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BEHAVIORAL PHARMACOLOGY

Involvement of Adenosine A₁ and A_2A Receptors in the Adenosinergic Modulation of the Discriminative-Stimulus Effects of Cocaine and Methamphetamine in Rats

Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland (Z.J., S.F., P.N.S., M.S., L.A.P., J.L.H., P.M., S.R.G.); Department of Pharmacology, Medical School, University of Athens, Goudi Athens, Greece (K.A.); and Pharmaceutical Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany (J.H.)

Adenosine, by acting on adenosine A₁ and A_2A receptors, is known to antagonistically modulate dopaminergic neurotransmission. We have recently reported that nonselective adenosine receptor antagonists (caffeine and 3,7-dimethyl-1-propargylxanthine) can partially substitute for the discriminative-stimulus effects of methamphetamine. In the present study, by using more selective compounds, we investigated the involvement of A₁ and A_2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of both cocaine and methamphetamine. The effects of the A₁ receptor agonist N⁶-cyclopentyladenosine (CPA; 0.01–0.1 mg/kg) and antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.3–23.7 mg/kg) and the A_2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; 0.03–0.18 mg/kg) and antagonist 3-(3-hydroxypropyl)-8-(3-methoxystyryl)-7-methyl-1-propargylxanthin phosphate disodium salt (MSX-3; 1–56 mg/kg) were evaluated in rats trained to discriminate either 1 mg/kg methamphetamine or 10 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. The A₁ and A_2A receptor antagonists (CPT and MSX-3) both produced high levels of drug-lever selection when substituted for either methamphetamine or cocaine and significantly shifted dose-response curves of both psychostimulants to the left. Unexpectedly, the A_2A receptor agonist CGS 21680 also produced drug-appropriate responding (although at lower levels) when substituted for the cocaine-training stimulus, and both CGS 21680 and the A₁ receptor agonist CPA significantly shifted the cocaine dose-response curve to the left. In contrast, both agonists did not produce significant levels of drug-lever selection when substituted for the methamphetamine-training stimulus and failed to shift the methamphetamine dose-response curve. Therefore, adenosine A₁ and A_2A receptors appear to play important but differential roles in the modulation of the discriminative-stimulus effects of methamphetamine and cocaine.

Address correspondence to: Dr. Steven R. Goldberg, Preclinical Pharmacology Section, NIDA, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: sgoldber{at}intra.nida.nih.gov