Biomedical subjects

E R Gillard

Publications and source records attributed to E R Gillard.

8 recordsLinked to original sources

PubMed2006

Vasopressin autoreceptors and nitric oxide-dependent glutamate release are required for somatodendritic vasopressin release from rat magnocellular neuroendocrine cells responding to osmotic stimuli.

Magnocellular neuroendocrine cells of the supraoptic nucleus (SON) release vasopressin (VP) systemically and locally during osmotic challenge. Although both central VP and nitric oxide (NO) release appear to reduce osmotically stimulated systemic VP release, it is unknown whether they interact locally in the SON to enhance somatodendritic release of VP, a phenomenon believed to regulate systemic VP release. In this study, we examined the contribution of VP receptor subtypes and NO to local VP release from the rat SON elicited by systemic injection of 3.5 m saline. Treatment of SON punches with VP receptor antagonists decreased osmotically stimulated intranuclear VP release. Similarly, blockade of NO production, or addition of NO scavengers, reduced stimulated VP, glutamate, and aspartate release, suggesting that local NO production and activity are critical for osmotically induced intranuclear VP and excitatory amino acid release. An increase in endogenous NO release from SON punches in response to hyperosmolality was confirmed by enzymatic NO assay. Consistent with enhanced glutamate and VP release from stimulated rat SON punches, the ionotropic glutamate receptor blocker kynurenate decreased stimulated local VP release without affecting NO release. These data suggest that NO enhances local VP release in part by facilitating local release of glutamate/aspartate and that glutamate receptor activity is required for the stimulation of local VP release by osmotic challenge. Collectively, these results suggest that local VP receptors, NO, and glutamatergic signaling mediate the amplification of intranuclear VP release during hyperosmolality and may contribute to efficient, but not exhaustive, systemic release of VP during osmoregulatory challenge.

Amino Acids↗

PubMed2005

A novel role for endogenous pituitary adenylate cyclase activating polypeptide in the magnocellular neuroendocrine system.

Central release of vasopressin (VP) by the magnocellular neuroendocrine cells (MNCs) responsible for systemic VP release is believed to be important in modulating the activity of these neurons during dehydration. Central VP release from MNC somata and dendrites is stimulated by both dehydration and pituitary adenylate cyclase activating polypeptide (PACAP). Although PACAP is expressed in MNCs, its potential role in the magnocellular response to dehydration is unexplored. The current study demonstrates that prolonged dehydration increases immunoreactivity for PACAP-27, PACAP-38, and the type I PACAP receptor in the supraoptic nucleus (SON) of the rat. In addition, PACAP stimulates local VP release in the euhydrated rat SON in vitro, and this effect is reduced by the PACAP receptor antagonist PAC(6-27) (100 nm), suggesting the participation of PACAP receptors. Concomitant with its effects on local VP release, PACAP also reduces basal glutamate and aspartate release in the euhydrated rat SON. Furthermore, somatodendritic VP release elicited by acute dehydration is blocked by PAC(6-27), suggesting that endogenous PACAP participates in this response. Consistent with this, RIA revealed that local PACAP-38 release within the SON is significantly elevated during acute dehydration. These results suggest that prolonged activation of hypothalamic MNCs is accompanied by up-regulation of PACAP and the type I PACAP receptor in these cells and that somatodendritic VP release in response to acute dehydration is mediated by activation of PACAP receptors by endogenous PACAP released within the SON. A potential role for PACAP in promoting efficient, but not exhaustive, systemic release of VP from MNCs during physiological challenge is discussed.

Adaptation, Physiological↗

PubMed2003

Vasopressin and oxytocin decrease excitatory amino acid release in adult rat supraoptic nucleus.

Oxytocin and vasopressin reduce the amplitude of excitatory postsynaptic responses in magnocellular neuroendocrine cells of the supraoptic nucleus (SON). To test whether synaptic glutamate release is modulated by these neuropeptides, we examined the combined effect of vasopressin and oxytocin on depolarization-induced glutamate and aspartate release from acutely dissected rat SON or fronto-parietal cortex punches. Glutamate release was stimulated with 60 mm K+ for 5-10 min and measured using ion exchange chromatography or high-performance liquid chromatography. During depolarization with high K+, extracellular glutamate levels increased, on average, to 204% of control values. In the presence of vasopressin/oxytocin, K+-stimulated glutamate and aspartate release were significantly reduced by 34% and 62%, respectively, in the SON. Treatment with the aminopeptidase inhibitor amastatin did not mimic the effects of exogenous vasopressin/oxytocin on glutamate or aspartate release, suggesting that, under the conditions tested here, amastatin treatment may produce more complex effects. The effects of exogenous neuropeptides are likely mediated by oxytocin and/or vasopressin receptors, as the oxytocin- and V1a-receptor antagonist, Manning Compound (10-100 micro m), partially reversed the effects of vasopressin/oxytocin on SON glutamate release. In contrast, in cortical punches, glutamate release was enhanced by high K+, but vasopressin/oxytocin did not significantly reduce glutamate/aspartate release, consistent with the relatively sparse distribution of vasopressin/oxytocin receptors in fronto-parietal cortex. These findings suggest that locally released oxytocin and vasopressin may autoregulate SON magnocellular neuroendocrine cell activity in part by modulating the release of excitatory amino acids from afferent terminals targeting these cells and/or from other cellular sources.

Age Factors↗

PubMed1999

Lateral hypothalamic NMDA receptor subunits NR2A and/or NR2B mediate eating: immunochemical/behavioral evidence.

Cells within the lateral hypothalamic area (LHA) are important in eating control. Glutamate or its analogs, kainic acid (KA) and N-methyl-D-aspartate (NMDA), elicit intense eating when microinjected there, and, conversely, LHA-administered NMDA receptor antagonists suppress deprivation- and NMDA-elicited eating. The subunit composition of LHA NMDA receptors (NMDA-Rs) mediating feeding, however, has not yet been determined. Identifying this is important, because distinct second messengers/modulators may be activated by NMDA-Rs with differing compositions. To begin to address this, we detected LHA NR2A and NR2B subunits by immunoblotting and NR2B subunits by immunohistochemistry using subunit-specific antibodies. To help determine whether NMDA-Rs mediating feeding might contain these subunits, we conducted behavioral studies using LHA-administered ifenprodil, an antagonist selective for NR2A- and/or NR2B-containing NMDA-Rs at the doses we used (0.001-100 nmol). Ifenprodil maximally suppressed NMDA- and deprivation-elicited feeding by 63 and 39%, respectively, but failed to suppress KA-elicited eating, suggesting its actions were behaviorally specific. Collectively, these results suggest that LHA NMDA-Rs, some of which contribute to feeding control, are composed of NR2A and/or NR2B subunits, and implicate NR2A- and/or NR2B-linked signal transduction in feeding behavior.

Animals↗

PubMed1998

The second messenger cAMP elicits eating by an anatomically specific action in the perifornical hypothalamus.

We have previously shown that a membrane-permeant analog of cAMP, 8-bromo-cAMP (8-br-cAMP), elicits a vigorous eating response when microinjected into the perifornical hypothalamus (PFH) or lateral hypothalamus (LH) of satiated rats, suggesting that increases in cAMP in these areas may be important in the neural control of eating. To determine the locus of this effect, we compared the ability of 8-br-cAMP (1-100 nmol/0.3 microl) to elicit eating after microinjection into the PFH, LH, or the following bracketing areas: the anterior and posterior LH, paraventricular nucleus of the hypothalamus, thalamus, and amygdala. 8-br-cAMP at 50 nmol elicited eating (>/=3.4 gm in 2 hr) exclusively in the PFH and LH. At 100 nmol, 8-br-cAMP elicited a larger response in these areas and elicited a smaller, more variable response in the thalamus. We similarly mapped the feeding-stimulatory effects of compounds that increase endogenous cellular cAMP in naive rats. Combined microinjection of matched doses (300 nmol) of 3-isobutyl-1-methylxanthine and 7-deacetyl-7-O-(N-methylpiperazino)-gamma-butyryl-forskolin was effective exclusively in the PFH, eliciting an average 2 hr food intake of 8.4 +/- 2.0 gm. Collectively, these results suggest that increases in cellular cAMP within a specific brain site, the PFH, may play a role in the neural stimulation of eating.

1-Methyl-3-isobutylxanthine↗

PubMed1998

Eating induced by perifornical cAMP is behaviorally selective and involves protein kinase activity.

It has previously been shown that agents that increase endogenous cAMP elicit robust eating when injected into the perifornical hypothalamus (PFH) but not when injected into surrounding brain sites, suggesting that PFH cAMP may play a role in eating control. We report here that bilateral microinjection of the adenylyl cyclase activator 7-deacetyl-7-O-(N-methylpiperazino)-gamma-butyryl-forskolin dihydrochloride (MPB forskolin; 300 nmol/0.3 microl) into the PFH is sufficient to elicit intense eating (up to 15.7 +/- 2.3 g in 2 h) in satiated rats, without concomitant effects on other behaviors, including gnawing and drinking. In contrast, the inactive analog 1, 9-dideoxyforskolin is ineffective, suggesting that the effects of MPB forskolin are behaviorally selective and pharmacologically specific. We also show that injection of the protein kinase A inhibitor H-89 (100 nmol) into the PFH reduced MPB forskolin-induced eating by up to 50%. Collectively, these results suggest that increased cAMP production in a single brain area may be sufficient to selectively generate a patterned, goal-oriented behavior by activating cAMP-dependent protein kinase.

Adenylyl Cyclases↗

PubMed1997

Stimulation of eating by the second messenger cAMP in the perifornical and lateral hypothalamus.

Despite intense study of neurotransmitters mediating hypothalamic controls of food intake, little is known about which second messengers are critical for these mechanisms. To determine whether adenosine 3',5'-cyclic monophosphate (cAMP) might participate in these mechanisms, we injected the membrane-permeant cAMP analog 8-bromo-cAMP (8-BrcAMP) hypothalamically in satiated rats. Injection of 8-BrcAMP (10-100 nmol) into the perifornical (PFH) and lateral hypothalamus (LH) dose dependently stimulated food intake of up to 15.7 g in 2 h. Significantly smaller responses were obtained with thalamic injections. In contrast to the strong stimulatory effects of PFH and LH 8-BrcAMP, cAMP and 8-bromo-guanosine 3',5'-cyclic monophosphate (100 nmol) were ineffective, suggesting a chemically specific, intracellular action. Consistent with this, combined PFH injection of 7-deacetyl-7-O-(N-methylpiperazino)-tau-butyryl-forskolin dihydrochloride and 3-isobutyl-1-methylxanthine, agents that increase endogeneous cAMP, stimulated eating of up to 9.9 g in 2 h. These results demonstrate that increases in PFH/LH cAMP can elicit complex, goal-oriented behavior, suggesting an important role for cAMP in hypothalamic mechanisms stimulating food intake.

1-Methyl-3-isobutylxanthine↗

PubMed1993

Evidence that neuropeptide Y and dopamine in the perifornical hypothalamus interact antagonistically in the control of food intake.

Mapping studies have revealed that the perifornical hypothalamus (PFH) is a primary locus for both the feeding-stimulatory effect of neuropeptide Y (NPY) and the anorectic effect of catecholamines (CAs), suggesting that NPY and CAs may interact antagonistically there. To investigate this, the CA-releasing agent amphetamine (AMPH) was injected through indwelling guide cannulas into the PFH of satiated adult male rats 5 min prior to injection of NPY (78 pmol/0.3 microliters) and food intake was measured 1, 2, and 4 h later. Amphetamine (50-200 nmol) dose-dependently reduced NPY feeding, usually eliminating it at the higher doses. The receptors mediating this effect were investigated by sequential injection of various CA antagonists, AMPH, and NPY into the PFH. Neither the alpha- nor beta-adrenergic receptor antagonists phentolamine (100 nmol) or propranolol (200 nmol) significantly affected AMPH suppression of NPY feeding. In contrast, the dopamine receptor antagonist haloperidol (5 nmol) abolished AMPH suppression of NPY feeding, suggesting that dopamine (DA) mediates the AMPH effect. To examine this, epinephrine (EPI, 50-200 nmol) and DA (25-200 nmol) were tested for suppression of NPY-induced feeding. While EPI had no significant effect, DA at the maximally effective dose (50 nmol) reduced the NPY feeding response by 36% or more. These findings provide convergent evidence for antagonistic interactions between endogenous DA and NPY in the control of eating behavior.

Amphetamine↗