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Ethanol Operant Self‐Administration in Rats Is Regulated by Adenosine A 2 Receptors
Author(s) -
Arolfo Maria Pia,
Yao Lina,
Gordon Adrienne S.,
Diamond Ivan,
Janak Patricia H.
Publication year - 2004
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1097/01.alc.0000139821.38167.20
Subject(s) - adenosine , eticlopride , endocrinology , medicine , nucleus accumbens , adenosine receptor , antagonist , adenosine a2a receptor , adenosine a1 receptor , protein kinase a , chemistry , receptor , dopamine receptor d2 , biology , pharmacology , dopamine , agonist , sch 23390 , biochemistry , kinase
Background: Recent findings suggest that adenosine is involved in the neural and behavioral effects of ethanol (EtOH). Studies in neural cell culture show that EtOH, via activation of adenosine A 2 receptors, triggers cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling and CRE (cAMP regulatory element)‐mediated gene expression and that this effect is blocked by inhibiting G‐protein βγ subunits. Recently, we reported that expression of a βγ inhibitor in the nucleus accumbens (NAc) reduces EtOH drinking in rats. The NAc expresses high levels of the adenosine A 2A receptor in GABAergic medium spiny neurons. If the reinforcing effects of EtOH are mediated through an A 2 activation of cAMP/PKA signaling via βγ, then A 2 receptor blockade should attenuate EtOH consumption. Here we tested this hypothesis. Because adenosine A 2 and dopamine D 2 receptors are coexpressed in neurons of the NAc, we compared the effects of A 2 blockade with those of D 2 receptor blockade. Methods: Male Long‐Evans rats were trained to self‐administer 10% EtOH in daily 30‐min sessions with an active and an inactive lever. Separate groups of rats were given the D 2 antagonist eticlopride (0.005, 0.007, and 0.01 mg/kg), the A 2 antagonist 3,7‐dimethyl‐1‐propargylxanthine (DMPX; 1, 3, 5, 7, 10, and 20 mg/kg), and the A 1 antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX; 0.125, 0.25, and 0.5 mg/kg) by systemic injection. Results: Eticlopride dose‐dependently reduced EtOH drinking. DMPX showed a bimodal effect: 10 and 20 mg/kg decreased, but 1 mg/kg increased, EtOH consumption. DPCPX was without effect. Conclusions: In support of our hypothesis, the A 2 antagonist DMPX attenuated EtOH self‐administration. Low doses of the A 2 antagonist enhanced EtOH drinking, consistent with the possibility that rats increase EtOH self‐administration to overcome partial A 2 blockade. The D 2 antagonist eticlopride also decreased EtOH self‐administration. These data provide the first evidence that pharmacological modulation of adenosine A 2 receptors can regulate EtOH consumption in rats.