Vol. 289, Issue 3, 1286-1292, June 1999

_2C Adrenoceptors Inhibit Adenylyl Cyclase in Mouse Striatum: Potential Activation by Dopamine¹

Weilie Zhang , Violetta Klimek, Joshua T. Farley, Meng-Yang Zhu and Gregory A. Ordway

Departments of Psychiatry & Human Behavior (W.Z., V.K., J.T.F., M-Y.Z., G.A.O.) and Pharmacology & Toxicology (W.Z., G.A.O.), University of Mississippi Medical Center, Jackson, Mississippi

_2C adrenoceptors occur in high density in the striatum, but the functional role of these receptors is uncertain. Mice with targeted inactivation of the _2C adrenoceptor gene (Adra2c^/) and genetically related control mice expressing the wild-type _2C adrenoceptor (Adra2c^+/+) were used to determine whether striatal _2C adrenoceptors modulate adenylyl cyclase activation. In striatal slices from Adra2c^+/+ mice, the ₂ adrenoceptor antagonist RX821002 facilitated forskolin-stimulated cyclic AMP accumulation in a concentration-dependent manner. In contrast, RX821002 had no effect on forskolin-stimulated cAMP accumulation in striatal slices from Adra2c^/ mice or in striatal slices from Adra2c^+/+ mice treated with reserpine and -methyl--tyrosine to deplete monoamine neurotransmitters. Given the sparse innervation of the striatum by noradrenergic neurons, the possibility that dopamine can activate the mouse _2C adrenoceptor at physiologically relevant concentrations was investigated using normal rat kidney (NRK) cells transfected with the mouse _2A or _2C adrenoceptor cDNA (NRK-_2A or NRK-_2C cells). Inhibition of [³H]RX821002 binding by agonists in homogenates of transfected cells revealed an affinity of dopamine for _2C adrenoceptors that was higher than the affinity of norepinephrine for its cognate receptor, the _2A adrenoceptor. Both norepinephrine and dopamine inhibited forskolin-stimulated cAMP accumulation in intact NRK-_2C cells. In NRK-_2A cells, norepinephrine facilitated forskolin-stimulated cAMP accumulation, an effect not observed for dopamine. Together, these data demonstrate that the _2C adrenoceptor is negatively coupled to adenylyl cyclase and is tonically activated in mouse striatal slices. The endogenous activator of the striatal _2C adrenoceptor may be dopamine, as well as norepinephrine.