title: Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels.
abstract: alpha2-Adrenoceptors (alpha2-AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three alpha2-AR subtypes (alpha2A, alpha2B, and alpha2C) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, alpha2-AR subtype-selective pharmacological probes are not available, mice with genetically altered alpha2C-AR expression were studied in order to investigate the possible involvement of the alpha2C-AR in physiological and behavioral responses to acute and repeated stress. A modified version of Porsolt's forced swimming test was used to assess the possible effects of altered alpha2C-AR expression on the development of behavioral despair. alpha2C-Overexpression increased and the lack of alpha2C-AR (alpha2C-KO) decreased the immobility of mice in the forced swimming test, ie alpha2C-AR expression appeared to promote the development of behavioral despair. In addition, alpha2C-KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of alpha2C-ARs was linked with increased corticosterone levels after repeated stress. Moreover, the brain dopamine and serotonin balance, but not norepinephrine turnover, was dependent on alpha2C-AR expression, and the expression of c-fos and junB mRNA was increased in alpha2C-KO mice. Since alpha2C-KO produced stress-protective effects, and alpha2C-AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective alpha2C-AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.
authors.affiliation: Orion Corporation, Orion Pharma, FIN-20101 Turku, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Sallinen
authors.forename: A
authors.initials: A
authors.lastname: Haapalinna
authors.forename: E
authors.initials: E
authors.lastname: MacDonald
authors.forename: T
authors.initials: T
authors.lastname: Viitamaa
authors.forename: J
authors.initials: J
authors.lastname: Lähdesmäki
authors.forename: E
authors.initials: E
authors.lastname: Rybnikova
authors.forename: M
authors.initials: M
authors.lastname: Pelto-Huikko
authors.forename: B K
authors.initials: BK
authors.lastname: Kobilka
authors.forename: M
authors.initials: M
authors.lastname: Scheinin
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002540:Cerebral Cortex / Q000737:chemistry; D003342:Corpus Striatum / Q000737:chemistry; D003345:Corticosterone / Q000097:blood*; D003863:Depression / Q000235:genetics / Q000503:physiopathology; D004298:Dopamine / Q000032:analysis; D017781:Genes, Immediate-Early / Q000502:physiology; D005819:Genetic Markers; D006624:Hippocampus / Q000737:chemistry; D006719:Homovanillic Acid / Q000032:analysis; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D017403:In Situ Hybridization; D008734:Methoxyhydroxyphenylglycol / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000032:analysis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D012149:Restraint, Physical; D012701:Serotonin / Q000032:analysis; D013312:Stress, Physiological / Q000235:genetics / Q000503:physiopathology*; D013550:Swimming
chemical_list: D005819:Genetic Markers; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine; D003345:Corticosterone; D009638:Norepinephrine; D006719:Homovanillic Acid