Differential actions of adenosine A1 and A2A antagonists on the effort-related effects of dopamine D2 antagonism

Adenosine and dopamine receptors in striatal areas interact to regulate a number of different functions, including aspects of motor control and motivation. Recent studies indicate that adenosine A2A receptor antagonists can reverse the effects of dopamine (DA) D2 antagonists on instrumental tasks that provide measures of effort-related choice behavior. The present experiments compared the ability of the adenosine A2A antagonist KW6002, the nonselective adenosine antagonist caffeine, and the adenosine A1 receptor selective antagonist DPCPX, to reverse the behavioral effects of the DA D2 antagonist haloperidol. For these studies, a concurrent choice procedure was used in which rats could select between lever pressing on a fixed ratio 5 schedule for a preferred food or approaching and consuming a less preferred lab chow that was concurrently available in the chamber. Under baseline or control conditions, rats show a strong preference for lever pressing, and eat little of the chow; IP injections of 0.1 mg/kg haloperidol significantly reduced lever pressing and substantially increased chow intake. The adenosine A2A antagonist KW6002 (0.125–0.5 mg/kg IP) and the nonselective adenosine antagonist caffeine (5.0–20.0 mg/kg) significantly reversed the effects of haloperidol. However, the adenosine A1 antagonist DPCPX (0.1875–0.75 mg/kg IP) failed to reverse the effects of the D2 antagonist. The rank order of effect sizes in the reversal experiments was KW6002 > caffeine > DPCPX. None of these drugs had any effect on behavior when they were injected in the absence of haloperidol. These results indicate that the ability of an adenosine antagonist to reverse the effort-related effects of a D2 antagonist depends upon the subtype of adenosine receptor being blocked. Together with other recent results, these experiments indicate that there is a specific interaction between DA D2 and adenosine A2A receptors, which could be related to the co-localization of these receptors on the same population of striatal neurons.