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

Rationale: A(1) and A(2A) adenosine receptors are co-localized with dopamine D-1 and D-2 receptors, respectively, and their stimulation attenuates dopaminergic functioning. Objective: To test whether adenosine antagonists with different selectivities for A(1) and A(2A) receptors mimic the discriminative-stimulus effects of dopamine releaser methamphetamine. Methods: Effects of the A(1) 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, meth amphetamine from saline under a fixed-ratio 10 schedule of food presentation. Results: The A(1) 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 D-2 antagonist spiperone (0.18 mg/kg) and partially by the D-1 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 A(1) adenosine receptors potentiates effects of lower methamphetamine doses and thus plays a rather indirect, modulatory role.