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␣ 2 -Adrenoceptors (␣ 2 -AR) modulate many central nervous system functions, such as regulation of sympathetic tone, vigilance, attention, and reactivity to environmental stressors. Three ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , and ␣ 2C ) with distinct tissue-distribution patterns are known to exist, but the functional significance of each subtype is not clear. Since specific, ␣ 2 -AR subtype-selective pharmacological probes are not available, mice with genetically altered ␣ 2C -AR expression were studied in order to investigate the possible involvement of the ␣ 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 ␣ 2C -AR expression on the development of behavioral despair. ␣ 2C -Overexpression increased and the lack of ␣ 2C -AR (␣ 2C -KO) decreased the immobility of mice in the forced swimming test, ie ␣ 2C -AR expression appeared to promote the development of behavioral despair. In addition, ␣ 2C -KO was associated with attenuated elevation of plasma corticosterone after different stressors, and overexpression of ␣ 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 ␣ 2C -AR expression, and the expression of c-fos and junB mRNA was increased in ␣ 2C -KO mice. Since ␣ 2C -KO produced stress-protective effects, and ␣ 2C -AR overexpression seemed to promote the development of changes related to depression, it is suggested that a yet-to-be developed subtype-selective ␣ 2C -AR antagonist might have therapeutic value in the treatment of stress-related neuropsychiatric disorders.

Exposure of organisms to repetitive mild hypoxia results in development of brain hypoxic/ischemic tolerance and cross-tolerance to injurious factors of a psycho-emotional nature. Such preconditioning by mild hypobaric hypoxia functions as a “warning” signal which prepares an organism, and in particular the brain, to subsequent more harmful conditions. The endogenous defense processes which are mobilized by hypoxic preconditioning and result in development of brain tolerance are based on evolutionarily acquired gene-determined mechanisms of adaptation and neuroprotection. They involve an activation of intracellular cascades including kinases, transcription factors and changes in expression of multiple regulatory proteins in susceptible areas of the brain. On the other hand they lead to multilevel modifications of the hypothalamic-pituitary-adrenal endocrine axis regulating various functions in the organism. All these components are engaged sequentially in the initiation, induction and expression of hypoxia-induced tolerance. A special role belongs to the epigenetic regulation of gene expression, in particular of histone acetylation leading to changes in chromatin structure which ensure access of pro-adaptive transcription factors activated by preconditioning to the promoters of target genes. Mechanisms of another, relatively novel, neuroprotective phenomenon termed hypoxic postconditioning (an application of mild hypoxic episodes after severe insults) are still largely unknown but according to recent data they involve apoptosis-related proteins, hypoxia-inducible factor and neurotrophins. The fundamental data accumulated to date and discussed in this review open new avenues for elaboration of the effective therapeutic applications of hypoxic pre- and postconditioning.

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