Genetic alteration of alpha(2C)-adrenoceptor expression in mice: Influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective alpha(2)-adrenoceptor agonist

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