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 (α_2A, α_2B, and α_2C) have been cloned. We investigated the involvement of the α_2C-AR in α₂-adrenergic pharmacology by applying molecular genetic techniques to alter the expression of α_2C-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 α_2C-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 α_2C-AR in striatum and other brain regions expressing α_2C-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 α_2C-AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of α_2C-AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased α_2C-AR expression had elevated concentrations of the dopamine metabolite compared with their controls.