Abstract
α2-Adrenergic receptors (α2-ARs) regulate many physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three human and mouse genes encoding α2-AR subtypes (α2A, α2B, and α2C) have been cloned. We investigated the involvement of the α2C-AR in α2-adrenergic pharmacology by applying molecular genetic techniques to alter the expression of α2C-AR in mice. The effects of dexmedetomidine, a subtype-nonselective α2-AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the α2C-AR gene and in their controls, but the hypothermic effect of the α2-AR agonist was significantly attenuated by the receptor gene inactivation. Correspondingly, another strain of transgenic mice with 3-fold overexpression of α2C-AR in striatum and other brain regions expressing α2C-AR showed normal reductions in brain monoamine metabolism and locomotor activity after dexmedetomidine, but their hypothermic response to the α2-AR agonist was significantly accentuated. The hypothermic effect of α2-AR agonists thus seems to be mediated in part by α2C-AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of α2C-AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased α2C-AR expression had elevated concentrations of the dopamine metabolite compared with their controls.
Footnotes
- Received June 24, 1996.
- Accepted October 2, 1996.
-
Send reprint requests to: Dr. Mika Scheinin, MediCity Research Laboratory, University of Turku, Tykistökatu 6A, FIN-20520 Turku, Finland. E-mail: mschein{at}utu.fi
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm 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.
|