Effects of adenosine A 2A receptor antagonists on cocaine-induced locomotion and cocaine seeking

Abstract

Rationale and objectives: Adenosine signaling through adenosine A 2A receptors (A 2A Rs) is known to influence cocaine-induced behaviors. These studies sought to elucidate how two A 2A R antagonists distinguished by their antagonist effects at presynaptic and postsynaptic A 2A R influence cocaine-induced locomotion and cocaine seeking. Methods: Sprague-Dawley rats were used to assess the differential effects of SCH 442416 and istradefylline that antagonize presynaptic and postsynaptic A 2A R, respectively. We evaluated the effects of these antagonists on both basal and cocaine-induced locomotion in cocaine-naïve rats and rats that received seven daily cocaine treatments. The effects of SCH 442416 or istradefylline on cocaine seeking were measured in animals extinguished from cocaine self-administration. We assessed the effects of the A 2A R antagonists to induce cocaine seeking when administered alone and their effects on cocaine seeking induced by a cocaine-priming injection. Lastly, we evaluated the effects of the antagonists on sucrose seeking in animals extinguished from sucrose self-administration. Results: Neither istradefylline nor SCH 442416 significantly altered basal locomotion. Istradefylline enhanced acute cocaine-induced locomotion but had no effect on the expression of locomotor sensitization. SCH 44216 had no effect on acute cocaine-induced locomotion but inhibited the expression of locomotor sensitization. Istradefylline was sufficient to induce cocaine seeking and augmented both cocaine-induced seeking and sucrose seeking. SCH 442416 inhibited cocaine-induced seeking, but had no effect on sucrose seeking and did not induce cocaine seeking when administered alone. Conclusions: These findings demonstrate differential effects of two A 2A R antagonists distinguished by their effects at pre- and postsynaptic A 2A R on cocaine-induced behaviors.