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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 2B, 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 3-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 2C-AR agonists 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.