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

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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.