Interactions between adenosine and dopamine receptor antagonists with different selectivity profiles: Effects on locomotor activity

Forebrain dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation. Adenosine A2A antagonists reverse many of the behavioral effects of DA antagonists, and A2A receptors are co-localized with D2 receptors on striatal medium spiny neurons. The present work was undertaken to determine if the ability of an A2A antagonist, a non-selective adenosine antagonist, or an A1 antagonist to reverse the locomotor effects of DA blockade in rats differed depending upon whether D1 or D2 family receptors were being antagonized. The adenosine antagonists MSX-3, caffeine, DPCPX and CPT were studied for their ability to reverse the locomotor suppression induced by the D1 antagonist SCH 39166 (ecopipam) and the D2 antagonist eticlopride. The D1 and D2 antagonists suppressed locomotion in all experiments. The adenosine A2A receptor antagonist MSX-3 (0.5–2.0 mg/kg IP) significantly reversed the suppression of locomotion induced by eticlopride. The non-selective adenosine antagonist caffeine (5.0–20.0 mg/kg IP) also reversed the effect of eticlopride, though the effect was not as robust as that seen with MSX-3. The adenosine A1 antagonists DPCPX (0.375–1.5 mg/kg) and CPT (3.0–12.0 mg/kg IP) were unable to reverse the locomotor impairment elicited by eticlopride. Furthermore, the attenuation of locomotion induced by the D1 antagonist could only be reversed by the highest dose of MSX-3, but not by caffeine, DPCPX or CPT. DA and adenosine receptor antagonists interact in the regulation of locomotor activation, but the nature of this interaction appears to depend upon the receptor selectivity profiles of the specific drugs being tested.