Function of brain α_2B-adrenergic receptor characterized with subtype-selective α_2B antagonist and KO mice

Noradrenergic signaling, through the α_2A and α_2C adrenergic receptors modulates the cognitive and behavioral symptoms of disorders such as schizophrenia, attention deficit hyperactivity disorder (ADHD), and addiction. However, it is unknown whether the α_2B receptor has any significant role in CNS function. The present study elucidates the potential role of the α_2B receptor in CNS function via the discovery and use of the first subtype-selective α_2B antagonist (AGN-209419), and behavioral analyses of α-receptor knockout (KO) mice. Using AGN-209419 as radioligand, α_2B receptor binding sites were identified within the olfactory bulb, cortex, thalamus, cerebellum, and striatum. Based on the observed expression patterns of α₂ subtypes in the brain, we compared α_2B KO, α_2A KO and α_2C KO mice behavioral phenotypes with their respective wild-type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. α_2B KO mice exhibited increased marble burying and α_2C KO mice exhibited an increased startle response to a pulse stimulus, but otherwise intact prepulse inhibition. To further explore compulsive behavior, we evaluated novelty-induced locomotor hyperactivity and found that α_2B KO and α_2C KO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, α_2C KO mice increased activity at lower doses relative to either α_2A KO or WT mice. However, α_2B KO mice exhibited stereotypy at doses of amphetamine that were only locomotor stimulatory to all other genotypes. Following co-administration of AGN-209419 with low-dose amphetamine in WT mice, stereotypy was observed, mimicking the α_2B KO phenotype. These findings suggest that the α_2B receptor is involved in CNS behaviors associated with sensorimotor gating and compulsivity, and may be therapeutically relevant for disorders such as schizophrenia, ADHD, post-traumatic stress disorder, addiction, and obsessive compulsive disorder.