N. Conforti

Participation of the Dorsal Hippocampus in the Glucocorticoid Feedback Effect on Adrenocortical Activity

The feedback effect of systemically administered dexamethasone on basal plasma corticosterone levels and on adrenocortical responses to ether plus skin incision stress were studied in intact rats and in animals with bilateral dorsal or ventral hippocampectomy or fimbria section. It was found that in rats with ventral hippocampectomy or fimbria section, the degree of the feedback was similar to that in intact rats. However, in animals with dorsal hippocampectomy, the inhibitory effect of dexamethasone on basal and stress-induced adrenocortical responses was significantly reduced. These results taken together with previous observations, that section of the dorsal fornix has a similar effect, suggest that dexamethasone exerts its influence on the brain and that the dorsal hippocampal formation participates in the feedback regulation of pituitary-adrenal function. It cannot be excluded, however, that dexamethasone may exert its influence on the pituitary, and the effect observed may be summation of dexamethasone action on the pituitary plus lack of hippocampal input.

Limbic pathways and hypothalamic neurotransmitters mediating adrenocortical responses to neural stimuli

One of the major phenomena related to the stress response is the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis. This axis consists of corticotropin releasing factor-41 in the paraventricular nucleus of the hypothalamus (PVN), which in response to a variety of stimuli is released into the portal circulation and stimulates pituitary ACTH secretion and subsequently adrenocortical discharge. The mechanisms involved in the activation are not uniform and the responses to various stimuli are mediated by different neural pathways. Since extrahypothalamic limbic structures play a significant role in the HPA function, it is the purpose of this review to describe the neural pathways between the hippocampus, septum and amygdala and the hypothalamus in relation to adrenocortical activity and the differential role of the medial forebrain bundle as well as the effects of various hypothalamic deafferentation on the transmission of the neural impulses to the hypothalamus. Also, the importance of norepinephrine and serotonin in the activation of the HPA axis will be delineated.

Differential effect of amygdaloid lesions on CRF-41, ACTH and corticosterone responses following neural stimuli

The effect of amygdaloid (AMG) lesions on changes in median eminence (ME) CRF-41 and serum ACTH and corticosterone (CS) levels following neural stimuli were investigated in rats. In intact animals photic or acoustic stimuli caused CRF-41 depletion from the ME and a rise in serum ACTH and CS levels. In rats with medial or central AMG nuclei lesions, these responses were blocked. Basal AMG lesions were not effective. Also, all groups of animals responded normally to ether stress. These results indicate a differential effect of AMG nuclei on the hypothalamo-pituitary-adrenocortical (HPA) axis and demonstrate that the facilitatory effect of the AMG nuclei on the HPA axis responses involves the release of ME CRF-41, which stimulates ACTH and consequently CS secretion.

The preoptic area and bed nucleus of the stria terminalis are involved in the effects of the amygdala on adrenocortical secretion

In view of the role of the amygdala in the modulation of adrenocortical secretion we have studied the neural pathways which mediate this response. Changes in plasma corticosterone following medial amygdala stimulation, under pentobarbital anaesthesia, were studied in rats which chronically implanted electrodes in intact and lesioned animals. The rise in plasma corticosterone following amygdala stimulation was inhibited by bilateral lesions of the stria terminals, medial preoptic area, and bed nucleus of the stria terminalis, and to a greater extent by a combined lesion of the latter two structures. The combined lesion also completely blocked the adrenocortical response to olfactory stimulation. These various lesions did not affect, however, the rise in plasma corticosterone following ether stress. These data thus demonstrate that the stria terminalis, preoptic area and bed nucleus of the stria terminalis are involved in the transmission of neural impulses to the hypothalamus which activate adrenocortical secretion.

Paraventricular nucleus serotonin mediates neurally stimulated adrenocortical secretion

The purpose of this study was to further elucidate the role of serotonin (5-HT) in adrenocortical regulation. The effects of stimulating the frontal cortex and extrahypothalamic limbic structures, on plasma corticosterone (CS) responses, were studied in rats with vehicle or 5,7-dihydroxytryptamine (5,7-DHT) injection into the midbrain raphe nuclei. In another group of rats the neurotoxin was injected locally into the paraventricular nucleus (PVN) in view of its importance in adrenocortical regulation, and the effects of photic and dorsal hippocampal stimulation on plasma CS were studied. 5,7-DHT caused a significant depletion of hypothalamic 5-HT and blocked the rise in plasma CS following the stimulation of the above neural modalities. These studies suggest that the PVN 5-HT mediates the adrenocortical responses following afferent neural stimuli.

Adrenocortical Responses following Limbic Stimulation in Rats with Hypothalamic Deafferentations

In view of the involvement of limbic structures in adrenocortical regulation, their afferent projections to the mediobasal hypothalamus were investigated. Electrical stimulation via chronically implanted electrodes in the dorsal hippocampus, the medial septal nuclei, the basolateral amygdala or the mesencephalic reticular formation all elicited a significant increment in plasma corticosterone levels in adult male rats under pentobarbital anesthesia. Complete or anterior hypothalamic deafferentation blocked these adrenocortical responses completely, and posterior hypothalamic deafferentation attenuated them to a marked extent. In animals with bilateral medial forebrain bundle lesions, hippocampal stimulation had no effect upon plasma corticosterone levels. These studies demonstrate that extrahypothalamic effects upon adrenocortical secretion are neurally mediated, and that the integrity of neural pathways impinging upon the mediobasal hypothalamus from both the rostral and the caudal directions is essential to these effects.

Amygdalectomy Inhibits Adrenocortical Responses to Somatosensory and Olfactory Stimulation

Adrenocortical responses, as measured by plasma corticosterone, to ether stress, photic, acoustic, sciatic and olfactory stimulation, were studied in amygdalectomized and in intact rats. While amygdalectomy had no effect on the adrenocortical responses following ether stress or photic and acoustic stimulation, the responses following sciatic and olfactory stimulation were markedly reduced. These results, taken together with our previous studies, suggest that the amygdala participates in the transmission of adrenocortical responses to olfactory stimulation and has also a modulatory facilitatory effect on the adrenocortical response to somatosensory stimulation. Amygdalectomy also reduced the effect of dexamethasone on basal plasma corticosterone secretion, indicating that the amygdala may participate in the feedback regulation of pituitary-adrenal function.

Effects of naloxone on basal and stress-induced ACTH and corticosterone secretion in the male rat - site and mechanism of action

The acute effects of naloxone upon basal and stress-induced secretion of ACTH and corticosterone (CS) in the adult male rat were investigated. Forty-five minutes subsequent to naloxone injection (5 mg/kg body wt, i.p.), basal serum levels of ACTH (by radioimmunoassay) and of CS (by corticosterone-binding globulin) were more than doubled, as compared to vehicle-treated animals. Upon exposure to either photic or audiogenic stress, the ACTH and CS secretory responses were greater in the naloxone-injected groups. In animals with complete hypothalamic deafferentation basal serum ACTH concentrations were significantly greater than in intact controls (2-fold), and naloxone elicited a further doubling of this parameter. In dexamethasone-pretreated rats (50 micrograms/animal, 4 h prior to naloxone), naloxone had no effect upon ACTH and CS secretion. This study demonstrates: (1) that acute naloxone administration leads to hypersecretion of ACTH, as well as of CS, in the adult male rat; and (2) that its effect is due to an action within the hypothalamo-hypophyseal unit. The data also suggest that these naloxone effects are not mediated by glucocorticoid hormones.

Modifications of adrenocortical responses following frontal cortex simulation in rats with hypothalamic deafferentations and medial forebrain bundle lesions

With the purpose of delineating the neural pathways in the rat which mediate adrenocortical responses following frontal cortex stimulation, the effects of partial hypothalamic deafferentations and medial forebrain bundle lesion were studied. In intact and sham-operated animals, cortical stimulation through permanently implanted electrodes caused a significant increase in plasma corticosterone levels. In rats with anterior hypothalamic deafferentation and bilateral medial forebrain bundle lesions the adrenal response to cortical stimulation was blocked completely, while in animals with posterior hypothalamic deafferentation there occurred a normal rise in plasma corticosterone. These studies demonstrate that the frontal cortex effects on adrenocortical secretion are neurally mediated and involve an anterior hypothalamic input, more specifically the medial forebrain bundle.

Alterations produced by cortisol in the spontaneous activity and responsiveness to sensory stimuli of single cells in the tuberal hypothalamus of the rat.

The effects of cortisol on the spontaneous activity of single cells in the tuberal hypothalamus and their responsiveness to photic, acoustic, and sciatic stimulation were studied in rats. The over-all rate of firing of the spontaneous activity of the majority of the units was changed significantly by the hormone, with approximately equal numbers showing facilitation and inhibition. The hormone also produced significant changes in the fluctuations of firing, as well as alterations in the time-interval histograms. When the responses were divided into facilitatory and inhibitory to sensory stimulation, it was found that cortisol significantly decreased the amount of facilitation and, to some extent, increased the amount of inhibition. The changes in firing in individual cells following cortisol administration did not depend upon the rate of spontaneous discharge. This and other data would indicate that the change in the sensory responsiveness of the hypothalamic units is an independent phenomenon produced by the hormone. The possible relationship of the electrophysio-logical findings to the role of cortisol in the neuroendocrine regulation of ACTH secretion is discussed.