Effects of adenosine A2A receptor stimulation on cocaine-seeking behavior in rats

Dopamine (DA) receptor stimulation in the nucleus accumbens (NAc) plays an important role in regulating cocaine-seeking behavior. Adenosine receptors antagonize the effects of DA receptor stimulation on intracellular signaling, neuronal output, and behavior. The goal of the present study is to determine the effects of adenosine A(2A) receptor stimulation on reinstatement of cocaine-seeking behavior in rats. Rats were trained to lever press for cocaine in daily self-administration sessions on a fixed-ratio 1 schedule for 3 weeks. After 1 week of abstinence, lever pressing was extinguished in six daily extinction sessions. We subsequently assessed the effects of the adenosine A(2A) receptor agonist, CGS 21680, on cocaine-, quinpirole (D-2 agonist)-, and cue-induced reinstatement to cocaine seeking. We also assessed the effects of CGS 21680 on sucrose seeking in rats extinguished from sucrose self-administration. Pretreatment of CGS 21680 dose-dependently blunted cocaine-induced reinstatement (15 mg/kg, i.p.). Pretreatment with CGS 21680 (0.03 mg/kg, i.p.) also attenuated quinpirole- and cue-induced reinstatement. A minimally effective dose of CGS 21680 failed to alter cocaine-induced locomotor activity or sucrose seeking. Stimulation of adenosine A(2A) receptors antagonizes reinstatement of cocaine seeking elicited by cocaine, DA D-2-receptor stimulation, and cocaine-conditioned cues. These findings suggest that adenosine A(2A) receptor stimulation may oppose DA D-2 receptor signaling in the NAc that mediates cocaine relapse.