Heterozygous α2A-Adrenergic Receptor Mice Unveil Unique Therapeutic Benefits of Partial Agonists

Genetic manipulation of the α2A-adrenergic receptor (α2A-AR) in mice has revealed the role of this subtype in numerous responses, including agonist-induced hypotension and sedation. Unexpectedly, α2-agonist treatment of mice heterozygous for the α2A-AR (α2A-AR+/-) lowers blood pressure without sedation, indicating that more than 50% of α2A-AR must be activated to evoke sedation. We postulated that partial activation of α2A-AR in wild-type α2A-AR+/+animals could be achieved with partial agonists, agents with variable ability to couple receptor occupancy to effector activation, and might elicit one versus another pharmacological response. In vitro assays reveal that moxonidine is a partial agonist at α2A-AR. Although moxonidine was developed to preferentially interact with imidazoline binding sites, it requires the α2A-AR to lower blood pressure because we observe no hypotensive response to moxonidine in α2A-AR-null (α2A-AR-/-) mice. Moreover, we observe that moxonidine lowers blood pressure without sedation in wild-type mice, consistent with the above hypothesis regarding partial agonists. Our findings suggest that weak partial agonists can evoke response-selective pathways and might be exploited successfully to achieve α2A-AR pharmacotherapy where concomitant sedation is undesirable, i.e., in treatment of depression or attention deficit hyperactivity disorder, in suppression of epileptogenesis, or enhancement of cognition. Furthermore, rigorous physiological and behavioral assessment of mice heterozygous for particular receptors provides a general strategy for elucidation of pathways that might be selectively activated by partial agonists, thus achieving response-specific therapy.