Shaul Feldman

Effect of the Brain Constituent Anandamide, a Cannabinoid Receptor Agonist, on the Hypothalamo-Pituitary-Adrenal Axis in the Rat

Anandamide (arachidonylethanolamide), an endogenous ligand of the cannabinoid receptor, was recently isolated from porcine brain. We report here for the first time on the effect of this ligand on the hypothalamo-pituitary adrenal (HPA) axis in comparison to that of the plant cannabinoid delta 9-tetrahydrocannabinol (THC). Intracerebroventricular injection of anandamide or THC (50 or 150 micrograms/rat) increased significantly the serum levels of ACTH and corticosterone in a dose-dependent manner and caused a pronounced depletion of CRF-41 in the median eminence. These data suggest that anandamide parallels THC in activating the HPA axis via mediation of a central mechanism which involves the secretion of CRF-41.

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.

The excitatory effects of the amygdala on hypothalamo-pituitary-adrenocortical responses are mediated by hypothalamic norepinephrine, serotonin, and CRF-41.

The hypothalamic neural mechanisms that are involved in the facilitatory effects of the amygdala (AMG) on the hypothalamo-pituitary-adrenocortical (HPA) axis have been investigated in rats. Stimulation of the central AMG nucleus caused a depletion of hypothalamic CRF-41, presumably due to its release into the portal circulation, and a subsequent rise in plasma ACTH and corticosterone (CS) levels. These effects were inhibited in rats in which hypothalamic norepinephrine (NE) or serotonin (5-HT) was depleted by catecholamine or serotonin neurotoxins, respectively. Furthermore, the administration of prazosin, an alpha1, but not of atenolol, which is a beta-blocker, as well as administration of the 5-HT2 blocker ketanserin inhibited the ACTH and CS responses to AMG stimulation. These results indicate that the facilitatory effects of the AMG on the HPA axis are mediated by hypothalamic NE via alpha1 receptors and by 5-HT via 5-HT2 receptors, as well as by CRF-41 in the paraventricular nucleus.

Glucocorticoid receptor antagonists in the hippocampus modify the negative feedback following neural stimuli.

The effects of local glucocorticoid receptor antagonists implanted into the dorsal hippocampus on the hypothalamo-pituitary-adrenal (HPA) axis responses following neural stimuli in freely moving rats, as well as their effects on the negative feedback exerted by dexamethasone (DEX) was studied in male rats. In animals with hippocampal cholesterol implants, photic and acoustic stimuli caused depletion in median eminence (ME) CRH-41 and a consequent rise in plasma ACTH and corticosterone levels. These effects were inhibited by systemic DEX, and the latter phenomenon was partially reversed by hippocampal implants of glucocorticoid (GR) and to a lesser degree by mineralocorticoid (MR) receptor antagonists. These data indicate that GR and MR receptors in the hippocampus play a role in the glucocorticoid negative feedback on the HPA axis, although the hippocampus may have also a modulatory effect, which does not depend on glucocorticoids.

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.

Iontophoretic application of glucocorticoids inhibits identified neurones in the rat paraventricular nucleus

In an electrophysiological study designed to examine the negative feedback effects of glucocorticoid hormones, we have recorded the electrical activity of 147 neurones in the paraventricular nucleus of the rat hypothalamus. 37 (25%) of the neurones were antidromically identified as projecting to the median eminence and were located at a mean depth of 2.35 +/- 0.08 mm from the base of the brain, corresponding with the corticotropin-releasing factor-rich region of the nucleus. The mean firing rate of the identified cells was 4.7 +/- 0.6 Hz which was not significantly different from that of adjacent, unidentified cells (5.6 +/- 0.6 Hz). Most (17/18, 94%) of these cells tested responded to painful somatosensory stimuli and 26 (74%) of the identified cells were inhibited by iontophoretic application of corticosterone and/or hydrocortisone, whereas only one cell was excited and 8 unaffected. Of the identified cells, only 18 (20%) were inhibited, 36 (41%) were excited and 34 (39%) were non-responsive. The proportion of inhibitory responses was thus greater for the identified cells (P less than 0.005; chi 2-test). For the identified cells, whose spontaneous activity was unaffected by glucocorticoid application, glutamate-evoked responses could usually be depressed by the application. The time course of all responses usually showed an immediate onset, increasing in magnitude and continuing for extended periods following cessation of iontophoresis. Electrophysiologically identified magnocellular neurones were also tested and the majority (7/12, 58%) of vasopressin-secreting neurons were also found to be inhibited, whilst all (8/8, 100%) of the oxytocin-secreting neurones were excited by the glucocorticoid application. These results may represent an electrophysiological correlate of the negative feedback control of adrenocortical secretion and are discussed within this context.

Effects of septal and hippocampal stimuli on paraventricular nucleus neurons

The electrical activity of 125 neurons within the hypothalamic paraventricular nucleus was recorded in urethan-anaesthetized male rats. Spontaneous activity of the cells and their responses following electrical stimuli delivered to the ipsilateral lateral septum and dorsal hippocampus were recorded. The mean firing rate of all the cells recorded was 3.5 +/- 0.4 Hz and the majority were located within the dorsal and medial components of the paraventricular nucleus. Forty-six percent of the cells were inhibited following stimulation of the lateral septum (onset, 22.8 +/- 6.7 ms; offset, 195.1 +/- 28.5 ms). Inhibitory responses to dorsal hippocampus stimulation were recorded from 44% of all cells (onset, 28.1 +/- 4.7 ms; offset, 180.7 +/- 28.7 ms). Stimulation of both sites caused excitation of equal proportions (26%) of the cells tested (lateral septum onset, 47.7 +/- 4.5 ms; offset, 64.8 +/- 6.6 ms; dorsal hippocampus onset, 48.7 +/- 5.6 ms; offset, 72.3 +/- 8.8 ms). Of the sub-population of cells identified as projecting to the median eminence, inhibition was recorded from 50% following lateral septum stimulation and 43% following dorsal hippocampus stimulation, excitatory responses being recorded from only 9% of cells tested. The excitatory responses were only recorded from phasically firing, vasopressin-secreting cells identified as projecting to the median eminence, and also to the neurohypophysis. Following stimulation of either site, more phasic cells were excited whilst only few were inhibited. Continuously active cells, identified as projecting to the neurohypophysis, showed more mixed responses following stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)