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 physiologic al 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)-adrene rgic pharmacology by applying molecular genetic techniques to alter th e expression of alpha(2C)-AR in mice. The effects of dexmedetomidine, a subtype-nonselective alpha(2)-AR agonist, on monoamine turnover in b rain and on locomotor activity were similar in mice with targeted inac tivation of the alpha(2C)-AR gene and in their controls, but the hypot hermic 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 reducti ons in brain monoamine metabolism and locomotor activity after dexmede tomidine, but their hypothermic response to the alpha(2)-AR agonist wa s significantly accentuated. The hypothermic effect of alpha(2)-AR ago nists thus seems to be mediated in part by alpha(2C)-AR. Some small bu t statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of alpha(2C)-AR expression wa s linked with reduced levels of homovanillic acid in brain, and mice w ith increased alpha(2C)-AR expression had elevated concentrations of t he dopamine metabolite compared with their controls.