Dopamine D2 receptor inhibition of adenylyl cyclase is abolished by acute ethanol but restored after chronic ethanol exposure (tolerance)

Dopamine D2 (D2) receptors seem to mediate reinforcing responses to addicti ng 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 modifi es D2 receptor coupling to adenylyl cyclase. Activation of D2L receptors by the D2 receptor-specific agonist R-(-)-2,10,11-trihydroxy-N-propylnorapomo rphine hydrobromide (NPA) inhibits both basal and receptor-stimulated CAMP production in these cells. Ethanol added acutely prevents D2L receptor inhi bition 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 inh ibition of CAMP production is restored. Acute ethanol does not change NPA b inding to D2 receptor in cell membranes but abolishes guanosine-5'-O-(3-thi o)triphosphate induction of a lower-affinity state; chronic ethanol is with out effect. The protein kinase A (PKA) inhibitor adenosine 3',5' cyclic mon ophosphorothioate, Rp-isomer, prevents acute ethanol inhibition of D2L rece ptor coupling. In contrast, the PKA activator adenosine 3',5' cyclic monoph osphorothioate, Sp-isomer, reverses chronic ethanol-induced tolerance of D2 L receptor coupling, restoring coupling to an ethanol-sensitive state. Thes e results suggest that D2L receptor coupling to adenylyl cyclase via G; dev elops tolerance to ethanol inhibition, which appears to be influenced by PK A activity.