FUNCTION OF BRAIN alpha(2B)-ADRENERGIC RECEPTOR CHARACTERIZED WITH SUBTYPE-SELECTIVE alpha(2B) ANTAGONIST AND KO MICE

摘要

Noradrenergic signaling, through the alpha(2A) and alpha(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 alpha(2B) receptor has any significant role in CNS function. The present study elucidates the potential role of the alpha(2B) receptor in CNS function via the discovery and use of the first subtype-selective am antagonist (AGN-209419), and behavioral analyses of alpha-receptor knockout (KO) mice. Using AGN-209419 as radioligand, alpha(2B) receptor binding sites were identified within the olfactory bulb, cortex, thalamus, cerebellum, and striatum. Based on the observed expression patterns of alpha(2) subtypes in the brain, we compared alpha(2B) KO, alpha(2A) KO and alpha(2C) KO mice behavioral phenotypes with their respective wild type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. alpha(2B) KO mice exhibited increased marble burying and alpha(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 loco motor hyperactivity and found that alpha(2B) KO and alpha(2C) KO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, alpha(2C) KO mice increased activity at lower doses relative to either alpha(2A) KO or WT mice. However, alpha(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 alpha(2B) KO phenotype. These findings suggest that the alpha(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. (C) 2016 Published by Elsevier Ltd on behalf of IBRO.