Abstract
α2C adrenoceptors occur in high density in the striatum, but the functional role of these receptors is uncertain. Mice with targeted inactivation of the α2C adrenoceptor gene (Adra2c−/−) and genetically related control mice expressing the wild-type α2C adrenoceptor (Adra2c+/+) were used to determine whether striatal α2C adrenoceptors modulate adenylyl cyclase activation. In striatal slices fromAdra2c+/+ mice, the α2adrenoceptor 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 fromAdra2c−/− mice or in striatal slices fromAdra2c+/+ mice treated with reserpine and α-methyl-ρ-tyrosine to deplete monoamine neurotransmitters. Given the sparse innervation of the striatum by noradrenergic neurons, the possibility that dopamine can activate the mouse α2Cadrenoceptor at physiologically relevant concentrations was investigated using normal rat kidney (NRK) cells transfected with the mouse α2A or α2C adrenoceptor cDNA (NRK-α2A or NRK-α2C cells). Inhibition of [3H]RX821002 binding by agonists in homogenates of transfected cells revealed an affinity of dopamine for α2C adrenoceptors that was higher than the affinity of norepinephrine for its cognate receptor, the α2Aadrenoceptor. Both norepinephrine and dopamine inhibited forskolin-stimulated cAMP accumulation in intact NRK-α2Ccells. In NRK-α2A cells, norepinephrine facilitated forskolin-stimulated cAMP accumulation, an effect not observed for dopamine. Together, these data demonstrate that the α2Cadrenoceptor is negatively coupled to adenylyl cyclase and is tonically activated in mouse striatal slices. The endogenous activator of the striatal α2C adrenoceptor may be dopamine, as well as norepinephrine.
Footnotes
-
Send reprint requests to: Dr. G. A. Ordway, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216. E-mail:gordway{at}psychiatry.umsmed.edu
-
↵1 This work was supported by a gift from the Hoechst-Marion-Roussel, Inc. W.Z. was supported by a graduate student stipend from the University of Mississippi Medical Center.
- Abbreviation:
- NRK
- normal rat kidney
- Received September 24, 1998.
- Accepted January 21, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|