Efferent projections from the paraventricular nucleus mediating alpha 2-noradrenergic feeding

Feeding behavior elicited by central injection of the alpha-noradrenergic agonists, norepinephrine (NE) and clonidine (CLON), are believed to be mediated via postsynaptic alpha 2-type receptors located in the paraventricular nucleus (PVN). To map the course taken by essential efferent (descending) fibers of this PVN system for noradrenergically-stimulated feeding, the impact of diencephalic and lower brainstem coronal knife cuts, on the responses elicited by PVN-injected NE and CLON, was assessed. Rats that sustained damage in the periventricular gray area of the caudal thalamus and midbrain exhibited significant losses in feeding elicited by PVN injections of these drugs. In the case of animals with midbrain periventricular gray knife cuts, a significant increase in daily food intake was also observed, and this increase was positively correlated in magnitude with the attenuation of NE-induced feeding. This decrease in sensitivity to alpha 2-noradrenergic stimulation occurred with discrete periventricular knife cuts extending only 0.5 mm lateral to midline. In contrast, large ventral or lateral coronal knife cuts throughout the dorsal and ventral midbrain tegmentum left intact NE- and CLON-induced feeding. These findings provide evidence for localization of anatomical substrates which underlie PVN alpha 2-noradrenergic feeding. The efferent fibers of this system appear to exit from the PVN in a dorsomedial direction and course through the thalamic periventricular area. As this projection descends into the midbrain, it remains quite medial, maintaining this position throughout the midbrain central gray substance. At the level of the pons, just rostral to the locus coeruleus, this fiber projection appears to course ventrolaterally into the dorsolateral pontine tegmentum and possibly continue towards the dorsal vagal complex of the dorsomedial medulla.     

3-Methoxy-4-hydroxyphenylethyleneglycol concentrations in discrete hypothalamic nuclei reflect the activity of noradrenergic neurons

An analytical technique is described which permits the quantitation of picogram concentrations of 3-methoxy-4-hydroxyphenylethylene-glycol (MHPG) in acid hydrolyzed extracts of microdissected regions of the rat brain, and this procedure is used to determine if alterations in the activity of noradrenergic neurons are reflected by changes in the concentrations of MHPG in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the rat hypothalamus. MHPG was not detected in non-hydrolyzed samples of either the PVN or SON, but following acid hydrolysis (heating of samples at 94 degrees C for 5 min in 0.16 M perchloric acid) MHPG was detected in both of these regions. These results indicate that MHPG exists primarily as a conjugate in the PVN and SON. Neurotoxin-induced lesions of the ventral noradrenergic bundle decreased norepinephrine (NE) and MHPG concentrations in the PVN and SON, demonstrating that tissue levels of MHPG in these brain regions are dependent upon the presence of noradrenergic neurons. Electrical stimulation of the locus coeruleus increased MHPG concentrations in the PVN, but not in the SON, whereas electrical stimulation of the medial forebrain bundle increased MHPG concentrations in both of these regions. The alpha 2-adrenergic receptor antagonist idazoxan increased, while the alpha 2-adrenergic receptor agonist clonidine decreased MHPG concentrations in both the PVN and SON, but neither idazoxan nor clonidine altered NE concentrations in these regions. Immobilization of rats in the supine position increased MHPG concentrations in the PVN and SON, and this was accompanied by a decrease in NE concentrations in the SON.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypothalamic paraventricular nucleus: interaction between alpha 2-noradrenergic system and circulating hormones and nutrients in relation to energy balance

Extensive evidence suggests that norepinephrine (NE) in the brain is active in the control of eating behavior. Central injection studies demonstrate a stimulatory effect of NE on food intake, a response which is mediated by alpha 2-noradrenergic receptors located in the medial hypothalamus, in particular the paraventricular nucleus (PVN). Activation of these PVN receptors stimulates ingestion specifically of carbohydrate-rich foods, and this response is believed to reflect the role of endogenous NE in controlling natural appetite for this macronutrient. This alpha 2-noradrenergic system in the PVN appears to be physiologically activated at the onset of the animals' active cycle, when there is a natural peak in preference for carbohydrate. At this time, the adrenal hormone corticosterone, which is known to play a major role in carbohydrate metabolism, is found to interact positively with NE in the potentiation of carbohydrate ingestion. Circulating glucose also influences the activity of PVN alpha 2-noradrenergic receptors at this time, and, moreover, alpha-noradrenergic stimulation of the PVN produces an increase in circulating levels of both corticosterone and glucose. This and other evidence has led to the hypothesis that NE in the PVN, through the activation of glucocorticoid- and glucose-sensitive alpha 2-receptor sites, is physiologically active in energy homeostasis, most particularly at the onset of the animal's active cycle. Specifically, this neurotransmitter in the PVN evokes a state of energy conservation. This state involves adjustments in carbohydrate ingestion as well as metabolism, that allow animals to maintain energy reserves by anticipating or responding to a depletion.     

Efferent projections from the paraventricular nucleus mediating α2-noradrenergic feeding

Feeding behavior elicited by central injection of the α-noradrenergic agonists, norepinephrine (NE) and clonidine (CLON), are believed to be mediated via postsynapticα₂-type receptors located in the paraventricular nucleus (PVN). To map the course taken by essential efferent (descending) fibers of this PVN system for noradrenergically-stimulated feeding, the impact of diencephalic and lower brainstem coronal knife cuts, on the responses elicited by PVN-injected NE and CLON, was assessed. Rats that sustained damage in the periventricular gray area of the caudal thalamus and midbrain exhibited significant losses in feeding elicited by PVN injections of these drugs. In the case of animals with midbrain periventricular gray knife cuts, a significant increase in daily food intake was also observed, and this increase was positively correlated in magnitude with the attenuation of NE-induced feeding. This decrease in sensitivity toα₂-noradrenergic stimulation occurred with discrete periventricular knife cuts extending only 0.5 mm lateral to midline. In contrast, large ventral or lateral coronal knife cuts throughout the dorsal and ventral midbrain tegmentum left intact NE- and CLON-induced feeding. These findings provide evidence for localization of anatomical substrates which underlie PVNα₂-noradrenergic feeding. The efferent fibers of this system appear to exit from the PVN in a dorsomedial direction and course through the thalamic periventricular area. As this projection descends into the midbrain, it remains quite medial, maintaining this position throughout the midbrain central gray substance. At the level of the pons, just rostral to the locus coeruleus, this fiber projection appears to course ventrolaterally into the dorsolateral pontine tegmentum and possibly continue towards the dorsal vagal complex of the dorsomedial medulla.     

The pharmaco-ontogeny of the perifornical lateral hypothalamic beta 2-adrenergic and dopaminergic receptor systems mediating epinephrine- and dopamine-induced suppression of feeding in the rat.

The functional ontogeny of beta 2-adrenergic and dopaminergic receptors in the perifornical lateral hypothalamus (PLH) that mediate adrenergic and dopaminergic suppression of feeding in rats was investigated. Rat pups, ranging in age from 2 to 15 days, were removed from their mothers and implanted with a brain cannula directed unilaterally at the PLH or a more rostral site lateral to the anterior nucleus of the hypothalamus. On the next day, following a 22-h period of food and water deprivation, each pup was implanted with an intra-oral cannula for oral infusion of milk that could be swallowed or rejected. Subsequently, each pup received an intracerebral injection of saline, or a single dose of epinephrine (EPI, 0.1-30.0 nmol), the beta 2-adrenergic receptor agonist salbutamol (1.0-30.0 nmol) or the dopaminergic receptor agonist apomorphine (1.0-30.0 nmol). Milk intake was then assessed following a 1-h period of infusion. The results showed significant dose-dependent suppression of milk intake in pups as young as 2 days of age in response to PLH injection of EPI, salbutamol and apomorphine. In contrast to its effectiveness in the PLH at 2 days of age, EPI failed to suppress milk intake at this age following injection into a more rostral site lateral to the anterior nucleus of the hypothalamus. Together, these findings suggest that both beta 2-adrenergic and dopaminergic receptors, mediating adrenergic and dopaminergic suppression of feeding, are functionally mature very early in the postnatal development of the rat. Moreover, consistent with evidence in adult rats, these catecholaminergic receptors in young pups appear to be located in the region of the PLH.     

Microinjection of the alpha 1-agonist methoxamine into the paraventricular hypothalamus induces anorexia in rats.

Adrenergic receptors within the paraventricular hypothalamus (PVN) play a prominent role in the control of food intake: stimulation of alpha 2-adrenoceptors induces food intake whereas stimulation of alpha 1-adrenoceptors suppresses food intake. This study further examines the role of PVN alpha 1-adrenoceptors by examining the effects on food and water intake of the alpha 1-adrenergic agonist methoxamine (100, 200, 400 nMol) microinjected into the rat paraventricular hypothalamus. Methoxamine suppressed food intake but not water intake. Doses of 100, 200, and 400 nMol methoxamine suppressed food intake by 47%, 64%, and 96%, respectively. These results further confirm the hypothesis that administration of alpha 1-agonists into the PVN acts to significantly suppress food intake; an action that is in opposition to the facilitory effects of alpha 2-adrenergic agonists on food intake.     

Peptide-amine interactions in the hypothalamic paraventricular nucleus: analysis of galanin and neuropeptide Y in relation to feeding.

The neuropeptide galanin (GAL) has been found to elicit feeding after injection into the paraventricular hypothalamic nucleus (PVN), where it coexists with norepinephrine (NE), a neurotransmitter believed to be important in the control of natural feeding behavior. Using pharmacological tools, this study investigated the possibility that PVN GAL influences food intake via its direct interaction with the noradrenergic system localized in this nucleus. Tests with alpha-adrenergic receptor blockers demonstrated that GAL-induced feeding, similar to NE-stimulated feeding, depends specifically upon functional alpha 2-receptor sites. Further, experimentation with the catecholamine synthesis inhibitors, alpha-methyl-p-tyrosine and Fla-63, suggested that GAL's action also depends upon the release of endogenous NE. This is in contrast to another hypothalamic peptide, neuropeptide Y, which is also a strong stimulant of food intake and coexists with NE in the PVN. Neuropeptide Y remains effective in eliciting feeding in the presence of alpha 2-receptor antagonists and catecholamine-synthesis inhibitors, suggesting that, unlike GAL, it can act independently of endogenous NE.     

Hypophysectomy disturbs the noradrenergic feeding system of the paraventricular nucleus

Injection of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN) of satiated rats is known to stimulate eating behavior. In addition, drinking behavior is potentiated just prior to the onset of eating, followed by a strong inhibition of water intake. To understand the relationship between these PVN noradrenergic phenomena and endocrine processes associated with the PVN, chronically hypophysectomized animals were tested for their behavioral responsiveness to PVN NE injection. Pituitary ablation was found to abolish the NE-elicited eating response and the NE drinking suppressive effect. However, hypophysectomy had no impact on the NE-elicited preprandial drinking response, nor did it affect drinking produced by carbachol, angiotensin, and histamine, or the feeding and drinking responses induced by insulin. These results demonstrate that hypophysectomy disturbs PVN noradrenergic mechanisms in a behaviorally and pharmacologically specific specific manner.     

Noradrenergic innervation of the paraventricular nucleus: Specific role in control of carbohydrate ingestion

Acute injections of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN) have been shown to elicit eating in satiated rats. The present report examines the effects of acute and chronic PVN infusion of NE on intake of various liquid and mixed solid diets and on selection of the pure macronutrients, carbohydrate, protein, and fat. The results demonstrate that noradrenergic stimulation of the PVN (40 nmoles of NE) reliably enhances ingestion of pure sucrose diets (liquid and solid) and also of sweet and non-sweet milk solutions. Saccharin intake, in contrast, is unaffected. In preference tests, rats injected with NE show a greater increase in consumption of sucrose cubes compared with lab chow pellets, but exhibit an equivalent preference for sweet and non-sweet carbohydrate-rich diets. Tests with the three pure macronutrients simultaneously available reveal, after NE injection, a strong and selective increase in consumption of carbohydrate, with little or no change in intake of fat and, in some cases, a suppression of protein intake. This clear preference for carbohydrate can be seen with chronic NE infusion (5 nmoles every 30 min over a 14-day period), as well as after acute NE injection (40 nmoles), and also with long-term (24-hr) as well as short-term (1-hr) food intake measurements. This and other evidence suggests that the PVN noradrenergic system may play a specific and unique role in the control of carbohydrate ingestion.     

CCK and other peptides modulate hypothalamic norepinephrine release in the rat: Dependence on hunger or satiety

The purpose of this investigation was to determine the functional relationship between putative satiety peptides and endogenous norepinephrine (NE) activity in the hypothalamus. Permanent guide cannulae for push-pull perfusion were implanted stereotaxically in Sprague-Dawley rats so as to rest above the medial or lateral hypothalamus (LH). Post-operatively, the animals were either satiated with food and water, both available ad lib, or fasted for 18-22 hr prior to an experiment. To perfuse a site in the LH, paraventricular (PVN) or ventromedial nucleus (VMN), a concentric 29-23 ga push-pull cannula system was lowered to a pre-determined site, in most cases after catecholamine stores had been pre-labeled with [3H]-NE. During control tests, an artificial CSF was perfused at a rate of 20-25 microliter/min for 5-8 min with a 5 min interval between each sample. The addition of cholecystokinin (CCK) in a concentration of 2.0-6.0 ng/microliter to the CSF perfused in PVN or VMN of the satiated rat enhanced the efflux of NE; however, in the fasted animal CCK often suppressed the catecholamine's release. Perfused in the LH, CCK exerted opposite effects, typically augmenting NE output when the rat was fasted but not affecting the amine's activity during the sated condition. Proglumide (1.2 micrograms/microliter) attenuated CCK's effect in releasing NE when the antagonist was perfused in the PVN of the satiated rat. Similar experiments in which neurotensin (NT) was perfused in the LH, PVN and VMN revealed virtually the same inverse effects on NE release in the fasted and satiated rat, which again were anatomically specific. Finally, insulin and 2-deoxy-D-glucose (2-DG) exerted similar state-dependent effects on the release of NE within LH and PVN. Overall, the results suggest that CCK or other neuroactive peptide could serve as a "neuromodulator" of the pre-synaptic release of NE within classical hypothalamic structures which are thought to underlie both hunger and satiety. The state-dependent nature of the peptides' activity on the noradrenergic feeding mechanism implies that these substances constitute a pivotal portion of the profile of factors which impinge functionally upon the hypothalamic neurons responsible for the feeding response and its cessation.     

Noradrenergic regulation of cytosol estrogen receptors in female rat hypothalamus: possible role of alpha 2-noradrenergic receptors

Because of the previous work demonstrating that the alpha 1-noradrenergic receptor antagonist, prazosin, decreases the concentration of cytosol estrogen receptors in rat mediobasal hypothalamus, a series of experiments was performed to determine the specificity of this effect to the alpha 1-noradrenergic system. Injection of the alpha 2-noradrenergic antagonist, yohimbine, caused a decrease in the concentration of estrogen receptors in mediobasal hypothalamus. In addition, the down-regulation of cytosol estrogen receptors by either the alpha 1-noradrenergic antagonist, prazosin, or the alpha 2-noradrenergic antagonist, yohimbine, could be blocked by pretreatment with the alpha 2-noradrenergic agonist, clonidine. The alpha 1-noradrenergic agonist, phenylephrine, was ineffective in blocking the effects of the alpha 1-noradrenergic antagonist, prazosin. These results add further support to the hypothesis that the alpha-noradrenergic system modulates the concentration of cytosol estrogen receptors in the rat hypothalamus. They suggest that the modulation may occur by way of alpha 2-noradrenergic receptors in addition to, or instead of, alpha 1-noradrenergic receptors.     

PVN steroid implants: effect on feeding patterns and macronutrient selection

The glucocorticoid corticosterone (CORT) plays a major role in feeding behavior, body weight regulation and metabolism. Recent work has demonstrated an interaction between circulating CORT and the alpha 2-noradrenergic feeding system of the hypothalamic paraventricular nucleus (PVN) and the existence of two different subtypes of glucocorticoid receptors in this nucleus. To examine the function of these specific PVN receptors, crystalline CORT and other steroid hormones were implanted directly into the PVN, and feeding patterns and macronutrient selection, of freely feeding adrenalectomized (ADX) and sham rats, were monitored at the beginning and end of the nocturnal feeding cycle. Results indicate that PVN CORT implants stimulate carbohydrate intake in ADX rats, at the onset of the dark cycle when the feeding-suppressive effects of ADX are strongest. Corticosterone was ineffective in sham rats and was also ineffective in potentiating food intake in ADX rats at the end of the dark phase. In contrast, implants of the mineralocorticoid aldosterone (ALDO) stimulated the ingestion of the fat diet, in both sham and ADX rats and during both the early and the late dark periods. Implants of ALDO also enhanced carbohydrate intake, but only in ADX rats and at dark onset. While the synthetic glucocorticoid, dexamethasone, had a small carbohydrate stimulatory effect similar to CORT, other steroids (deoxycorticosterone, progesterone and estrogen) were without effect. These results indicate a central site of action for the adrenal hormones in modulating nutrient intake. Based on a variety of evidence, it is suggested that the stimulatory effects of ALDO and CORT on macronutrient intake may be differentially mediated by Type 1 and Type 2 steroid receptor subtypes within the brain.     

The noradrenergic innervation of vasopressin neurons in the paraventricular nucleus of the hypothalamus: An ultrastructural study using radioautography and immunocytochemistry

Immunocytochemical and radioautographic procedures were combined at the ultrastructural level to study the noradrenergic synaptic input to vasopressin neurons in selected portions of the paraventricular nucleus of the hypothalamus (PVN) of the rat. Radioactive norepinephrine (NE) was infused into the lateral ventricle or applied topically to the region of the PVN. After appropriate survival times, brain tissues were processed for ultrastructural immunocytochemical demonstration of vasopressin using a monoclonal antibody. [3H]NE varicosities were detected by electron microscopic radioautography. In the periventricular zone of the PVN, radioactive varicosities were numerous accounting for 20-30% of all nerve terminals in this zones. These NE terminals primarily innervated dendritic processes of non-vasopressinergic neurons. Although an occasional axosomatic synapse was observed, input to vasopressin positive neurons was exclusively to their dendrites. In the lateral magnocellular sub-nucleus of the PVN (designed pvl2), noradrenergic terminals were fewer in number accounting for only 1-2% of the total. These terminals were found predominately but not exclusively making axodendritic synapses onto non-vasopressin processes. In both regions, many of the radiolabeled terminals had well-defined membrane appositions with their post-synaptic partners which included a synaptic cleft and post-synaptic density of varying thickness. In both the periventricular zone and the lateral magnocellular regions, noradrenergic varicosities were seen in close proximity to numerous blood vessels.     

Chronic infusion of norepinephrine and clonidine into the hypothalamic paraventricular nucleus

Previous experiments have shown that acute injection of NE and CLON into the PVN initiates a short-term feeding response in satiated rats. This study examined, in brain-cannulated rats, the impact of remote, chronic injections of NE, CLON, or saline on daily food intake and body weight gain. Over a period of 14 days, NE was infused into the PVN, either continuously at a rate of 12 nm/microliter/hr, or discretely at a rate of 6 nm/microliter/sec. In addition, the alpha 2-adrenergic agonist CLON was infused into the PVN discretely at a rate of 3 nm/0.5 microliter/30 sec. Relative to saline infusion, chronic (continuous or discrete) stimulation of the PVN with either of these drugs was effective in potentiating daily food intake by 12-19% and in increasing body weight gain, from approximately 1.5 g/day to 3.3 g/day. This evidence indicates that medial hypothalamic NE, especially within the PVN, is sufficiently robust to alter long-term feeding patterns and body weight regulation.     

Impact of food deprivation on alpha 1- and alpha 2-noradrenergic receptors in the paraventricular nucleus and other hypothalamic areas

Hypothalamic norepinephrine may modulate normal eating behavior through activation of alpha 2-noradrenergic receptors, localized in the paraventricular nucleus (PVN). We investigated whether these receptors, which stimulate food ingestion, may in turn be altered by the nutritional state of the organism. Thus the impact of food deprivation, on the specific binding of [3H]-p-aminoclonidine ([3H]PAC) to alpha 2-noradrenergic receptors in discrete hypothalamic areas, was examined in rats. The results of our first experiment revealed that 48 hr food deprivation reduced (by 50%) the maximum number of binding sites (Bmax) of the high affinity component of [3H]PAC binding to alpha 2 receptors. This effect occurred exclusively in the medial hypothalamus (which includes the PVN), without any change in the affinity (Kd) of these receptors. A smaller decline was seen in the low affinity binding sites of the medial hypothalamus, whereas no changes were observed in the density or affinity of the high and low affinity alpha 2 receptor sites in the lateral hypothalamus or frontal cortex. The alpha 1-noradrenergic receptor sites, as defined by [3H]prazosin and [3H]WB-4101 binding, were also unaffected in the different brain areas by 48 hr food deprivation. An additional analysis of alpha 2 receptors in discrete hypothalamic nuclei demonstrated that the deprivation-induced decline in alpha 2-receptor binding: occurred specifically in the PVN; was apparent after as little as 3 hr food deprivation; and occurred only when this brief deprivation fell at the onset of the dark cycle, as opposed to at the end of the dark cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of norepinephrine infused in the paraventricular hypothalamus on energy expenditure in the rat

The metabolic effects of norepinephrine (NE), when infused into the paraventricular nucleus of the hypothalamus (PVN), were examined using indirect calorimetry. In two separate experiments, it was found that NE infused into the PVN reduced energy expenditure in freely moving rats. While NE also reduced motor activity, these reductions were not statistically significant. Reductions in voluntary motor activity were not necessary for a reduction in energy expenditure, as NE still reduced energy expenditure in rats that were lightly sedated. Clonidine, but not L-phenylephrine, mimicked the hypometabolic effect of NE, suggesting an action at alpha 2 receptors. Infusions of NE were also found to increase blood glucose shortly after infusion, although the specificity of this effect is questionable. Taken together, these data suggest that activation of noradrenergic neurons within the PVN results in a metabolic shift towards energy conservation.     

Microinjection of the α1-agonist methoxamine into the paraventricular hypothalamus induces anorexia in rats

Adrenergic receptors within the paraventricular hypothalamus (PVN) play a prominent role in the control of food intake: stimulation of α2-adrenoceptors induces food intake whereas stimulation of α1-adrenoceptors suppresses food intake. This study further examines the role of PVN α1-adrenoceptors hy examining the effects on food and water intake of the α1-adrenergic agonist methoxamine (100, 200, 400 nMol) microinjected into the rat paraventricular hypothalamus. Methoxamine suppressed food intake but not water intake. Doses of 100, 200, and 400 nMol methoxamine suppressed food intake by 47%. 64%, and 96%, respectively. These results further confirm the hypothesis that administration of α1-agonists into the PVN acts to significantly suppress food intake; an action that is in opposition to the facilitory effects of α2-adrenergic agonists on food intake.     

Prefrontal cortex alpha 2 adrenoceptors and energy balance.

The sulcal prefrontal cortex (SPC) influences thermogenesis, energy substrate utilization and feeding behaviour. The present study examined the role of SPC alpha noradrenergic receptors in these effects. Fifty nmol norepinephrine (NE) injected into the SPC produced a large and long-lasting increase in respiratory quotient (RQ), indicating enhanced carbohydrate utilization and fat synthesis. This dose also reduced energy expenditure without corresponding decreases in locomotor activity, suggesting an inhibition of thermogenesis. Neither a lower dose of NE (25 nmol) injected into the SPC, nor injections of NE (50 nmol) into a variety of sites adjacent to the SPC affected energy balance. The alpha 2 agonist clonidine (20 nmol) injected into the SPC produced similar effects to 50 nmol NE, with a large increase in RQ and a decrease in thermogenesis. Forty nmol clonidine, however, decreased RQ and reduced both energy expenditure and activity. The alpha 1 agonist L-phenylephrine (20 and 40 nmol) injected into the SPC had no clear effect on energy balance. Finally, it was shown that clonidine or NE injected into the SPC promotes food intake. These results implicate alpha 2 adrenoceptors in the sulcal prefrontal cortex in the control of food intake, thermogenesis and metabolic substrate utilization.     

Mapping study of noradrenergic stimulation of vasopressin release

The precise role of hypothalamic norepinephrine (NE) in the control of vasopressin (AVP) release has remained unclear, due to reports of both inhibitory and excitatory effects of NE and only a few studies with direct hypothalamic manipulations. The present study utilized a chronically implanted swivel brain cannula to investigate, in undisturbed and freely behaving rats, the impact of acute hypothalamic infusions of monoamines on circulating AVP levels. The first study examined and compared the responsiveness of six hypothalamic sites to NE infusion through the swivel cannula. Results indicated that the excitatory effect of central noradrenergic stimulation on serum AVP is highly site specific, localized to the paraventricular (PVN) and supraoptic (SON) nuclei. These two nuclei appeared to be equally responsive to NE infusion, yielding a threefold rise in serum AVP over baseline levels. In contrast, NE in the dorsomedial nucleus produced a significantly smaller increase in AVP, and no response was observed in the ventromedial nucleus, posterior hypothalamus, or perifornical lateral hypothalamus. Further tests conducted in the PVN showed this nucleus to respond in a dose-dependent manner to NE infusion. In contrast, under similar test conditions, dopamine caused only a small increase in AVP at a relatively high dose, while a PVN injection of serotonin produced no response. These results support the existence of an excitatory noradrenergic system controlling AVP release and specifically demonstrate that this function of NE is localized to the PVN and SON, in contrast to other hypothalamic areas, and is mimicked to some extent by dopamine but not by serotonin.     

Alpha2-adrenoceptor-mediated restraint of norepinephrine synthesis, release, and turnover during immobilization in rats

Stress-related release of norepinephrine (NE) in the brain and periphery probably underlies several neuroendocrine and neurocirculatory responses. NE might influence its own synthesis, release, and turnover, by negative feedback regulation via alpha2-adrenoceptors. We examined central and peripheral noradrenergic function by measuring concentrations of NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylacetic acid (DOPAC) in hypothalamic paraventricular nucleus (PVN) microdialysate and arterial plasma simultaneously during immobilization (IMMO) in conscious rats. The alpha2-adrenoceptor antagonist yohimbine (YOH) was injected i.p. or perfused locally into the PVN via the microdialysis probe. The i.p. YOH increased plasma NE, epinephrine (EPI), DHPG, dihydroxyphenylalanine, and DOPAC levels by 4.3, 7.3, 2.5, 0.6 and 1.8-fold and PVN microdialysate NE, DHPG, and DOPAC by 1. 2, 0.6 and 0.5-fold. The i.p. YOH also enhanced effects of IMMO on plasma and microdialysate NE, DHPG, and DOPAC. YOH delivered via the PVN microdialysis probe did not affect microdialysate or plasma levels of the analytes at baseline and only slightly augmented microdialysate NE responses to IMMO. The results indicate that alpha2-adrenoceptors tonically restrain NE synthesis, release, and turnover in sympathetic nerves and limit IMMO-induced peripheral noradrenergic activation. In the PVN, alpha2-adrenoceptors do not appear to contribute to these processes tonically and exert relatively little restraint on IMMO-induced local noradrenergic activation.