EFFECTS OF ACUTE INHALATION EXPOSURE TO ISOAMYL NITRITE ON THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS IN MALE SPRAGUE-DAWLEY RATS

Isoamyl nitrite (IAN) is a member of the family of volatile organic ni trites that exert vasodilatory effects and have recently exhibited a c onsiderable potential for inhalation abuse. In an effort to provide me chanistic insight into the neurotoxic effects and abuse potential of t hese agents, the present study was designed to evaluate the acute effe cts of IAN on the hypothalamo-pituitary-adrenal (HPA) axis. Attempts w ere also made to correlate the neuroendocrine effects of IAN with its pharmacokinetic profile. Male Sprague-Dawley rats were exposed to 600 or 1200 ppm IAN by inhalation for 10 or 30 min. Following exposure, ad renocorticotropic hormone (ACTH) and corticosterone in plasma and cort icotropin-releasing factor (CRF) in three brain regions (hypothalamus, hippocampus, and frontal cortex) were determined by radioimmunoassay. Levels of IAN in the three brain regions as well as in blood were mea sured by gas chromatography to determine the target tissue concentrati ons responsible for neuroendocrine changes. Uptake of IAN into blood a nd all brain regions was very rapid, as stable concentrations were ach ieved within 10 min of exposure and maintained for 30 min of continuou s inhalation. Plasma corticosterone decreased significantly after 10 m in inhalation of both IAN doses, and returned to control levels after 30 min. Moreover, plasma ACTH was significantly increased by 70 and 30 min of exposure to 600 and 7200 ppm IAN, while hypothalamic CRF incre ased significantly after 30 min of exposure to the 600 ppm dose. These latter findings suggest activation of the hypothalamus and pituitary due to a reduction in negative feedback resulting from the initial dec rease in corticosterone. Although plasma ACTH was greatly increased af ter 30 min, plasma corticosterone levels were unchanged, indicating th at IAN primarily acts to inhibit the synthesis or secretion of adrenal steroids and that activation of the HPA axis is not involved in the b ehavioral manifestations of IAN inhalation. These compensatory effects of HPA axis regulation, and possibly the vasodilatory properties of I AN, also likely precluded the establishment of definitive relationship s between observed changer in hormone levels and blood or regional bra in concentrations of the inhalant.