Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism

Abstract

Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A_2A antagonists can reverse the effects of DA D₂ antagonists on effort-related choice. However, less is known about the effects of adenosine A₁ antagonists. Despite anatomical data showing that A₁ and D₁ receptors are co-localized on the same striatal neurons, it is uncertain if A₁ antagonists can reverse the effects DA D₁ antagonists. The present work systematically compared the ability of adenosine A₁ and A_2A receptor antagonists to reverse the effects of DA D₁ and D₂ antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D₁ antagonist ecopipam (0.2 mg/kg i.p.) and the D₂ antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A₁ receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D₁ or D₂ antagonist. In contrast, the adenosine A_2A antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of ecopipam. Adenosine A_2A and DA D₂ receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders. © 2010 IBRO.