Centrally administered urocortin 2 decreases gorging on high-fat diet in both diet-induced obesity-prone and -resistant rats.

OBJECTIVE: Obesity is a costly, deadly public health problem for which new treatments are needed. Individual differences in meal pattern have been proposed to have a role in obesity risk. The present study tested the hypothesis that (i) the microstructure of chronic high-fat diet intake differs between genetically selected diet-induced obesity (DIO) and diet-resistant (DR) rats, and (ii) central administration of urocortin 2 (Ucn 2), a corticotropin-releasing factor type 2 agonist, decreases high-fat diet intake not only in lean DR rats, but also in obese DIO rats. DESIGN: Male, selectively bred DIO and DR rats (n=10/genotype) were chronically fed a high-fat diet. Food and water intake as well as ingestion microstructure were then compared under baseline conditions and following third intracerebroventricular injection of Ucn 2 (0, 0.1, 0.3, 1, 3 µg). RESULTS: Irrespective of genotype, Ucn 2 reduced nocturnal food intake with a minimum effective dose of 0.3 µg, suppressing high-fat diet intake by ∼40% at the 3 µg dose. Ucn 2 also made rats of both genotypes eat smaller and briefer meals, including at doses that did not reduce drinking. Obese DIO rats ate fewer but larger meals than DR rats, which they ate more quickly and consumed with two-third less water. CONCLUSIONS: Unlike leptin and insulin, Ucn 2 retains its full central anorectic efficacy to reduce high-fat diet intake even in obese, genetically prone DIO rats, which otherwise show a 'gorging' meal pattern. These results open new opportunities of investigation toward treating some forms of DIO.

Selective blockade of hypothalamic hyperphagia and obesity in rats by serotonin-depleting midbrain lesions.

Adult female rats, depleted of 70 percent of forebrain serotonin by dorsal and median raphe lesions, showed little overeating of food pellets and obesity following medial hypothalamic lesions. However, these rats showed the same reduced acceptance of sucrose solutions, enhanced rejection of quinine solutions, and exaggerated weight gain on a high-fat diet as did other rats made obese by medial hypothalamic lesions alone. Since raphe lesions alone produced none of these effects, the pattern of behaviors observed suggests a hitherto unknown (perhaps secondary) role for brain serotonin metabolism in selective aspects of the medial hypothalamic syndrome.

Research on "feeding behavior": quantitative information vs. qualitative perceptions about where it is published.

To gain some understanding of where research on "feeding behavior" is published, a Medline search was conducted for the years 1980-1990 inclusive using the above key phrase to capture published articles coded in this way. Furthermore, an eight-item questionnaire was mailed to all 451 persons listed in the 1990 membership directory of the Society for the Study of Ingestive Behavior (SSIB) soliciting views on the top five journals publishing the greatest number, as well as the most "prestigious," articles in this field, along with demographic information about the respondents. After deleting journals that published agriculturally based research relating to insects or parasites, the Medline search generated 1,813 articles in the top 25 journals, the top 5 of which were Physiology and Behavior (462 articles), Pharmacology, Biochemistry and Behavior (211 articles), Brain Research (118 articles), American Journal of Physiology (106 articles) and Brain Research Bulletin (87 articles). This fact accorded well with weighted scores generated from perceptions of SSIB respondents (24.4% return rate), whose top 25 rankings correlated highly (r14 = +0.829, p < .001) with the Medline data. Although the top 5 number 1 choices of "prestige" journals by SSIB members did not match up well with the Medline list, weighted "prestige" scores correlated reasonably well with the Medline data (r15 = +0.766, p < .001), but a bit less so with SSIB perceptions of where greatest numbers of articles appeared (r12 = +0.588, p < .05). Discussion is presented about the validity of these data, their implications, and their potential utility in helping researchers decide where to publish work in this field.

Neonatal 6-hydroxydopamine alters the behavior of enriched-impoverished rats in a novel test environment.

The hypothesis that neonatal norepinephrine (NE) depletion lessens the behavioral consequences of differential housing was tested. Male Wistar rats were injected with 6-hydroxydopamine (6-OHDA) or vehicle twice within 24 hr of birth, weaned at 25 days, and reared under either impoverished (IC) or enriched conditions (EC) for 30 days. In 3 experiments, rats were tested in the Morris water maze, the colony-intruder test, and 2 tests of dominance. 6-OHDA treatment reduced cortical and hypothalamic NE concentrations and increased brainstem NE concentrations. EC housing increased cortical dopamine (DA). Behavioral differences caused by postweaning enrichment-isolation were reduced by neonatal NE depletion, primarily in early test trials. The authors conclude that forebrain NE afferents from the locus coeruleus are important for housing-related behavioral changes and responsivity to novel testing environments.

Influence of taste and food texture on the feeding responses induced by 8-OH-DPAT and gepirone.

Previously it has been shown that 5-hydroxy-tryptamine (5-HT)1A agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone increase food intake in free-feeding rats. These experiments were conducted to examine the possible influence of taste and textural factors on the feeding responses induced by these two drugs. Separate groups of non-water-deprived rats were given access to one of a variety of different solutions of saccharin (0.02, 0.04, 0.20 and 2.0% w/v) or water for 2 h each day. Rats were then treated with different doses of 8-OH-DPAT (10, 60 or 100 micrograms/kg) or gepirone (1 or 2.5 mg/kg) in a repeated measures design. Under saline injection an inverted-U shaped concentration-response curve was obtained, with the highest level of intake occurring in rats drinking from the 0.20% saccharin solution. The highest doses of 8-OH-DPAT and gepirone suppressed drinking of saccharin, particularly over the first 30 min of the test period, leading to a flattening of the concentration response curve. At 2 h post-injection 60 micrograms/kg 8-OH-DPAT enhanced the consumption of the 0.04% saccharin solution only. In a second experiment, 8-OH-DPAT or gepirone was administered to rats eating either standard pelleted chow or the same food presented in powdered form. Both drugs stimulated feeding. However, interactions with food type were found. At 60 and 100 micrograms/kg 8-OH-DPAT increased eating of both food types equally, but with 500 micrograms/kg rats are significantly more of the pelleted food.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of central 5,7-dihydroxytryptamine on the medical hypothalamic syndrome in rats.

The present study attempted to replicate and extend two recent studies that implicated aberrant brain 5-HT neurotransmission in the etiology of overeating and BW grain. Adult female rats received 25 mg/kg of desipramine hydrochloride 30--45 min prior to an intracisternal injection of 200 microgram (free base) of 5,7-DHT creatinine sulfate or its 1% ascorbic acid aqueous vehicle. After 7 weeks of measuring food intake, water intake, and BW change, rats from both groups received radiofrequency lesions of the MH or sham surgery. After 5 additional weeks of intake and BW measurements, all rats were tested for 24-hr acceptance of varying sucrose and quinine solutions and for 25-day acceptance of a high-fat replacement diet. While 5,7-DHT depleted brain 5-HT by 45%, it did not induce overeating and BW gain alone nor did it modify the overeating, obesity, or "finickiness" produced by hypothalamic injury. Several factors that relate to specificity, sufficiency, and compatibility with other 5-HT depletory techniques were discussed, as were factors of similarity and dissimilarity between this and the previous experiments that we attempted to replicate.

Stimulation of 5-HT(2A/2C) receptors within specific hypothalamic nuclei differentially antagonizes NPY-induced feeding.

The present study examined the impact of the 5-HT(2A/2C) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on the feeding-stimulant action of neuropeptide Y (NPY) injected into three hypothalamic sites, the paraventricular nucleus (PVN), the perifornical hypothalamus (PFH) and the ventromedial nucleus (VMH). Injections of NPY (100-200 pmol) into each region potentiated food intake. Pretreatment with DOI (5-20 nmol) into the PVN effectively suppressed feeding elicited by PVN NPY (100 pmol). In contrast, DOI injections into the PFH and VMH failed to modify NPY-stimulated eating. This suggests that 5-HT(2A/2C) receptor modulation of NPY feeding within the hypothalamus is localized to the PVN.

Effect of the CCKA antagonist devazepide on eating stimulated by raphe injection of 8-OH-DPAT.

Several recent studies have suggested that feeding suppression is mediated jointly by enhanced neurotransmission of cholecystokinin (CCK) and serotonergic (5-HT) systems. In the present study the CCKA receptor antagonist devazepide (50-200 micrograms kg-1, s.c.) was found reliably to potentiate the feeding response elicited by dorsal or median raphe injection of the 5-HT1A agonist 8-OH-DPAT (0.2-0.8 nmol). This effect was evident following co-administration of both feeding threshold and subthreshold doses of either compound, suggesting that the simultaneous suppression of CCK and 5-HT function may interact as joint effectors of overeating.

Diurnal variations in the feeding response to 8-OH-DPAT injected into the dorsal or median raphe.

To determine the impact on food intake of the 5-HT1A agonist, 8-OH-DPAT, administered at various times throughout the nocturnal cycle, rats were implanted with cannulae in either the dorsal or median raphe nuclei and injected with saline or 8-OH-DPAT (0.4, 0.8 or 1.6 nmol) immediately following dark onset, or during the mid or late dark periods. 8-OH-DPAT potentiated feeding when administered in the mid or late dark phase, whereas treatment during the early dark actually suppressed food intake. These findings indicate that the feeding responses to dorsal and median raphe 8-OH-DPAT vary greatly depending on the time of administration in the diurnal cycle and are consistent with recent reports of a biphasic action of this compound on ingestive behaviour.

Paraventricular nucleus injections of naloxone methiodide inhibit NPY's effects on energy substrate utilization.

Microinjection of neuropeptide Y (NPY) into the paraventricular nucleus (PVN) of the hypothalamus stimulates eating and increases respiratory quotient. In contrast, administration of opioid receptor antagonists reduces food intake and suppresses NPY-induced feeding. The present study examined whether naloxone methiodide, an opioid antagonist, would suppress the potentiation of NPY on energy substrate utilization, when injected into the PVN. Naloxone methiodide was injected at doses of 0.1 and 1.0 g, 10 min prior to NPY treatment. NPY was administered immediately prior to the start of the nocturnal period and RQ was determined using an open-circuit calorimeter. Doses of 50 and 100 pmol NPY alone evoked reliable increases in RQ within 30min of treatment. Following naloxone methiodide pretreatment, the stimulatory action of NPY was significantly attenuated. These data indicate that opioid receptors in the PVN influence the action of NPY on energy substrate utilization.

5-HT receptor blockade in the posterior amygdala elicits feeding in female rats.

Previous work suggests that feeding following intraventricular (i.v.t.) injections of the serotonin (5-HT)(1/2/7) antagonist metergoline (MET) is not localized to the hypothalamus. Since lesions of the posterior basolateral amygdala (pBLA) block feeding following systemic 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin, the ability of intra-pBLA MET to elicit feeding was investigated. In two separate experiments, feeding of female rats was measured over 2 h following 0, 3, 10 and 30 nmol and 0, 0.03, 0.3 and 3 nmol MET (mol. wt. 403.5) injected bilaterally into each pBLA. All three doses used in Experiment 1 increased feeding over 2 h. In Experiment 2, feeding over the first hour was enhanced after the two highest doses. Since intra-pBLA MET elicits feeding comparable to that seen using much higher doses administered i.v.t. these data implicate the pBLA as an extra-hypothalamic site mediating the effects of 5-HT in feeding control.

Dissociated feeding and hypothermic effects of neuropeptide Y in the paraventricular and perifornical hypothalamus.

The present study investigated the effects of neuropeptide Y (NPY) on food intake and body temperature (Tbo) in free-feeding unrestrained rats following injection into the medial hypothalamic paraventricular nucleus (PVN) or the lateral perifornical hypothalamus (PFH). NPY (78-235 pmol) or saline was infused unilaterally into the PVN or PFH in a volume of 0.4 microliter and simultaneous measures of food intake and Tbo were taken every 30 min for 3 h. Results indicated that NPY evoked changes in eating behavior and Tbo that were dependent upon the site of hypothalamic injection. Although PVN and PFH administration of NPY both increased food intake dose dependently within 30 min of treatment, PFH NPY-injected rats (n = 9) showed a stronger behavioral response compared to rats (n = 9) receiving NPY injections into the PVN. In PVN-treated rats, however, the increased eating was associated with a significant decline in Tbo evident within the first 30-min test interval. A mean maximal decline of 0.92 +/- 0.26 degree C occurred within 90 min of PVN treatment of the highest dose, which produced a reduction in Tbo that was maintained for 2.5 h. In contrast, NPY infusion into the PFH failed to reliably alter Tbo at any of the doses tested. These findings are consistent with evidence that NPY in the PVN and PFH may have distinct functions and suggest that although PFH NPY acts to stimulate a robust and relatively specific ingestive response, PVN NPY may participate in the complex integrative mechanisms responsible for the simultaneous regulation of feeding, thermoregulatory, and metabolic processes.

Neuropeptide Y-induced operant responding for sucrose is not mediated by dopamine.

Neuropeptide Y (NPY) induces feeding in previously satiated animals after injection into the hypothalamus, especially the perifornical region (PFH). NPY also appears to have rewarding properties as evidenced by its ability to produce a conditioned place preference following injection into the nucleus accumbens (N.Acc), an effect ostensibly mediated by mesolimbic dopamine (DA). Since the progressive-ratio (PR) operant schedule has also been used to assess an organism's motivation to respond for rewarding stimuli, we tested the possibility that NPY increases PR responding for sucrose pellets. Adult male rats were injected with NPY (0-235 pmol) bilaterally through cannulae aimed to terminate in the PFH. This produced a dose-dependent increase in the total number of responses made and the number of reinforcers earned. The DA receptor blocker, alpha-flupenthixol (FLU)(0-0.2 mg/kg intraperitoneally), attenuated both NPY(156 pmol)-induced and drug-free PR responding while having no effect on NPY(156 pmol)-induced free-feeding. FLU injected directly into the N.Acc (0-5 microg) also failed to reduce sucrose free-feeding. These results suggest that distinct reward mechanisms are activated during PFH NPY-induced feeding vs. PR responding, since FLU disrupted the latter but not the former.

The rewarding properties of neuropeptide Y in perifornical hypothalamus vs. nucleus accumbens.

There is a high coexistence of substance abuse in humans with eating disorders. One theory offered to account for this fact is that a common biochemical substrate may exist that mediates both processes. Brain neuropeptide Y (NPY) is one neurochemical system that might contribute to these separate, yet related, problems. To clarify the role of NPY in mediating reward processes and the possible interaction between reward and feeding, the present study examined the effects of injecting NPY bilaterally into the perifornical hypothalamus (PFH) vs. the nucleus accumbens (NAC) on intake of preferred vs. non-preferred food types, as well as on conditioned place preference (CPP) learning. NPY (24, 78, 156 and 235 pmol/side) stimulated intake of both regular powdered chow and sucrose when injected into the PFH, but not the NAC. A CPP that was negatively correlated with food intake occurred with the low (24 pmol/side) dose of NPY in the PFH, while a CPP that was not correlated with food intake was produced with the same dose in the NAC. The extent of the CPPs produced by NPY injection in both brain sites mirrored that produced by peripheral injection of amphetamine (2.5 mg/kg). These results indicate that NPY elicits reward-related behavior, but not feeding, from the NAC, and both behaviors from the PFH. However, the feeding effect derived from the PFH appears to overshadow a rewarding effect derived from this site. Considered together, these findings suggest that altered NPY functioning in both brain regions may contribute to some of the pathophysiological processes observed in eating disordered patients who have additional proclivities for substance abuse.

Graded increases in brain GABA: differential effects on feeding and other behaviours in rats.

Elevations of brain gamma-aminobutyric acid (GABA) induced by inhibitors of GABA transaminase (GABA-T) are known to induce a number of functional effects including depression of food intake. The aim of the present study was to determine the brain GABA elevation threshold for changes in feeding and several other behaviours, in an effort to clarify whether feeding changes might be secondary to other functional deficits. To this end, various doses of the GABA-T inhibitors ethanolamine-o-sulfate (EOS) and gamma-vinyl GABA (GVG) were injected intracisternally and effects on whole brain GABA, food and water intake, open field activity, catalepsy indices, pain sensitivity, and core temperature were assessed 24 h later. Progressive increases in brain GABA levels were found to differentially affect the responses studied. At the low end of the continuum, significant decreases in feeding behaviour were associated with relatively modest increases in brain GABA (40-60%). At higher levels of GABA elevation (greater than 100%), changes in motoric functions and rectal temperature became apparent. At still higher levels (greater than 200% increases in brain GABA), significant antinociceptive effects were detected. These results support the notion that feeding decreases induced by low doses of GABA-T inhibitors may reflect a fairly specific effect on appetite mechanisms, but also indicate that with increasingly higher doses several other deficits are likely to contribute to the overall decrease in food intake.

Regional hypothalamic differences in neuropeptide Y-induced feeding and energy substrate utilization.

Previous research has shown that both the paraventricular nucleus (PVN) of the hypothalamus and the perifornical hypothalamus (PFH) are sites at which microinjection of neuropeptide Y (NPY) can induce eating. The PVN has also been shown to be responsive to the effects of exogenous NPY on energy substrate utilization. Therefore, the objective of the present study was to further characterize and compare the effects of NPY on whole-body calorimetry and feeding after microinjection into either the PVN or the PFH. The metabolic effects of NPY (19.5-78 pmol) were determined using an open-circuit calorimeter by measuring the volumes of oxygen consumed and carbon dioxide expired in order to compute respiratory quotients (RQs). Following NPY injection into the PVN (n = 10) or PFH (n = 10), RQs and locomotor activity were monitored over three hours. Additional groups of rats with PVN (n = 10) or PFH (n = 10) cannulae were tested for their feeding responses to these same doses of peptide. While NPY injections into the PVN evoked dose-dependent increases in RQ within 30-40 min of treatment, PFH NPY did not alter RQ at any of the doses tested. Locomotor activity was unaffected by NPY in either site. NPY administration into both the PVN and PFH stimulated eating, although the PFH was found to be the more sensitive in terms of absolute amount of food consumed. These findings support the hypothesis that the PVN may regulate metabolic processes that either produce or coincide with NPY-induced feeding. This contrasts with the PFH, which appears to mediate only the feeding-stimulatory actions of NPY.

Central injections of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS): effects on brain [14C]2-deoxy-D-glucose uptake and behavior in rats.

Brain glucose utilization was examined 24 h after single intracisternal injections of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS) in rats. Qualitative autoradiography indicated a pronounced and homogeneous depression in [14C]2-deoxy-D-glucose ([14C]2DG) uptake throughout the brains of rats treated with 200 or 400 micrograms EOS. Quantitative scintillation counting of 14C in 9 brain areas of other rats confirmed the marked, generalized decrease in label uptake 24 h after EOS. Food intake measurements confirmed previous reports of dose-dependent anorexia after EOS. Rats treated with the 200 micrograms dose showed decreased open-field activity 24 h after injection but no other deficits in various tests of sensorimotor function or in tail-pinch-induced feeding. Rats treated with the 400 micrograms dose also showed deficits in open-field activity, plus deficits in orientation to touch stimuli, longer latencies than controls in catalepsy tests, and faster habituation of startle responses to sound. This group showed normal feeding responses to tail-pinch stimulation in the presence of solid food but not in the presence of liquid food. It was concluded that sensorimotor deficits may play some role in the anorexigenic effects of EOS but are probably not their primary cause. The discrepancy between the apparent degree of depression of brain glucose utilization and the comparatively mild behavioral deficits observed would suggest the possibility that metabolic fuels other than glucose may be mobilized following central EOS treatment.

5-Hydroxytryptaminergic receptor agonists: effects on neuropeptide Y potentiation of feeding and respiratory quotient.

The objective of the present report was to characterize further the potential interactive effects of NPY and 5-HT on feeding and whole-body calorimetry. Specifically, several experiments examined the impact of various 5-HT receptor agonists on NPY stimulated eating and alterations in respiratory quotient (RQ). This included the 5-HT1A/1B receptor agonist RU 24969, the 5-HT1B/2C agonist TFMPP and the 5-HT2A/2C agonist DOI. In feeding tests conducted at the onset of the dark cycle, RU 24969, TFMPP and DOI were administered 5 min prior to PVN injection of NPY and food intake was measured 1 h postinjection. The metabolic effects of NPY following similar pretreatment were monitored using an open-circuit calorimeter measuring the volume of oxygen consumed (VO2), carbon dioxide produced (VCO2) and RQ (VCO2/VO2). PVN injection of NPY (50-100 pmol) potentiated feeding and evoked reliable increases in RQ. DOI (5-20 nmol), but not RU 24969 (5-20 nmol) or TFMPP (10-40 nmol), antagonized NPY induced eating and blocked the peptide's effects on RQ. These findings suggest that 5-HT2A receptors within the PVN modulate NPY's effect on feeding and energy substrate utilization at the start of the nocturnal period.

Paraventricular nucleus injections of idazoxan block feeding induced by paraventricular nucleus norepinephrine but not intra-raphe 8-hydroxy-2-(di-n-propylamino)tetralin.

Previous work has shown that injection of the 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the midbrain raphe nuclei activates somatodendritic 5-HT autoreceptors leading to decreased 5-HT synthesis and release in terminal forebrain regions and an increase in feeding behaviour. Since 5-HT is believed to function antagonistically with norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN) to control feeding, it has been proposed that 8-OH-DPAT elicits food intake by removing the inhibitory influence of 5-HT over PVN alpha 2-adrenergic feeding mechanisms. This hypothesis was tested by examining the ability of PVN injection of the alpha 2-adrenoceptor antagonist idazoxan (IDAZ) to attenuate the feeding stimulant action induced by raphe injection of 8-OH-DPAT. In the first series of experiments the dose-response effects of dorsal and median raphe injection of 8-OH-DPAT in addition to PVN NE on feeding were examined. Injection of NE (5-40 nmol) and 8-OH-DPAT (0.4-1.6 nmol) both elicited reliable dose-dependent increases in 1 h food intake compared to saline control. Similar doses of 8-OH-DPAT injected into the PVN failed to alter baseline feeding. A second series of experiments examined the effects of IDAZ on 8-OH-DPAT and NE-stimulated food intake in rats implanted with dorsal or median raphe cannulae as well as cannulae aimed at the PVN.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of three neurochemical stimuli on delayed feeding and energy metabolism.

Infusions of norepinephrine (NE), the gamma-aminobutyric acid agonist, muscimol (MUS), or neuropeptide Y (NPY) into the paraventricular nucleus (PVN) of the hypothalamus all increase food intake. Such feeding may be due to direct activation of behavioral processes driving ingestion and/or to alterations in nutrient metabolism that feeding serves to normalize. To examine these possibilities, male Sprague-Dawley rats received PVN infusions of vehicle, 20 nmol NE, 1 nmol MUS or 100 pmol NPY at dark onset, then food intake was measured under three feeding conditions: (1) 1 and 2 h immediately after injections, (2) 1 h after a 1 h delay between injections and access to food, and (3) 1 h after a 1 h feeding delay, but with injections occurring just before presenting food. Measures of energy expenditure (EE) and respiratory quotients (RQs) in the absence of food were made over 2 h in parallel experiments. Results confirmed that NE, MUS and NPY all increased dark-onset feeding, but only NPY increased intake above control levels after a 1 h feeding delay. No neurochemically-induced changes in EE were observed, nor were there changes in RQs after NE or MUS. However, NPY reliably enhanced RQs from 30 to 120 min of testing. Our findings imply that NE and MUS initiate relatively immediate, short-term feeding that is not associated with changes in nutrient metabolism and does not summate with cues stimulated by delayed access to food. NPY initiates more protracted feeding temporally linked to enhanced carbohydrate metabolism. This may indicate that part of NPY's feeding stimulatory effects are secondary to physiological processes driving ingestion.