Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells

α2-Adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether α2-adrenoceptors on adrenergic neurons or α2-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of α2-agonists, we used the dopamine β-hydroxylase (Dbh) promoter to drive expression of α2A-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-α2A transgenic mice were crossed with double knockout mice lacking both α2A- and α2C-receptors to generate lines with selective expression of α2A-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express α2A- and α2C-receptors in both adrenergic and nonadrenergic cells, and α2A/α2C double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to α2-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by α2-receptors in nonadrenergic cells. In dopamine β-hydroxylase knockout mice lacking norepinephrine, the α2-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of α2-adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the α2-adrenergic receptors, and it provides important new considerations for future drug development.