title: Function of brain α2B-adrenergic receptor characterized with subtype-selective α2Bantagonist and KO mice.
abstract: Noradrenergic signaling, through the α2Aand α2Cadrenergic 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 α2Breceptor has any significant role in CNS function. The present study elucidates the potential role of the α2Breceptor in CNS function via the discovery and use of the first subtype-selective α2Bantagonist (AGN-209419), and behavioral analyses of α-receptor knockout (KO) mice. Using AGN-209419 as radioligand, α2Breceptor binding sites were identified within the olfactory bulb, cortex, thalamus, cerebellum, and striatum. Based on the observed expression patterns of α2subtypes in the brain, we compared α2BKO, α2AKO and α2CKO mice behavioral phenotypes with their respective wild-type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. α2BKO mice exhibited increased marble burying and α2CKO 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 α2BKO and α2CKO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, α2CKO mice increased activity at lower doses relative to either α2AKO or WT mice. However, α2BKO 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 α2BKO phenotype. These findings suggest that the α2Breceptor 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.
authors.affiliation: Allergan, 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Luhrs
authors.affiliation: Allergan, 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Manlapaz
authors.affiliation: Allergan, 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kedzie
authors.affiliation: Allergan, 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Rao
authors.affiliation: Allergan, 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Cabrera-Ghayouri
authors.affiliation: Allergan, 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: John
authors.initials: J
authors.lastname: Donello
authors.affiliation: Allergan, 2525 Dupont Drive, Irvine, CA 92612, USA. Electronic address: Gil_Daniel@Allergan.Com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gil
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003192:Compulsive Behavior / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D018341:Receptors, Adrenergic, alpha-2; D000661:Amphetamine
keywords: adrenergic; compulsivity; sensorimotor; stereotypy; α(2B)-receptor