Roles of Hippocampal Somatostatin Receptor Subtypes in Stress Response and Emotionality

Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst₂ or sst₄ knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst₂ or sst_4, but not sst₁ or sst₃ receptor agonists produced rapid and sustained inhibition of HPA axis. sst₂ agonists selectively produced anxiolytic-like behaviors whereas both sst₂ and sst₄ agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst₂KO mice and depressive-like behaviors observed in both sst₂KO and sst₄KO strains. Both hippocampal sst₂ and sst₄ receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.