TY - JOUR T1 - Dopamine D2 Receptor Inhibition of Adenylyl Cyclase Is Abolished by Acute Ethanol but Restored after Chronic Ethanol Exposure (Tolerance) JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 833 LP - 839 VL - 298 IS - 2 AU - Lina Yao AU - Kiyofumi Asai AU - Zhan Jiang AU - Akira Ishii AU - Peidong Fan AU - Adrienne S. Gordon AU - Ivan Diamond Y1 - 2001/08/01 UR - http://jpet.aspetjournals.org/content/298/2/833.abstract N2 - Dopamine D2 (D2) receptors seem to mediate reinforcing responses to addicting drugs. A stably transfected NG108–15 cell line expressing the long form of the rat brain D2 receptor (D2L) was used to determine how ethanol modifies D2 receptor coupling to adenylyl cyclase. Activation of D2L receptors by the D2 receptor-specific agonistR-(−)-2,10,11-trihydroxy-N-propylnorapomorphine hydrobromide (NPA) inhibits both basal and receptor-stimulated cAMP production in these cells. Ethanol added acutely prevents D2L receptor inhibition of cAMP production. After chronic exposure to ethanol, however, D2L receptor coupling to adenylyl cyclase becomes tolerant to rechallenge with ethanol, i.e., ethanol no longer inhibits D2L receptor coupling and NPA inhibition of cAMP production is restored. Acute ethanol does not change NPA binding to D2 receptor in cell membranes but abolishes guanosine-5′-O-(3-thio)triphosphate induction of a lower-affinity state; chronic ethanol is without effect. The protein kinase A (PKA) inhibitor adenosine 3′,5′ cyclic monophosphorothioate, Rp-isomer, prevents acute ethanol inhibition of D2L receptor coupling. In contrast, the PKA activator adenosine 3′,5′ cyclic monophosphorothioate, Sp-isomer, reverses chronic ethanol-induced tolerance of D2L receptor coupling, restoring coupling to an ethanol-sensitive state. These results suggest that D2L receptor coupling to adenylyl cyclase via Gi develops tolerance to ethanol inhibition, which appears to be influenced by PKA activity. The American Society for Pharmacology and Experimental Therapeutics ER -