alpha(2C) adrenoceptors inhibit adenylyl cyclase in mouse striatum: Potential activation by dopamine

alpha(2C) adrenoceptors occur in high density in the striatum, but the func tional role of these receptors is uncertain. Mice with targeted inactivatio n of the alpha(2C) adrenoceptor gene (Adra2c(-/-)) and genetically related control mice expressing the wild-type alpha(2C) adrenoceptor (Adra2c(+/+)) were used to determine whether striatal alpha(2C) adrenoceptors modulate ad enylyl cyclase activation. In striatal slices from Adra2c(+/+) mice, the al pha(2) adrenoceptor antagonist RX821002 facilitated forskolin-stimulated cy clic AMP accumulation in a concentration-dependent manner. In contrast, RX8 21002 had no effect on forskolin-stimulated cAMP accumulation in striatal s lices from Adra2c(-/-) mice or in striatal slices from Adra2c(+/+) mice tre ated with reserpine and alpha-methyl-rho-tyrosine to deplete monoamine neur otransmitters. Given the sparse innervation of the striatum by noradrenergi c neurons, the possibility that dopamine can activate the mouse alpha(2C) a drenoceptor at physiologically relevant concentrations was investigated usi ng normal rat kidney (NRK) cells transfected with the mouse alpha(2A) or al pha(2C) adrenoceptor cDNA (NRK-alpha(2A) or NRK-alpha(2C) cells). Inhibitio n of [H-3]RX821002 binding by agonists in homogenates of transfected cells revealed an affinity of dopamine for alpha(2C) adrenoceptors that was highe r than the affinity of norepinephrine for its cognate receptor, the alpha(2 A) adrenoceptor, Both norepinephrine and dopamine inhibited forskolin-stimu lated cAMP accumulation in intact NRK-alpha(2C) cells. In NRK-alpha(2A) cel ls, norepinephrine facilitated forskolin-stimulated cAMP accumulation, an e ffect not observed for dopamine. Together, these data demonstrate that the alpha(2C) adrenoceptor is negatively coupled to adenylyl cyclase and is ton ically activated in mouse striatal slices. The endogenous activator of the striatal alpha(2C) adrenoceptor may be dopamine, as well as norepinephrine.