The α2C-adrenergic receptor mediates hyperactivity of coloboma mice, a model of attention deficit hyperactivity disorder

Drugs that modify noradrenergic transmission such as atomoxetine and clonidine are increasingly prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). However, the therapeutic targets of these compounds are unknown. Norepinephrine is also implicated in the hyperactivity exhibited by coloboma mice. To identify the receptor subtypes that regulate the hyperactivity, coloboma mice were systematically challenged with adrenergic drugs. The β-adrenergic receptor antagonist propranolol and the α1-adrenergic receptor antagonist prazosin each had little effect on the hyperactivity. Conversely, the α2-adrenergic receptor antagonist yohimbine reduced the activity of coloboma mice but not control mice. Subtype-selective blockade of α2C-, but not α2A- or α2B-adrenergic receptors, ameliorated hyperactivity of coloboma mice without affecting activity of control mice, suggesting that α2C-adrenergic receptors mediate the hyperactivity. Localized in the basal ganglia, α2C-adrenergic receptors are in a prime position to impact locomotor activity and are, therefore, potential targets of pharmacotherapy for ADHD.