The effects of destroying the paraventricular nucleus (PVN) of the rat hypothalamus on pituitary-adrenal function were studied. Four days after PVN lesions were placed with a rotating knife, the basal plasma corticosterone level was normal, but the corticosterone response to electrical stimulation of the medial basal hypothalamus, surgical trauma, and ether-venesection stress was significantly inhibited. Four and 8 days after PVN lesioning and adrenalectomy, the basal plasma ACTH level was lower, and the rise of plasma ACTH level elicited by a 3-min ether inhalation was significantly smaller than in the adrenalectomized controls. Corticotropin-releasing factor (CRF) activity in the stalk-median eminence extracts from PVN-lesioned rats was significantly less than in the control extracts. The weight of the adrenals was decreased by both 2 and 4 wk after PVN destruction, and 2 wk after hemiadrenalectomy, the compensatory adrenal hypertrophy was inhibited. The plasma corticosterone response to ether-venesection stress was inhibited only temporarily because it returned to normal by the end of the 4th postoperative week. The results are consistent with the hypothesis that a substantial portion of CRF-containing fibers in the stalk-median eminence region either originate from or run though the PVN or its immediate vicinity.
Corticotrophin (ACTH) release has been studied in rats given intraventricular gamma-aminobutyric acid (GABA) infusions or injections of picrotoxin and bicuculline. As an index of ACTH release the corticosterone level of blood or plasma was determined. GABA (1 M/liter), infused at a rate of 1 µl/min into the 3rd ventricle, inhibited the rise in plasma corticosterone normally produced by surgical trauma. 60 min after surgical trauma the rats given GABA infusions had lower blood corticosterone levels than the control rats given infusions of 1 M/liter of proline, 1 M/liter of glycine, or 0.15 M/liter of sodium chloride. Picrotoxin, an antagonist of GABA, is a potent stimulus of ACTH release. In sub-convulsive intraperitoneal doses it produced a significant rise in plasma corticosterone in conscious rats with complete hypothalamic deafferentation. Under pentobarbital anesthesia 12.5 µg of picrotoxin injected into the 3rd ventricle produced a small but significant rise in plasma corticosterone in rats with hypothalamic deafferentation. After intraventricular injections of bicuculline methiodide a significant rise in plasma corticosterone occurred in rats with hypothalamic deafferentation; the ACTH releasing effect of 2.5 µg of bicuculline methiodide was strongly inhibited by a simultaneous infusion of 0.15 M/liter of GABA. On the basis of this pharmacological evidence, we suggest that GABA may be an inhibitory neurotransmitter of hypothalamic interneurons and/or afferent pathways involved in the regulation of ACTH release.
The effect of short-term (1 wk) and long-term (6 wk) lesion of the paraventricular nucleus (PVN) on the hypothalamopituitary-adrenal axis was studied. Six weeks after PVN lesion there was no change in resting morning plasma ACTH and corticosterone levels. The increase of plasma ACTH levels that occurs 8 days after adrenalectomy was inhibited 6 wk after placing a lesion in the PVN. In contrast, 6 wk after PVN lesion the plasma ACTH response measured 3 min after laparatomy and intestinal traction under ether anesthesia was not significantly different from that in the controls. The responsiveness to corticotropin-releasing factor (CRF)-41 of anterior pituitary segments incubated in vitro increased slightly at 6 wk after PVN lesion. The amount of CRF-41-like immunoreactive material in the stalk-median eminence decreased to approximately 14% of the control, while that in neural lobe failed to change. We suggest that the ACTH hypersecretion after adrenalectomy is driven predominantly by CRF-and/or AVP-producing neurons in and around the PVN, whereas other sources of CRF-41, increased pituitary sensitivity or other hypothalamic factors, may restore stress-induced ACTH release in the absence of the region of the PVN.
Sodium glutamate infused into the 3rd ventricle is a potent stimulus of ACTH release, as shown by the rise in plasma corticosterone levels. Glutamate failed to consistently increase the plasma corticosterone level in rats with deafferentation of the medial basal hypothalamus (MBH). We suggest that intraventricular glutamate interferes with central nervous function outside the MBH and stimulates ACTH release via afferent neural pathways.
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