The effect of the antidepressant agent, tianeptine, on the hypothalamo-pituitary-adrenal (HPA) axis was studied in adult male rats under basal and stressed conditions. Chronic treatment with tianeptine (10 mg/kg; 2 weeks; twice a day) induced a significant decrease of hypothalamic CRF (–12%) and pituitary ACTH concentrations (–21%), suggesting that tianeptine reduces the activity of hypothalamic CRF neurons and pituitary corticotrophs. The possible effect of tianeptine in the neuroendocrine response to stress was thus investigated. Rats were submitted to restraint stress for 30 min; under these conditions ACTH and corticosterone levels were considerably increased. A single injection of tianeptine was found to significantly reduce stress-evoked elevations of plasma ACTH and corticosterone. Time-course experiments, consisting of administering tianeptine 1–3 h before immobilization stress, revealed that the maximum inhibitory effect of tianeptine occurs about 2 h after injection of the antidepressant. Administration of various doses of tianeptine (from 2.5 to 20 mg/kg) showed that the effect of the drug was dose-dependent; the maximum effective dose being 10 mg/kg. Taken together, these data indicate that tianeptine may exert original ‘anti-stress’ activity.

Decreased levels of brain-derived neurotrophic factor (BDNF) in the hippocampus are implicated in the pathophysiology of major depression, although the mechanism has yet to be characterized. Epigenetic studies revealed that DNA methylation and histone modifications at the promoter of exons of the BDNF gene are the pivotal factors in the regulation of BDNF transcription. Histone acetylation regulates gene transcription through chromatin remodelling. We examined the influence of a single immobilization stress (SIS) at 2 h and 24 h afterwards on the levels of total BDNF mRNA with each exon mRNA by quantitative real-time PCR, acetylated histone at the promoters of the BDNF gene by chromatin immunoprecipitation followed by real-time PCR, and BDNF protein by ELISA in the rat hippocampus. SIS significantly decreased the levels of total BDNF mRNA with significantly reduced levels of exons I and IV mRNA followed by a significant reduction in BDNF protein 4 h after SIS. Significant decreases in the levels of acetylated histone H3, but not H4, were found at the promoters of exons I, IV, and VI. In contrast, no marked changes in the levels of either acetylated histone or BDNF mRNA and protein were found 24 h after SIS. This study demonstrated the involvement of histone acetylation in the regulation of BDNF transcription by SIS, and the plastic change in histone acetylation after SIS. These findings suggest that stress affects BDNF gene transcription via epigenetic regulation, and glucocorticoid may be involved in this regulation.