Site selective activation of lateral hypothalamic mGluR1 and R5 receptors elicits feeding in rats.

Recent findings from our lab indicate that metabotropic glutamate receptor (mGluR) activation elicits eating, and the goal of the current study was to specify whether the lateral hypothalamus (LH) is the actual brain site mediating this effect. To examine this issue we injected the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) unilaterally into the LH and surrounding regions (n=5-8 subjects/brain site) of satiated adult male Sprague-Dawley rats and measured elicited feeding. We determined that 1.0 nmol elicited food intake only within the LH. Increasing the dose to 10 or 25 nmol produced a more sustained effect in the LH, and also elicited eating in several other brain sites. These results, demonstrating that the LH mediates the eating elicited by low doses of DHPG, suggest that the LH may contain mGluR whose activation can produce eating behavior.

Activation of lateral hypothalamic mGlu1 and mGlu5 receptors elicits feeding in rats.

Metabotropic glutamate receptors (mGluRs) have been popular drug targets for a variety of central nervous system (CNS) disease models, ranging from seizures to schizophrenia. The current study aimed to determine whether mGluRs participate in lateral hypothalamic (LH) stimulation of feeding. To this end, we used satiated adult male Sprague-Dawley rats stereotaxically implanted with indwelling bilateral LH guide cannulas to determine if injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a broad mGluR group I and II agonist, would elicit feeding. Administration of 100 nmol ACPD induced feeding with a short latency. Similarly, unilateral LH injection of the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) elicited significant feeding beginning 60 min postinjection and continuing until 4 h postinjection. Administration of the mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) produced a smaller delayed feeding response. These delayed but prolonged eating responses suggest that activation of LH mGluR1 and/or mGluR5 might be sufficient to elicit feeding. To determine which subtypes were involved, LH DHPG injections were preceded by LH injection of either the group I antagonist n-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), the mGluR1 antagonist 6-amino-n-cyclohexyl-n,3-dimethylthiazolo[3,2-a]benzimi dazole-2-carboxamide hydrochloride (YM-298198) or the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP), and food intake was measured. PHCCC blocked DHPG-elicited feeding, and each of the other antagonists produced significant feeding suppression. These findings suggest roles for mGluR1 and/or mGluR5 in lateral hypothalamic circuits capable of stimulating feeding behavior.

Glutamate and GABA in lateral hypothalamic mechanisms controlling food intake.

By the 1990s a convergence of evidence had accumulated to suggest that neurons within the lateral hypothalamus (LH) play important roles in the stimulation of feeding behavior. However, there was little direct evidence demonstrating that neurotransmitters in the LH could, like electrical stimulation, elicit feeding in satiated animals. The present paper is a brief review in honor of Bartley Hoebel's scientific contributions, emphasizing the evidence from my lab that the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma aminobutyric acid (GABA) in the LH mediate feeding stimulation and feeding inhibition respectively. Specifically, we summarize evidence that LH injection of glutamate, or agonists of its N-methyl-D-aspartate (NMDA) and non-NMDA receptors, elicits feeding in satiated rats, that NMDA receptor antagonists block the eating elicited by NMDA and, more importantly, that NMDA blockade suppresses natural feeding and can reduce body weight. Conversely, GABA(A) agonists injected into the LH suppress feeding and can also reduce body weight, while GABA(A) receptor antagonists actually elicit eating when injected into the LH of satiated rats. It is suggested that natural feeding may reflect the moment-to-moment balance in the activity of glutamate and GABA within the LH.

Reverse microdialysis of N-methyl-D-aspartic acid into the lateral hypothalamus of rats: effects on feeding and other behaviors.

The effects of reverse microdialysis of N-methyl-D-aspartic acid (NMDA) into the lateral hypothalamus (LH) on feeding and other behaviors were examined. Consistent with similar studies utilizing central microinjections, NMDA reverse microdialysed into the rat LH rapidly elicited a strong concentration-dependent stimulation of feeding. The minimum perfusate concentration of NMDA needed to elicit feeding with reverse microdialysis was 660 microM, a concentration 1/50 of that needed with pressure injections. Further, eating responses could be consistently elicited in sequential tests separated by 2-4 h in the same subject, and the magnitude of the eating in the first and second tests was highly correlated (r=0.87). Behavioral analysis revealed that the main response to NMDA consisted of eating without the concomitant hyperactivity produced by central microinjections of this agonist. The other behaviors exhibited during NMDA administration were those that normally occur during spontaneous feeding in rats. Also, rats precisely compensated for the increased food intake elicited by NMDA by reducing spontaneous feeding during the subsequent nocturnal phase, so as to maintain normal daily intakes. In contrast, N-methyl-L-aspartate (NMLA) reverse microdialysed in to the LH (660 microM) did not elicit feeding nor affect any other behaviors we examined. These data support a role for LH glutamate and NMDA receptors in the control of feeding.

N-methyl-D-aspartate receptor subunit NR2B is widely expressed throughout the rat diencephalon: an immunohistochemical study.

Glutamate (Glu), a major excitatory neurotransmitter within the hypothalamus and thalamus, acts upon many receptors, including the N-methyl-D-aspartate (NMDA) subtype. Abundant evidence suggests that variations in the subunit composition of NMDA receptors (NMDA-Rs) contribute to differences in Glu's immediate electrophysiological effects as well as to the patterns of signal transduction cascades it triggers to mediate long-term changes in neuronal function. We have previously shown that hypothalamic NMDA-Rs containing the NR2B subunit may be involved in the control of eating as well as in the mediation of physiological responses to osmotic stimuli. To broaden our understanding of diencephalic NMDA-R participation in other functions, we localized the NR2B subunit in the diencephalon of the adult male rat using immunoperoxidase, immunogold, and immunofluorescence techniques and an affinity-purified polyclonal antibody specific for the NR2B subunit of the NMDA-R. In addition, we used a monoclonal NR2B antibody with immunoperoxidase detection to confirm the NR2B distribution seen with the polyclonal antibody. In the hypothalamus, the highest levels of NR2B immunoreactivity (-ir) were found in the magnocellular neurosecretory system, including the paraventricular and supraoptic nuclei. A new finding was that intense NR2B-ir was present within perivascular "accessory" magnocellular groups of this system, including the nucleus circularis, anterior fornical nucleus, and scattered clusters of lateral hypothalamic cells apposed to blood vessels. Robust NR2B-ir was also present within the arcuate nucleus, the median eminence, and the tuberal nucleus, and light immunostaining was found in all other hypothalamic nuclei examined. In the thalamus, the highest NR2B-ir was observed in the medial habenula and the anterodorsal, paraventricular, rhomboid, reticular, and dorsal lateral geniculate nuclei. As in the hypothalamus, all thalamic nuclei examined displayed at least light immunostaining for this subunit. Control sections, including those incubated with the polyclonal NR2B antibody preadsorbed with its fusion protein, were virtually devoid of immunostaining. This demonstration that the NR2B subunit of the NMDA-R is widely distributed in the diencephalon, implicates it in a wide variety of functions, and provides a useful anatomical framework for establishing a comprehensive map of Glu receptor populations within this major subdivision of the brain.

Brain regions where cholecystokinin suppresses feeding in rats.

The gut-brain peptide, cholecystokinin (CCK), inhibits food intake when injected either systemically or within the brain. To determine whether CCK's effect in the brain is anatomically specific, CCK-8 (0. 8, 4, 20, 100, 500 pmol) was microinjected into one of 14 different brain sites of rats, and its impact on subsequent food intake was measured. CCK-8 at 500 pmol significantly suppressed intake during the first hour post-injection following administration into six hypothalamic sites (anterior hypothalamus, dorsomedial hypothalamus, lateral hypothalamus, paraventricular nucleus, supraoptic nucleus, ventromedial hypothalamus) and two hindbrain sites (nucleus tractus solitarius, fourth ventricle). Although lower doses were sometimes effective (anterior hypothalamus, dorsomedial hypothalamus, nucleus tractus solitarius), there appeared to be no significant difference in potency among sites. Injections into the medial amygdala, nucleus accumbens, posterior hypothalamus, dorsal raphe, and ventral tegmental area were either ineffective or produced a delayed response. The higher doses required for most sites, as well as the widespread effectiveness of CCK-8 within the hypothalamus, suggest that spread of CCK-8 to adjacent brain sites, and (or) to the periphery, may have been required for anorexia to occur. Findings reported in an accompanying paper provide strong evidence that paraventricular nucleus injection of CCK-8 (500 pmol) did not increase plasma CCK-levels sufficiently to suppress feeding by a peripheral mechanism. Together, these results suggest that CCK may be acting as a neurotransmitter or neuromodulator within two different brain regions to produce satiety - one region which includes the nucleus tractus solitarius in the hindbrain, and another more distributed region within the medial-basal hypothalamus.

Effects of paraventricular nucleus injection of CCK-8 on plasma CCK-8 levels in rats.

The aim of the study was to determine whether paraventricular nucleus (PVN) injection of an anorexic 500-pmol dose of cholecystokinin (CCK)-8 could increase plasma CCK-8 levels sufficiently to suppress feeding by a peripheral mechanism. Rats received PVN injections of CCK-8 either alone or with 3H-labelled propionylated CCK-8 (3H-pCCK-8) and plasma samples were taken at various times from 3 to 120 min post-injection. Plasma CCK-8 levels were estimated from measurements of both total plasma CCK-like immunoreactivity (CCK-LI) and 3H-pCCK-8 activity. PVN injections of CCK-8 and 3H-pCCK-8 produced estimated peak increases in plasma CCK-8 of 15+/-11 and 22+/-3 pM, respectively. The i.v. infusion of CCK-8 doses (0.2 and 1 nmol/kg h) that bracketed the threshold dose for suppression of feeding, increased plasma CCK-LI from a basal level of 6+/-1 to 49+/-10 and 166+/-36 pM, respectively. The i.v. injections of 600 and 4800 pmol of CCK-8 did not suppress feeding. These results suggest that PVN injection of an anorexic 500-pmol dose of CCK-8 does not increase plasma CCK-8 levels sufficiently to suppress feeding by a peripheral mechanism.

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.

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.

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.

Similar feeding patterns are induced by perifornical neuropeptide Y injection and by food deprivation.

Although hypothalamic injections of neuropeptide Y (NPY) induce robust feeding, there is little information about the patterns of feeding elicited by this peptide. To reveal these patterns, NPY (0, 8, 24, 78, 235 pmol/10 nl) was injected into the perifornical hypothalamus (PFH) of satiated adult male rats and their subsequent food intake was monitored every minute for 24 h. For comparison, feeding patterns were similarly observed following fasts of 0, 3, 6, 9, 12, and 24 h. The results demonstrated that NPY and food deprivation both produced dose- or deprivation-dependent increases in food intake that were most evident in the first 6 h. The increased intakes induced by NPY were characterized by combinations of increased meal size and frequency, with the predominant effects being increases in the size of and decreased latency to eat the first meal. Similarly, fasting progressively increased food intake by combinations of increased meal size and frequency, with the predominant effects being increases in the size of and decreased latency to eat the first meal. These similarities between NPY-induced and food deprivation-induced feeding are consistent with a stimulatory role for endogenous NPY in deprivation-induced feeding. These findings also suggest that NPY may increase eating by acting on mechanisms of both meal initiation and of meal termination.

NMDA receptor coagonist glycine site: evidence for a role in lateral hypothalamic stimulation of feeding.

To investigate the role of the glycine coagonist binding site on the N-methyl-D-aspartate (NMDA) receptor in feeding control, we injected the glycine site antagonist 7-chlorokynurenic acid (7-CK) into the lateral hypothalamus (LH) of satiated rats before LH injection of NMDA, 7-CK (10-44 nmol) blocked the 6- to 10-g eating response elicited by NMDA. This block was reversed by LH pretreatment with glycine, arguing for a specific action at the glycine site. In contrast to the suppression produced by high doses, 7-CK at 0.1 nmol enhanced NMDA-elicited eating. For examination of behavioral specificity, 7-CK was injected into the LH before kainic acid (KA) or DL-alpha-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA). 7-CK at a dose of 0.1 nmol suppressed feeding elicited by KA or AMPA, but at 10 nmol it suppressed eating elicited by AMPA while enhancing eating elicited by KA. Finally, bilateral LH injection of 7-CK effectively suppressed eating produced by fasting. These findings support a role for the NMDA receptor coagonist glycine site in LH regulation of eating behavior.

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.

Lateral hypothalamic NMDA receptors and glutamate as physiological mediators of eating and weight control.

To determine whether endogenous lateral hypothalamic (LH) glutamate and its N-methyl-D-aspartate (NMDA) receptors might participate in the stimulation of natural eating, LH injection of the NMDA antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) was tested in adult male rats for suppressive actions on feeding elicited by 1) NMDA, kainic acid or D, L-alpha-amino-3-hydroxy-5-methylisoxazole (AMPA) injected into the LH; 2) food deprivation; and 3) the onset of the nocturnal period. D-AP5 (10-100 nmol) reduced by 72-90% the approximately 10-g eating response elicited by NMDA (10 nmol) without affecting the quantitatively similar eating responses elicited by kainic acid (1.0 nmol) or AMPA (1.0 nmol). This treatment also suppressed deprivation-induced eating by as much as 61% and nocturnal eating by as much as 40%. To determine its long-term effects, D-AP5 (50 nmol) was injected bilaterally into the LH twice a day for 8 consecutive days. This treatment caused up to 65% reductions in daily food intake and body weight loss of up to 13 g/day. These findings, showing behaviorally selective suppressions of eating and body weight by D-AP5, argue that endogenous LH glutamate acts to regulate natural eating and body weight and that NMDA receptors participate in these functions.

Neuropeptide Y receptor agonists: multiple effects on spontaneous activity in the paraventricular hypothalamus.

In vitro rat hypothalamic slices were used to examine the ability of neuropeptide Y (NPY), and the putative Y1 and Y2 receptor agonists [Pro34]NPY and [C2]NPY, to modify spontaneous single-neuron discharge in the paraventricular nucleus (PVN). NPY and [Pro34]NPY, at high concentrations (1500 nM), decreased discharge rates. At intermediate concentrations (150 nM) these peptides produced multiple effects, including increases, decreases, and biphasic changes. At lower concentrations (0.15-15 nM), they typically increased discharge rates. In contrast, [C2]NPY, at all concentrations (1.5-1500 nM), predominantly increased discharge rates. Thus, these NPY subtype agonists have multiple effects on discharge rate, which may be due to actions on multiple NPY receptor subtypes.

The lateral hypothalamus: a primary site mediating excitatory amino acid-elicited eating.

Lateral hypothalamic (LH) injections of the excitatory neurotransmitter glutamate, or its excitatory amino acid (EAA) agonists, kainic acid (KA), D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA), or N-methyl-D-aspartic acid (NMDA), can rapidly elicit an intense feeding response in satiated rats. To determine whether the LH is the actual locus of this effect, we compared these compounds' ability to stimulate feeding when injected into the LH, versus when injected into sites bracketing this region. Food intake in groups of adult male rats was measured 1 h after injection of glutamate (30-900 nmol), KA (0.1-1.0 nmol), AMPA (0.33-3.3 nmol), NMDA (0.33-33.3 nmol) or vehicle, through chronically implanted guide cannulas, into one of seven brain sites. These sites were: the LH, the anterior and posterior tips of the LH, the thalamus immediately dorsal to the LH, the amygdala just lateral to the LH, or the paraventricular and perifornical areas medial to the LH. The results show that across doses and agonists the eating-stimulatory effects were largest with injections into the LH. In the LH, glutamate between 300 and 900 nmol elicited a dose-dependent eating response of up to 5 g within 1 h (P < 0.01). Each of the other agonists at doses of 3.3 nmol or less elicited eating responses of at least 10 g with injections into this site. Injections into the other brain sites produced either no eating, or occasionally smaller and less consistent eating responses.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats.

A convergence of evidence suggests that stimulation of lateral hypothalamic (LH) neurons can elicit eating, but the neurotransmitters that mediate this effect are unknown. To determine whether glutamate might be involved, it was injected through chronic guide cannulas directly into the LH of satiated adult male rats and consequent food intake was measured. Glutamate produced a dose-dependent eating response (mean intakes of 3.7 g at 300 nmol and 5.2 g at 900 nmol) only within the first hour after injection. As a first step in determining the receptor types mediating this response, agonists for specific excitatory amino acid (EAA) receptors were similarly tested. Kainic acid (KA), D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA) injected into the LH each elicited eating in a dose-dependent fashion beginning at 0.33 to 1.0 nmol. At maximally effective doses (1.0-33 nmol), each agonist elicited food intakes of approximately nine grams within 1 h. Finally, analysis of meal and behavioral patterns produced by LH injection of glutamate (600 nmol) and KA (1.0 nmol) revealed that the elicited eating usually began 2-3 min postinjection and consisted of a single normal to large size meal. There were no other behavioral effects during this initial postinjection period and no effects on other oral behaviors, like drinking or gnawing, at any time. Collectively, these findings suggest that glutamate may act through several subtypes of its receptors on some LH neurons to elicit eating.

Feeding responses to perifornical hypothalamic injection of neuropeptide Y in relation to circadian rhythms of eating behavior.

Hypothalamic injection of neuropeptide Y (NPY) can elicit eating in satiated rats, and the perifornical hypothalamus (PFH) is the site where this effect is most pronounced (48). Additionally, there is a well-documented circadian rhythm of spontaneous eating behavior. Our objective was to determine whether there are daily rhythms of sensitivity to NPY in the PFH that might contribute to this behavioral rhythm. To accomplish this, the effectiveness in eliciting eating of PFH injection of NPY was examined at six different time points in the light-dark cycle. Neuropeptide Y (78 pmol/10 nl) or vehicle (10 nl) were injected through chronically implanted guide cannulas into the PFH of satiated adult male rats and food intake was measured 1, 2, and 4 h later. In animals on 12-12 h light-dark cycles, these injections were given 1 h before and after the onset of the light and dark phases, and in the middle of these phases. Additionally, dose-response effects of NPY were examined at two points: the first hour of both the dark and the light phases. The results show that NPY was effective at every time tested, and that the magnitude of the peptide-elicited intakes was primarily additive to the underlying patterns of spontaneous intake, with only a modest daily cycle of sensitivity to NPY. Consistent with this, NPY dose-dependently increased intake in the early light and in the early dark, and the magnitude of these effects across doses was similar at these times. This suggests that the sensitivity of the PFH system mediating NPY eating exhibits only a modest daily cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Microdialysis analysis of norepinephrine levels in the paraventricular nucleus in association with food intake at dark onset.

It has been proposed that norepinephrine (NE) in the paraventricular nucleus (PVN) acts to stimulate carbohydrate feeding specifically at the start of the active (dark) cycle in rats. This study used microdialysis to examine the relationship between endogenous levels of NE in the PVN at dark onset and the amount of food consumed at this time. The results indicated that: (1) in satiated rats on a lab chow diet, NE levels in the PVN, as opposed to sites anterior or lateral to this nucleus, were significantly higher during large meals around dark onset then they were during small meals or during intervals that preceded the large meals, and (2) in food-deprived animals given a pure carbohydrate diet at dark onset, PVN levels of NE just before the initiation of the meal were significantly higher in animals that consumed a relatively large carbohydrate meal (> 2.0 g) during the first dark hour, and they were significantly correlated across animals with the size of their carbohydrate meal. These findings are consistent with other evidence linking endogenous PVN NE to food intake at the beginning of the natural feeding cycle.