کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6270635 1614737 2016 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Function of brain α2B-adrenergic receptor characterized with subtype-selective α2B antagonist and KO mice
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب (عمومی)
پیش نمایش صفحه اول مقاله
Function of brain α2B-adrenergic receptor characterized with subtype-selective α2B antagonist and KO mice
چکیده انگلیسی


- A novel selective α2B antagonist was identified through high-throughput screen (AGN-209419).
- Used radiolabeled AGN-209419 in localization and inhibition assays to demonstrate the role of α2B receptors in CNS function.
- Utilized behavioral analyses in α-receptor KO mice to demonstrate role of α2B receptors in CNS function.
- Results indicate the α2B receptor may be therapeutically relevant for disorders such as schizophrenia, ADHD, and OCD.

Noradrenergic signaling, through the α2A and α2C 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 α2B receptor has any significant role in CNS function. The present study elucidates the potential role of the α2B receptor in CNS function via the discovery and use of the first subtype-selective α2B antagonist (AGN-209419), and behavioral analyses of α-receptor knockout (KO) mice. Using AGN-209419 as radioligand, α2B 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 α2B KO, α2A KO and α2C KO mice behavioral phenotypes with their respective wild-type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. α2B KO mice exhibited increased marble burying and α2C 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 α2B KO and α2C KO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, α2C KO mice increased activity at lower doses relative to either α2A KO or WT mice. However, α2B 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 α2B KO phenotype. These findings suggest that the α2B 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuroscience - Volume 339, 17 December 2016, Pages 608-621
نویسندگان
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