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 A2AR KO mice

• Low doses of theophylline and A2A receptor antagonists induce exploration in mice.
• These pharmacological agents can reverse antipsychotic-induce psychomotor slowing.
• A1 antagonists do not have the same therapeutic and stimulant properties.
• Behavioral responses parallel striatal neural activity as shown by cFos expression.
• A2ARKO mice are resistant to haloperidol-induced reduction of activity and running.

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 A2A 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 A2A antagonists were expected to be more selective for reversing the effects of the D2 antagonist haloperidol, A2A receptor knockout (A2ARKO) mice were also assessed. CD1 and A2ARKO male mice were tested in an open field and in a running wheel. Only the A1/A2A receptor antagonist theophylline (5.0–15.0 mg/kg) and the A2A antagonist MSX-3 (2.0 mg/kg) increased spontaneous locomotion and rearing. Co-administration of theophylline (10.0–15.0 mg/kg), and MSX-3 (1.0–3.0 mg/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. A2ARKO mice were resistant to the behavioral effects of haloperidol at intermediate doses (0.1 mg/kg) in the open field and in the running wheel. A2A receptors are important for regulating behavioral activation, and interact with D2 receptors in striatal areas to regulate neural processes involved in exploratory activity.