| First Author | Luhrs L | Year | 2016 |
| Journal | Neuroscience | Volume | 339 |
| Pages | 608-621 | PubMed ID | 27751959 |
| Mgi Jnum | J:238220 | Mgi Id | MGI:5818620 |
| Doi | 10.1016/j.neuroscience.2016.10.024 | Citation | Luhrs L, et al. (2016) Function of brain alpha2B-adrenergic receptor characterized with subtype-selective alpha2B antagonist and KO mice. Neuroscience 339:608-621 |
| abstractText | Noradrenergic signaling, through the alpha2A and alpha2C 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 alpha2B receptor has any significant role in CNS function. The present study elucidates the potential role of the alpha2B receptor in CNS function via the discovery and use of the first subtype-selective alpha2B antagonist (AGN-209419), and behavioral analyses of alpha-receptor knockout (KO) mice. Using AGN-209419 as radioligand, alpha2B receptor binding sites were identified within the olfactory bulb, cortex, thalamus, cerebellum, and striatum. Based on the observed expression patterns of alpha2 subtypes in the brain, we compared alpha2B KO, alpha2A KO and alpha2C KO mice behavioral phenotypes with their respective wild-type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. alpha2B KO mice exhibited increased marble burying and alpha2C 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 alpha2B KO and alpha2C KO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, alpha2C KO mice increased activity at lower doses relative to either alpha2A KO or WT mice. However, alpha2B 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 alpha2B KO phenotype. These findings suggest that the alpha2B 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. |
