CPA treatment from extinction did not alter extinction responding or subsequent reinstatement. Administration of SCH 442416 had no direct effects on extinction responding but produced dose-dependent persistent impairment of cocaine- and quinpirole-induced seeking. These findings demonstrate that adenosine A(1) or A(2A) receptor stimulation directly impair extinction responding. Interestingly, adenosine A(1) receptor stimulation or presynaptic adenosine A(2A) receptor blockade during extinction produces lasting changes in relapse susceptibility.