Effect of subtype-selective adenosine receptor antagonists on basal or haloperidol-regulated striatal function: Studies of exploratory locomotion and c-Fos immunoreactivity in outbred and A_2AR KO mice

Behavioral activation is regulated by dopamine (DA) in striatal areas. At low doses, while typical antipsychotic drugs produce psychomotor slowing, psychostimulants promote exploration. Minor stimulants such as caffeine, which act as adenosine receptor antagonists, can also potentiate behavioral activation. Striatal areas are rich in adenosine and DA receptors, and adenosine A_2A receptors are mainly expressed in the striatum where they are co-localized with DA D₂ receptors. Adenosine antagonists with different receptor-selectivity profiles were used to study spontaneous or haloperidol-impaired exploration and c-Fos expression in different striatal areas. Because A_2A antagonists were expected to be more selective for reversing the effects of the D₂ antagonist haloperidol, A_2A receptor knockout (A_2ARKO) mice were also assessed. CD1 and A_2ARKO male mice were tested in an open field and in a running wheel. Only the A₁/A_2A receptor antagonist theophylline (5.0-15.0mg/kg) and the A_2A antagonist MSX-3 (2.0mg/kg) increased spontaneous locomotion and rearing. Co-administration of theophylline (10.0-15.0mg/kg), and MSX-3 (1.0-3.0mg/kg) reversed haloperidol-induced suppression of locomotion. The A₁ antagonist CPT was only marginally effective in reversing the effects of haloperidol. Although adenosine antagonists did not affect c-Fos expression on their own, theophylline and MSX-3, but not CPT, attenuated haloperidol induction of c-Fos expression. A_2ARKO mice were resistant to the behavioral effects of haloperidol at intermediate doses (0.1mg/kg) in the open field and in the running wheel. A_2A receptors are important for regulating behavioral activation, and interact with D₂ receptors in striatal areas to regulate neural processes involved in exploratory activity.