Involvement of adenosine A2A and dopamine receptors in the locomotor and sensitizing effects of cocaine

Recent data indicate that cocaine locomotor responses may be influenced by dopamine (DA) neurotransmission and adenosine neuromodulation involving the A2A receptor (A2AR). Male Wistar rats were injected with MSX-3 (1–25 mg/kg; an antagonist of A2AR), CGS 21680 (0.05–0.2 mg/kg; an agonist of A2AR), SCH 23390 (0.125–0.25 mg/kg; an antagonist of DA D1/5R), raclopride (0.1–0.8 mg/kg; an antagonist of DA D2/3R), nafadotride (0.2–0.4 mg/kg; an antagonist of DA D3R) or 7-OH-PIPAT (0.01–1 mg/kg; an agonist of DA D3R) to verify the hypothesis that adenosine A2AR and DA receptors and their antagonistic interactions may control locomotor and sensitizing effects of cocaine. In well-habituated animals, MSX-3 (5 mg/kg) increased, while raclopride (0.4–0.8 mg/kg) decreased basal locomotor activation; the other drugs were inactive. The locomotor hyperactivation induced by acute cocaine (10 mg/kg) was enhanced by MSX-3 (5–25 mg/kg) or nafadotride (0.4 mg/kg), while CGS 21680 (0.2 mg/kg), SCH 23390 (0.25 mg/kg), raclopride (0.2–0.8 mg/kg) or 7-OH-PIPAT (0.1 mg/kg) decreased this effect of cocaine. Given during the development of sensitization (in combination with 5-daily cocaine, 10 mg/kg, injections), MSX-3 (5–25 mg/kg) increased, but CGS 21680 (0.2 mg/kg) and raclopride (0.8 mg/kg) reduced the locomotor response to a cocaine challenge dose (10 mg/kg) on day 10. When injected acutely with a cocaine challenge dose (on day 10), CGS 21680 (0.2 mg/kg), raclopride (0.2–0.8 mg/kg) or 7-OH-PIPAT (1 mg/kg) reduced, while MSX-3 (5 mg/kg) or nafadotride (0.4 mg/kg) enhanced the expression of cocaine sensitization. The present results show that adenosine A2ARs and DA D3Rs exert inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, while DA D2Rs had an opposing role in such effects. Pharmacological stimulation of adenosine A2ARs protected against both the development and expression of cocaine sensitization, which may offer a therapeutic potential of A2AR agonists in the treatment of cocaine dependence. The results suggest an antagonistic role of A2ARs in D2R-mediated cocaine actions based at least in part on the existence of A2A/D2 heteromeric receptor complexes.