SUMMARY␣ 2 -Adrenergic receptors (␣ 2 -ARs) regulate many physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three human and mouse genes encoding ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , and ␣ 2C ) have been cloned. We investigated the involvement of the ␣ 2C -AR in ␣ 2 -adrenergic pharmacology by applying molecular genetic techniques to alter the expression of ␣ 2C -AR in mice. The effects of dexmedetomidine, a subtype-nonselective ␣ 2 -AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the ␣ 2C -AR gene and in their controls, but the hypothermic effect of the ␣ 2 -AR agonist was significantly attenuated by the receptor gene inactivation. Correspondingly, another strain of transgenic mice with 3-fold overexpression of ␣ 2C -AR in striatum and other brain regions expressing ␣ 2C -AR showed normal reductions in brain monoamine metabolism and locomotor activity after dexmedetomidine, but their hypothermic response to the ␣ 2 -AR agonist was significantly accentuated. The hypothermic effect of ␣ 2 -AR agonists thus seems to be mediated in part by ␣ 2C -AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of ␣ 2C -AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased ␣ 2C -AR expression had elevated concentrations of the dopamine metabolite compared with their controls.␣ 2 -ARs mediate many physiological functions and pharmacological effects in the central nervous system, mainly by inhibiting neuronal firing and release of NE and other neurotransmitters. ␣ 2 -ARs are also involved in a wide range of functions in peripheral tissues (e.g., in the regulation of NE release from sympathetic nerves, smooth muscle contraction, platelet aggregation, insulin secretion, glomerular filtration, and energy metabolism) (1). Activation of ␣ 2 -ARs with the highly specific ␣ 2 -AR agonist dexmedetomidine results in bradycardia, hypotension, hypothermia, locomotor inhibition, anxiolysis, analgesia, sedation, and, with higher doses, anesthesia. Dexmedetomidine also reduces the turnover of the monoamine neurotransmitters NE, DA, and 5-HT (serotonin) in brain (2).Recent pharmacological and biochemical research has led to a subdivision of ␣ 2 -ARs into three distinct subtypes: ␣ 2A -, ␣ 2B -, and ␣ 2C -ARs. This classification was first based on the pharmacological properties of the receptors and was confirmed through the cloning of three distinct ␣ 2 -AR genes in humans, rats, mice, and other species (3). Each receptor has a distinct tissue distribution. In the central nervous system of the rat, ␣ 2A -ARs are widely expressed, whereas the other ␣ 2 -AR subtypes have more limited distributions. ␣ 2C -ARs are present in the basal ganglia, olfactory tubercle, hippocam-ABBREVIATIONS: AR, adrenergic receptor; DA, dopamine; NE, norepinephrine; MHPG, 3-methoxy-4-hydroxyphenylglycol; HVA, homovanillic acid; 5-HT,...
