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

α 2 -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 α 2 -adrenoceptors on adrenergic neurons or α 2 -adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of α 2 -agonists, we used the dopamine β-hydroxylase ( Dbh ) promoter to drive expression of α 2A -adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh -α 2A transgenic mice were crossed with double knockout mice lacking both α 2A - and α 2C -receptors to generate lines with selective expression of α 2A -autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express α 2A - and α 2C -receptors in both adrenergic and nonadrenergic cells, and α 2A /α 2C 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 α 2 -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 α 2 -receptors in nonadrenergic cells. In dopamine β-hydroxylase knockout mice lacking norepinephrine, the α 2 -agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of α 2 -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 α 2 -adrenergic receptors, and it provides important new considerations for future drug development.