Genetic Alteration of α2C-Adrenoceptor Expression in Mice: Influence on Locomotor, Hypothermic, and Neurochemical Effects of Dexmedetomidine, a Subtype-Nonselective α2-Adrenoceptor Agonist

α 2 -Adrenergic receptors (α 2 -ARs) regulate many physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three human and mouse genes encoding α 2 -AR subtypes (α 2A , α 2B , and α 2C ) have been cloned. We investigated the involvement of the α 2C -AR in α 2 -adrenergic pharmacology by applying molecular genetic techniques to alter the expression of α 2C -AR in mice. The effects of dexmedetomidine, a subtype-nonselective α 2 -AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the α 2C -AR gene and in their controls, but the hypothermic effect of the α 2 -AR agonist was significantly attenuated by the receptor gene inactivation. Correspondingly, another strain of transgenic mice with 3-fold overexpression of α 2C -AR in striatum and other brain regions expressing α 2C -AR showed normal reductions in brain monoamine metabolism and locomotor activity after dexmedetomidine, but their hypothermic response to the α 2 -AR agonist was significantly accentuated. The hypothermic effect of α 2 -AR agonists thus seems to be mediated in part by α 2C -AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of α 2C -AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased α 2C -AR expression had elevated concentrations of the dopamine metabolite compared with their controls.