Adenosine A_2A receptor antagonism reverses the effects of dopamine receptor antagonism on instrumental output and effort-related choice in the rat: Implications for studies of psychomotor slowing

Rationale: Organisms frequently make effort-related decisions based upon assessments of motivational value and response costs. Energy-related dysfunctions such as psychomotor slowing and apathy are critically involved in some clinical syndromes. Dopamine (DA), particularly in the nucleus accumbens, regulates effort-related processes. Dopamine antagonism and accumbens dopamine depletions cause rats performing on choice tasks to reallocate their behavior away from food-reinforced tasks that have high response requirements. Objective: There is evidence of a functional interaction between DA and adenosine A _2A receptors in the neostriatum and nucleus accumbens. The present experiments were conducted to determine if adenosine A_2A receptor antagonism could reverse the effects of dopamine receptor antagonism on instrumental behavior and effort-related choice. Materials and methods: The adenosine A_2A receptor antagonist MSX-3 was investigated for its ability to reverse the effects of the dopamine receptor antagonist haloperidol (0.1 mg/kg) on fixed ratio 5 instrumental lever-pressing and on response allocation using a concurrent lever-pressing/chow-feeding choice task. Results: Haloperidol significantly suppressed fixed ratio 5 responding, and with rats responding on the concurrent choice task, it altered choice behavior, significantly reducing lever-pressing for food and increasing chow intake. Injections of MSX-3 (0.5-2.0 mg/kg) produced a dose-related attenuation of the effects of 0.1 mg/kg haloperidol on both tasks. The high dose of MSX-3, when administered in the absence of haloperidol, did not significantly affect responding on either task. Conclusions: Adenosine and dopamine systems interact to regulate instrumental behavior and effort-related processes, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anergia.