David Saphier

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.

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 stimulation of the preoptic area on hypothalamic paraventricular nucleus unit activity and corticosterone secretion in freely moving rats

Recordings were made of single unit activity through chronically implanted electrodes within the hypothalamic paraventricular nucleus of freely moving male rats also bearing chronically implanted stimulating electrodes in the preoptic area (POA) and indwelling jugular cannulae. High frequency electrical stimulation of the POA evoked increases in the rate of electrical discharge in 58% of the units tested. Increases were recorded during each period of stimulation and were subsequently followed by a significant decrease in the rate of firing. In a substantial proportion of these neurones, bursting patterns of electrical discharge were observed before, during, and following stimulation of POA. When simultaneous removal of blood samples from these animals was performed, a significant increase in plasma corticosterone concentration, immediately following POA stimulation, was observed. The data obtained have provided a possible neurophysiological correlate of hypothalamic electrical activity that may be directly related to the neural control of adrenocortical secretion.

Selective facilitation of putative corticotropin-releasing factor-secreting neurones by interleukin-1.

The activity of single hypothalamic paraventricular nucleus (PVN) neurones was recorded in order to examine the mechanism by which the endogenous pyrogen interleukin-1 (IL-1) increases activity of the hypothalamo-hypophyseal-adrenocortical axis. IL-1 injected intravenously caused a rapid increase in the electrical activity of putative corticotropin-releasing factor (CRF)-secreting neurones located within the PVN. The activity of neighboring, electrophysiologically identified, vasopressin-secreting neurones was not altered by the stimulus, indicating a lack of involvement of this secretagogue of adrenocorticotropic hormone (ACTH) in this response to IL-1. These results support the concept of a rapid and specific activating effect of IL-1 upon hypothalamic CRF secretion as a part of a bidirectional communicating link between immune and central nervous systems.

Multiunit electrical activity in conscious rats during an immune response

Mechanisms by which the central nervous system may be influenced during the course of an immune response probably exist but remain obscure. In an attempt to determine any neurophysiological changes during such responses, we have employed a conscious animal model bearing chronically implanted recording electrodes in the preoptic area/anterior hypothalamus (PO/AH) and hypothalamic paraventricular nucleus (PVN). Rats were sensitized to sheep red blood cells (SRBC) injected intraperitoneally. Basal PO/AH multiunit activity (MUA) increased significantly to a maximum 5 days after SRBC injection and correlated with the initial appearance of anti-SRBC serum antibodies. Significant decreases in PO/AH MUA were recorded on Days 3 and 8 following the sensitization. PVN MUA decreased significantly for the first 3 days following immunization and then returned to a basal rate before increasing on Day 6. On the ninth and tenth days following the SRBC injection, both PO/AH and PVN MUA levels had returned to those recorded before immunization. A further group of animals was examined for PO/AH MUA changes during induction of a secondary response to SRBC. Firing rates increased significantly between Days 4 and 9 following the injection, the maximum increase being on Day 6. The profile of this response was different from that recorded during the first response, with no decreases recorded. The results are discussed in terms of neuroimmunomodulatory mechanisms such as those influencing neuroendocrine secretory function.

Central 5-HT1A Receptors Inhibit Adrenocortical Secretion

Serotonin (5-HT) is generally considered to serve a facilitatory role in the regulation of adrenocortical secretion. Numerous studies have shown that administration of 5-HT1A receptor agonists increases plasma corticosterone (CS) concentrations in rats; however, the mechanism has not been established. Rats were prepared with a cannula implanted above the lateral cerebral ventricle, or bilateral cannulae above the hypothalamic paraventricular nuclei (PVN), the site of the perikarya of corticotropin-releasing factor (CRF)-secreting neurons regulating adrenocortical secretion. In sodium pentobarbital-anesthetized rats, intracerebroventricular and intra-PVN administration of 5-HT resulted in a multi-component dose-response curve in plasma CS, whereas administration of 5-HT in conscious animals resulted in low-dose inhibition and higher dose elevation of plasma CS levels. Under pentobarbital anesthesia, central administration of the selective 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone decreased plasma CS levels, relative to saline-treated control rats, at all doses tested (0.001-20 nmol). In conscious rats, administration of 8-OH-DPAT decreased adrenocortical secretion at lower doses and significantly increased plasma CS concentrations at higher doses. Ipsapirone produced similar but less pronounced effects. In contrast, intraperitoneal injection of 8-OH-DPAT (2 mumol/kg) increased plasma CS concentrations, but this was not prevented by prior intracerebroventricular administration of the 5-HT1A antagonist, NAN-190 (5 nmol). Pentobarbital anesthesia completely blocked the plasma CS response to peripheral administration of 8-OH-DPAT. In view of the adrenocortical activating effects of hypotensive stimuli, we speculate that the well-documented hemodynamic changes following 5-HT1A receptor stimulation may be responsible for the adrenocortical responses observed. Our data demonstrate that low doses of 5-HT1A agonists delivered directly into the CNS decrease adrenocortical secretion. Since intra-PVN injections of 8-OH-DPAT to pentobarbital-anesthetized rats also decreased hypothalamo-pituitary-adrenocortical activity, it appears that a component of the inhibitory effect of 5-HT1A receptor activation is mediated by a direct effect at the level of the PVN, and presumably involves CRF-secreting neurons.

Electrophysiology of limbic forebrain and paraventricular nucleus connections

The connections of forebrain structures with the hypothalamic paraventricular nucleus (PVN) were examined electrophysiologically in anaesthetized male rats. Single unit recordings from 336 neurons were made within the cingulate cortex (CC, n = 78), lateral septum (LS, 114), bed nucleus of the stria terminalis (BST, 27). bed nucleus proprioris commissurae (BCA, 27) and preoptic area (POA, 90). Following PVN stimulation, some cells in all regions were identified as projecting to the PVN. Antidromic (24%), orthodromic excitatory (44%) and inhibitory (22%) responses recorded from CC units demonstrated the presence of reciprocal pathways between PVN and CC. Thirty-eight percent of LS units were antidromically identified as projecting to the PVN and these appeared to show some discrete topographic organization. Fifty-seven percent of LS units responded orthodromically to stimulation of the PVN, the majority of such responses being excitatory. Within the bed nuclei, 24% of units were antidromically identified as projecting to PVN and 70% of cells in these regions responded orthodromically following PVN stimulation, excitatory responses predominating within the BST and inhibitory responses within the BCA. Within the POA, 38% of units were identified as projecting to the PVN and the remaining units were approximately divided between orthodromic excitatory and inhibitory responses. A small proportion of antidromically identified units (less than 20%) in all regions also exhibited responses suggesting the presence of reciprocal connections with the PVN.

Effects of Intracerebroventricular and Intrahypothalamic Cocaine Administration on Adrenocortical Secretion

Cocaine (COC) has been described as exerting potent stimulatory effects on the hypothalamo-pituitary-adrenocortical (HPA) axis. In the present study, we investigated the acute and chronic effects of intracerebroventricular and intrahypothalamic injections of COC in rats. Twenty minutes following intracerebroventricular injection of COC (1-100 micrograms), dose-dependent increases in plasma corticosterone (CS) were observed, although the highest dose tested (100 micrograms) evoked a significantly smaller response than that following 50 micrograms. Prior stressing of the animals resulted in elevated plasma CS levels (315 +/- 16 ng/ml) and significantly decreased plasma CS concentrations following 50 micrograms COC (87.8 +/- 3.2%). Injections above the hypothalamic paraventricular nucleus (PVN), the site of corticotropin-releasing-factor-secreting neurons which regulate HPA activity, required relatively higher doses of COC in order to elicit increases in plasma CS; injections of 0.5 microgram had no effect, 1 microgram resulted in an increase to 168 +/- 68 ng/ml (p < 0.005), and 2.5 micrograms produced an increase to 146 +/- 29 ng/ml (p < 0.025). Post-PVN injections of COC, behind the posterior margin of the PVN in the vicinity of the ventral noradrenergic ascending bundle, also required a high dose (2.5 micrograms) in order to elicit a plasma CS response (208 +/- 19 ng/ml; p < 0.005), with no significant response seen following 0.5 microgram COC. No effects of specific neurotoxic lesions of the catecholaminergic or serotonergic innervation of the hypothalamus were observed upon adrenocortical responses to COC.(ABSTRACT TRUNCATED AT 250 WORDS)

Catecholaminergic projections to tuberoinfundibular neurones of the paraventricular nucleus: I. Effects of stimulation of A1, A2, A6 and C2 cell groups

Extracellular electrical activity was recorded from 203 paraventricular nucleus (PVN) neurones antidromically identified as projecting to the median eminence. Spontaneous activity and the effects of stimulation of the A1, A2, A6 and C2 catecholaminergic cell groups upon the PVN neurones were examined. Cells were located at a mean height 2.29 +/- 0.03 mm above the base of the brain, corresponding with the corticotropin-releasing factor (CRF) rich component of the nucleus. The mean firing rate was 3.2 +/- 0.3 Hz and antidromic invasion latency was 9.9 +/- 0.3 msec. Seventy-six % of cells tested were activated by painful somatosensory stimuli. Electrical stimulation of the A1 or A2 region evoked excitatory responses from the majority of cells tested (76% and 85%, respectively), whilst stimulation of the A6 and C2 regions evoked more inhibitory responses (43% and 59%, respectively). Most responses (56%), whether excitatory or inhibitory, were not clearly defined in terms of latency, and were only observed following delivery of 5-10 single shocks at 0.5 Hz. Excitation recorded following A1 and A2 stimulation suggests a facilitatory role for noradrenaline in the regulation of PVN activity. Inhibitory responses following C2 stimulation indicate that adrenaline may serve to inhibit such activity, whilst the more mixed responses following A6 stimulation suggest that the projections of this region differ in some way from those of the A1 and A2 cells. Response reversals were observed, after delivery of higher frequency stimulation, for a substantial proportion (20%) of the cells tested.

Effect of interleukin-1 on adrenocortical activity in intact and hypothalamic deafferentated male rats.

SummaryThe present study was designed to elucidate the site of action of interleukin 1 (IL-1) modulation of the hypothalamic-hypophyseal-adrenal (HHA) axis. An intraperitoneal injection of recombinant human IL-1β (160 U/rat) significantly elevated serum levels of ACTH and corticosterone (CS). In rats with complete mediobasal hypothalamic deafferentation, the HHA response to IL-1 was inhibited. An intracerebroventricular injection of rIL-1 (2 U/ rat) caused a marked increase in serum ACTH and CS. These results suggest that IL-1 activates the HHA axis by a direct effect upon the brain, and that intact neural connections between the mediobasal hypothalamus and extrahypothalamic brain regions are essential for IL-1-induced HHA responses.