Stress and the activation of periventricular substance P receptors differently regulate the serotonergic system in the brain and ACTH release in male rats.

Activation of periventricular and hypothalamic substance P (SP) (NK1) receptors triggers the classical defence (stress) reaction but inhibits the hypothalamic-pituitary-adrenal (HPA) axis. The mechanisms of the HPA axis inhibition by SP are not clearly understood. This study in rats was designed to investigate the effect of stress and intracerebroventricular (ICV) SP injection on serotonin (5-HT) neurotransmission in the raphe nuclei and the hypothalamus. Immobilisation stress increased ACTH release, accelerated 5-HT turnover in the dorsal raphe nucleus (DRN) and in individual hypothalamic nuclei, but not in the paraventricular nucleus (PVN). ICV SP injection (500 pmol) produced a strong stress response, however, ACTH concentrations in plasma did not increase. SP accelerated 5-HT utilisation in the DRN but did not alter 5-HT synthesis and its degradation to 5-hydroxyindolacetic acid (5-HIAA) in the hypothalamic nuclei examined; minor changes were observed in the dorsomedial nucleus (DMN). A microdialysis study in conscious rats showed a drop in 5-HT release in the PVN (- 42%, P < 0.05) and DMN (- 56%, P < 0.01) compared to the values detected prior to ICV injection of SP. We demonstrate that activation of periventricular SP receptors considerably enhances 5-HT metabolism in the DRN, but not in the hypothalamic nuclei, the terminal projection field of the nucleus. Our data indicate that the decline in 5-HT release in the PVN and DMN, which indicates a rapid decrease in 5-HT neurotransmission, may represent an important mechanism in preventing the rise in ACTH following ICV SP.