Dual roles in feeding for AMPA/kainate receptors: receptor activation or inactivation within distinct hypothalamic regions elicits feeding behavior

We have previously shown that hypothalamic injections of glutamate, or agonists of its ionotropic receptors (iGluRs), elicit intense feeding responses in satiated rats [Brain Res. 613 (1993) 88, Brain Res. 630 (1993) 41]. While attempting to clarify the role of the AMPA and kainate (KA) receptor subtypes in glutamatergic feeding systems, we discovered that lateral hypothalamic (LH) injection of high doses of the competitive AMPA/KA receptor antagonist, NBQX (10 and 30 nmol), elicited a pronounced feeding response. We questioned whether this effect was due to inactivation of AMPA or possibly KA receptors. To determine whether other AMPA/KA antagonists can also elicit feeding, we tested whether injection of CNQX, another AMPA/KA receptor antagonist, also stimulates eating and whether these feeding stimulatory effects were due to antagonists' actions in the LH or in other hypothalamic sites. Here we report that NBQX and CNQX elicit feeding in a dose dependent manner and are most effective when injected into the perifornical hypothalamus (PFH), or into the paraventricular nucleus (PVN) and, to a lesser extent, into the LH of satiated rats. In contrast, AMPA was most effective in stimulating feeding when injected into the LH, confirming previous reports. These data suggest that either activation or inactivation of AMPA/KA receptors in distinct but overlapping hypothalamic sites may be sufficient to induce feeding behavior, indicating a broadened role for glutamate in hypothalamic feeding mechanisms.     

Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status

Neuropeptide Y (NPY) is believed to regulate the normal eating behavior and body weight in rats via central mechanisms. We have investigated whether NPY, which stimulates food intake, may in turn be modified by the nutritional state of the animals. Thus the impact of food deprivation (FD) (48 h) and subsequent refeeding on the levels of NPY in discrete hypothalamic areas was examined in this study. The results showed site specific change in only 3 of 7 hypothalamic sites. A 5-fold increment in NPY was reported in the paraventricular nucleus (PVN) and a 10-fold increase was observed in the arcuate nucleus-median eminence (ARC-ME). While subsequent refeeding for 6 h reversed the effect of FD in the ARC-ME, the levels of NPY in the PVN remained high in the refed rats. The perifornical lateral hypothalamus displayed a different pattern, namely, a significant increase in NPY content in refed as compared to satiated and deprived rats. The NPY levels in 4 other hypothalamic sites, namely, the dorsomedian, ventromedian, supraoptic and suprachiasmatic nuclei, and two extrahypothalamic sites, namely caudate nucleus and nucleus accumbens, showed total resistance to any change following deprivation and refeeding. These data emphasize the important and specific role of the paraventricular and arcuate nuclei in NPY's regulation of food intake and provide support for the idea that the variations of hypothalamic NPY after food deprivation reflect a specific physiological response of feeding regulatory system to alterations in the animal nutritional state and body weight.     

Hypothalamic neuronal histamine modulates ad libitum feeding by rats

Manipulating histamine endogenously, its effects on brain functions were assessed in rats. alpha-Fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, elicited feeding (P less than 0.01) after intra-third cerebroventricular infusion at the early light phase when hypothalamic histamine was normally highest. No periprandial drinking was observed. The effect of FMH was attenuated, and thioperamide, an antagonist of auto-inhibitory effects on both histamine synthesis and release at presynaptic H3-receptor, conversely suppressed food intake (P less than 0.05), when these probes were carried out during the minimum histamine level early in the dark period. Bilateral microinfusion of FMH into the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN) selectively induced feeding, but the infusion into the remaining sites of the hypothalamus had no effect. These data show that neuronal histamine plays a physiological role in feeding suppression through the VMH and the PVN in the rat.     

Anorexic action of a new potential neuropeptide Y antagonist [ -Tyr, -Thr]-NPY (27–36) infused into the hypothalamus of the rat

Neuropeptide Y (NPY) produces a vigorous feeding response in several species when it is injected into hypothalamic structures involved in eating behavior. The purpose of this study was to determine whether a unique carboxy terminal fragment of NPY would alter the pattern of eating induced in the rat either by NPY injected into the hypothalamus or by a 24-h period of food deprivation. In this case, two -tyrosine residues and one t.-threonine residue of the NPY_27–36 fragment were transformed to their D-conformation to produce [ -Tyr^27,36, -Thr³²]-NPY (27–36), i.e., D-NPY_27–36. Guide cannulae for microinjection were implanted stereotaxically just dorsal to the paraventricular nucleus (PVN) or ventromedial hypothalamus (VMH) of 24 adult male Sprague-Dawley rats. Following postoperative recovery, a microinjection of artificial CSF or 1.1 jig or 3.3 μg of a peptide was made directly into the PVN or VMH as follows; native NPY; D-NPY_27–36; or [L-Tyr^27,36 L-Thr³²]-NPY (27–36), i.e., L-NPY_27–36. Food intakes were measured at intervals of 0.25, 0.5, 1.1, 2.0, 4.0, and 24 h. When D-NPY_27–36 was microinjected at NPY reactive sites in the PVN or VMH of the rat 15 min before a similar microinjection of NPY, the intense eating response induced by the peptide was reduced significantly. Not only was the effect dose dependent, but D-NPY_27–36 also augmented the latency to feed. A mixture of the two doses of NPY and DNPY_27–36 injected at the same hypothalamic loci did not attenuate the intake of food but tended to enhance the feeding response in the rats. After the rats were deprived of food for 24 h, D-NPY_27–36 microinjected in the same hypothalamic sites similarly caused a dose-dependent suppression of normal feeding behavior. However, the CSF control vehicle and L-NPY_27–36 microinjected in the PVN or VMH were without effect on the pattern of eating. Further, D-NPY_27–38 injected in the same hypothalamic sites affected neither body temperature nor water intakes of the rats significantly. These results demonstrate that the D substitution of this C-fragment of the NPY molecule, i.e., D-NPY_27–36, serves to inhibit feeding evoked in the rat by hypothalamic NPY as well as the natural eating response to food deprivation. Thus, the D-NPY_27–36 molecule may act as an antagonist at one or more subtypes of the NPY receptor in the brain of the rat.     

Opioid-induced feeding: Localization of sensitive brain sites

These experiments were designed to identify brain sites at which opioids might act to influence ingestive behavior and to determine which opioid receptor types are involved. After food deprivation, rats were given microinjections of naloxone into several brain regions and food intake was measured. Injections into or near the paraventricular (PVN) or ventromedial (VMH) hypothalamic nuclei or the globus pallidus (GP) reduced food intake; injections into the striatum or lateral hypothalamus (LH) were ineffective. A second study examined the ingestive effects of roughly equimolar doses (1.43-1.75 nmol) of dynorphin A (DYN), beta-endorphin (beta-END), and D-Ala2,D-Leu5-enkephalin (DADLE) when injected into 4 different brain regions. Only DYN significantly increased food intake, and this effect was seen only with injections into the PVN and VMH. Beta-END stimulated water intake when injected into the PVN, VMH and GP but not the LH. Further studies indicated that with PVN injections, DYN was effective at a dose as low as 0.47 nmol, and that a higher dose of DADLE (4.39 nmol) did stimulate food intake. These studies support an important role for dynorphin and the kappa opioid receptor in the regulation of feeding and suggest that the opioid regulation of food and water intake can be differentiated both by sites of action and by effective agonists.     

Anorexic action of a new potential neuropeptide Y antagonist [d-Tyr, d-Thr]-NPY (27–36) infused into the hypothalamus of the rat

Neuropeptide Y (NPY) produces a vigorous feeding response in several species when it is injected into hypothalamic structures involved in eating behavior. The purpose of this study was to determine whether a unique carboxy terminal fragment of NPY would alter the pattern of eating induced in the rat either by NPY injected into the hypothalamus or by a 24-h period of food deprivation. In this case, two l-tyrosine residues and one t.-threonine residue of the NPY_27–36 fragment were transformed to their D-conformation to produce [d-Tyr^27,36,d-Thr³²]-NPY (27–36), i.e., D-NPY_27–36. Guide cannulae for microinjection were implanted stereotaxically just dorsal to the paraventricular nucleus (PVN) or ventromedial hypothalamus (VMH) of 24 adult male Sprague-Dawley rats. Following postoperative recovery, a microinjection of artificial CSF or 1.1 jig or 3.3 μg of a peptide was made directly into the PVN or VMH as follows; native NPY; D-NPY_27–36; or [L-Tyr^27,36 L-Thr³²]-NPY (27–36), i.e., L-NPY_27–36. Food intakes were measured at intervals of 0.25, 0.5, 1.1, 2.0, 4.0, and 24 h. When D-NPY_27–36 was microinjected at NPY reactive sites in the PVN or VMH of the rat 15 min before a similar microinjection of NPY, the intense eating response induced by the peptide was reduced significantly. Not only was the effect dose dependent, but D-NPY_27–36 also augmented the latency to feed. A mixture of the two doses of NPY and DNPY_27–36 injected at the same hypothalamic loci did not attenuate the intake of food but tended to enhance the feeding response in the rats. After the rats were deprived of food for 24 h, D-NPY_27–36 microinjected in the same hypothalamic sites similarly caused a dose-dependent suppression of normal feeding behavior. However, the CSF control vehicle and L-NPY_27–36 microinjected in the PVN or VMH were without effect on the pattern of eating. Further, D-NPY_27–38 injected in the same hypothalamic sites affected neither body temperature nor water intakes of the rats significantly. These results demonstrate that the D substitution of this C-fragment of the NPY molecule, i.e., D-NPY_27–36, serves to inhibit feeding evoked in the rat by hypothalamic NPY as well as the natural eating response to food deprivation. Thus, the D-NPY_27–36 molecule may act as an antagonist at one or more subtypes of the NPY receptor in the brain of the rat.     

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--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. These results, demonstrating that glutamate and several of its agonists can act within the LH to elicit eating, suggest that glutamate and several of its receptor subtypes may participate in LH regulation of eating behavior.     

Mapping of hypothalamic sites involved in the effects of NPY on body temperature and food intake

The objective of the present study was to identify hypothalamic sites that might be implicated in the effects of neuropeptide Y (NPY) on both body temperature and food intake. For this purpose, the effects of direct microinjections of NPY in several doses (0.156–20 μg) into discrete hypothalamic nuclei on body temperature were examined in rats. To examine specificity of effects, food consumption of animals following injections was also measured. Results indicate that the influence of NPY on body temperature varies with the hypothalamic region where the peptide is administered. NPY had no effect on temperature after administration into the ventromedial (VMH) and the perifornical hypothalamus (PeF). However, a significant hypothermia was seen following administration into the preoptic (POA) and arcuate nucleus (Arc), and hyperthermia was seen after injection into the paraventricular nucleus (PVN). Finally, a biphasic effect was observed after injection into the lateral hypothalamus (LH): hyperthermia with relatively small doses and hypothermia with higher doses. Similar effects were obtained when administred into the third ventricle (3V) but in an inverted dose-related fashion: hypothermia at low and hyperthermia at higher doses. For feeding, NPY consistently increased food intake in all regions examined, with the strongest effect obtained after administration into the PeF. The present results clearly dissociate the effects of NPY on food intake and body temperature, and demonstrate that these effects are related to specific hypothalamic nuclei.     

Effect of d-fenfluramine on neuropeptide Y concentration and release in the paraventricular nucleus of food-deprived rats.

Recent evidence indicates that Neuropeptide Y (NPY) is an important signal in the hypothalamic neural circuitry that stimulates feeding in the rat. Administration of d-fenfluramine (FEN) has been shown to rapidly inhibit feeding in the rat. Because food deprivation increases the levels and release of NPY in the paraventricular nucleus (PVN) of the hypothalamus, the aim of this study was to investigate whether the rapid anorectic effects of FEN in food-deprived (FD) rats are associated with alterations in the hypothalamic NPYergic system. In the first experiment, the effect of FEN (10 mg/kg) on NPY concentrations in nine microdissected hypothalamic sites was assessed by radioimmunoassay (RIA) in rats either food deprived for 3 days or fed ad lib during the experimental period. In response to food deprivation, NPY concentrations increased significantly in the PVN and arcuate nucleus, but NPY levels remained unchanged in the remaining seven hypothalamic sites. In control rats maintained on ad lib food supply, FEN injection produced little effect on NPY concentration in hypothalamic sites. However, FEN suppressed NPY levels selectively in the PVN of FD rats, so that NPY concentrations measured in the nucleus were within the range found in satiated control rats. In the second experiment, the effect of FEN on NPY release in the PVN was examined in FD rats by the push-pull cannula (PPC) technique. NPY levels in the PPC perfusate were unchanged in FD rats during the period 30-120 min after saline or FEN injection. Also, the mean rate of NPY release was similar in vehicle- and FEN-treated FD rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of neuropeptide Y-elicited eating by adrenalectomy or hypophysectomy: reversal with corticosterone

Neuropeptide Y (NPY) injected into the paraventricular hypothalamus (PVN) stimulates a robust eating response in the satiated rat. To examine whether the NPY-feeding system interacts with the pituitary-adrenal axis, the eating response to PVN injections of NPY (78 pmol) was tested in adult male rats before and after sham surgery, adrenalectomy (ADX), hypophysectomy (HYPX), and/or corticosterone (CORT) replacement therapy. In unoperated or sham groups, NPY elicited 5.7-8.8 g of food intake in 1 h as compared to 0.4-1.1 g for vehicle-injected animals. In ADX groups, the NPY-elicited response was reduced by 60-71%, to between 2.4 and 2.8 g. Likewise, the average response of the HYPX group was reduced by 69%, to 1.7 g. Corticosterone replacement, via subcutaneous implant of a 100 mg CORT pellet, normalized the NPY-induced feeding response in both the ADX and HYPX groups. These findings suggest that the hypothalamic NPY-feeding system is largely dependent upon circulating CORT and that no other adrenal or pituitary hormone is essential.     

Feeding response to central orexins

Orexin A and orexin B were microinjected into the perifornical hypothalamus (PFH), lateral hypothalamus (LH), hypothalamic paraventricular nucleus (PVN), and ventral tegmental area (VTA) of male Sprague-Dawley rats. Orexin B (15 nmol) was also injected into the lateral cerebral ventricle (i.c.v.). Orexin A (>/=500 pmol) stimulated feeding in the PFH and LH, but not in the VTA or PVN. Orexin B stimulated feeding only when injected i.c.v.     

Opposite dopaminergic activity in lateral and median hypothalamic nuclei in relation to the feeding effect ofd-Ser-Leu-Enk-Thr (DSLET)

The Leu-enkephalin analogue D-Ser2-Leu-Enk-Thr6 (DSLET) had been shown to enhance feeding in rats, increase dopaminergic activity in the striatum like other opiate agonists, and particularly to decrease dopaminergic activity in the hypothalamus. In this study, the latter effect was found to be localized in the hypothalamic nuclei involved in the regulation of feeding such as the paraventricular (PVN), ventromedian (VMH), dorsomedian (DMH) nuclei and the lateral hypothalamus (LH). DSLET produced the same decrease in dopaminergic activity in the LH as in the whole hypothalamus. In the median nuclei (PVN and VMH and to a lesser extent in the DMH), an opposite effect was observed, resembling that in the striatum. The relevance of these opposite variations with regard to the feeding effect of DSLET is discussed. The decreased dopaminergic activity in the LH would appear to be the most specifically related to the behavioural effect given the known role of dopamine in this region. These data reconcile apparently contradictory aspects of the role of dopamine and the functional opposition between the lateral and median hypothalamus in food intake control.     

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.     

Amygdala enterostatin induces c-Fos expression in regions of hypothalamus that innervate the PVN

Enterostatin selectively inhibits the intake of the dietary fat after both central and peripheral administration. Our previous studies have shown that a central site of action is the central nucleus of amygdala. Serotonergic agonists administered into the paraventricular nucleus (PVN) inhibit fat intake and serotonergic antagonists block the feeding suppression induced by amygdala enterostatin, suggesting that there are functional connections between the PVN and amygdala that affect the feeding response to enterostatin. Our purpose was to identify the anatomic and functional projections from the amygdala to the PVN and hypothalamic area that are responsive to enterostatin, by using a retrograde tracer fluorogold (FG) and c-Fos expression. Rats were injected with fluorogold unilaterally into the PVN and a chronic amygdala cannula was implanted ipsilaterally. After 10 days recovery, rats were injected with either enterostatin (0.1 nmol) or saline vehicle (0.1 microl) into the amygdala and sacrificed 2 h later by cardiac perfusion under anesthesia. The brains were subjected to dual immunohistochemistry to visualize both FG and c-Fos-positive cells. FG/c-Fos double-labeled cells were found in forebrain regions including the PVN, amygdala, lateral hypothalamus (LH), ventral medial hypothalamus (VMH) and arcuate nucleus (ARC). The data provides the first anatomical evidence that enterostatin activates amygdala neurons that have functional and anatomic projections directly to the PVN and also activates neurons in the arcuate, LH and VMH, which innervate the PVN.     

Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats

Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K⁺-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH.     

Neuropeptide Y in the specific hypothalamic nuclei of rats treated neonatally with monosodium glutamate

Neuropeptide Y (NPY) concentration was determined by radioimmunoassay in selected hypothalamic regions microdissected from fresh brain slices of rats treated neonatally with monosodium glutamate (MSG). Fourteen weeks after MSG treatment, significant decreases in NPY concentration were found in the paraventricular nucleus (PVN) and arcuate nucleus (ARH), while there was no appreciable change in the ventromedial nucleus (VMH) and lateral area (LH). The decrease in NPY in the ARH-PVN system may contribute to the endocrine and metabolic disturbances seen in MSG-treated animals.     

Neuropeptide Y and food intake in fasted rats: effect of naloxone and site of action

Central administration of neuropeptide Y (NPY) induces food intake in freely feeding animals and this effect is mediated by hypothalamic sites. Little is known, however, about the effect of NPY on food intake and site of action in food-deprived animals. To examine this further, 24-h fasted rats received injections of saline or NPY into the lateral cerebral ventricle (10 micrograms/10 microliters; n = 8) or into the lateral (LH) or ventromedial hypothalamus (VMH) (1 microgram/0.5 microliters; n = 44). In addition, intracerebroventricular (i.c.v.) injections of NPY were carried out with or without i.c.v. naloxone (25 micrograms), a specific opioid receptor antagonist. During the first 40 min food intake was not different with or without NPY. After 60 and 120 min, food intake was 5.9 +/- 0.4 g and 8.3 +/- 0.6 g with i.c.v. saline which was significantly augmented by i.c.v. NPY to 8.7 +/- 0.9 g and 14.4 +/- 1.5 g, respectively (P less than 0.05). This increase in food consumption was due to a prolongation of feeding time. The opioid receptor antagonist naloxone significantly augmented latency to feed, both in the absence and presence of NPY (8.0 vs 1.7 min or 14.7 vs 2.8 min, respectively) and abolished the NPY-induced increase in food intake. Following intrahypothalamic injection of NPY, an increase in food intake (greater than 20%) was observed in 50% of the histologically identified LH and VMH sites, but only in 15% of the injection sites outside the LH/VMH.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.