Genetic alteration of the α₂-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels

Abstract

α₂-Adrenoceptors (α₂-AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three α₂-AR subtypes (α_2A, α_2B, and α_2C) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, α₂-AR subtype-selective pharmacological probes are not available, mice with genetically altered α_2C-AR expression were studied in order to investigate the possible involvement of the α_2C-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 α_2C-AR expression on the development of behavioral despair. α_2C-Overexpression increased and the lack of α_2C-AR (α_2C-KO) decreased the immobility of mice in the forced swimming test, ie α_2C-AR expression appeared to promote the development of behavioral despair. In addition, α_2C-KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of α_2C-ARs was linked with increased corticosterone levels after repeated stress. Moreover, the brain dopamine and serotonin balance, but not norepinephrine turnover, was dependent on α_2C-AR expression, and the expression of c-fos and junB mRNA was increased in α_2C-KO mice. Since α_2C-KO produced stress-protective effects, and α_2C-AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective α_2C-AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.