Adenosinergic modulation of the discriminative-stimulus effects of methamphetamine in rats

Abstract

Rationale. A₁ and A_2A adenosine receptors are co-localized with dopamine D₁ and D₂ receptors, respectively, and their stimulation attenuates dopaminergic functioning.

Objective. To test whether adenosine antagonists with different selectivities for A₁ and A_2A receptors mimic the discriminative-stimulus effects of dopamine releaser methamphetamine.

Methods. Effects of the A₁ antagonist DPCPX, the preferential A_2A antagonist DMPX and the non-selective adenosine antagonist caffeine were evaluated in Sprague-Dawley rats trained to discriminate 1.0 mg/kg, IP, methamphetamine from saline under a fixed-ratio 10 schedule of food presentation.

Results. The A₁ antagonist DPCPX (1.0–10.0 mg/kg) failed to substitute for methamphetamine. However, 5.6 mg/kg DPCPX shifted the methamphetamine dose-response curve to the left. The A_2A antagonist DMPX (1.8–18.0 mg/kg) produced about 70% methamphetamine-appropriate responding and the non-selective antagonist caffeine (3.0–56.0 mg/kg) about 50% methamphetamine-appropriate responding at the highest tested doses. Both DMPX (5.6 mg/kg) and caffeine (30.0 mg/kg) shifted the methamphetamine dose-response curve to the left. Methamphetamine-like effects of DMPX were blocked fully by the D₂ antagonist spiperone (0.18 mg/kg) and partially by the D₁ antagonist SCH-23390 (0.018 mg/kg).

Conclusions. Antagonism at A_2A adenosine receptors directly mimics the discriminative-stimulus effects of methamphetamine through the interaction with dopamine receptors. Antagonism at A₁ adenosine receptors potentiates effects of lower methamphetamine doses and thus plays a rather indirect, modulatory role.