The effect of ghrelin on water intake during dipsogenic conditions

Ghrelin has been studied extensively in the context of food intake and energy homeostasis, but less is known about its role in other ingestive behaviors. The present studies investigated the effects of this orexigenic peptide on both food and water intake during dipsogenic conditions. Specifically, animals were exposed to one of five dipsetic stimuli: (1) 24-h water deprivation, (2) replacement of drinking water with 2.5% NaCl, (3) peripheral administration of hypertonic saline, (4) ICV injection of angiotensin II (AngII), or (5) the combination of peripheral hypertonic saline and central AngII. Animals then were given an ICV injection of ghrelin (0.5  µg) or vehicle, and subsequent food and water intakes were measured. Ghrelin reliably increased food intake under each stimulus condition. Ghrelin also affected water intake, but with less consistency across the conditions. Specifically, ghrelin attenuated water intake stimulated by acute injection of AngII or hypertonic saline, but failed to affect drinking in the other three stimulus conditions. Investigation of the temporal pattern of food and water intakes in three of these dipsogenic conditions failed to support a role of different intake patterns in the observed differences in water intake by ghrelin-treated rats. Although the effect of ghrelin on water intake was not present in every dipsogenic condition, these data provide evidence that the actions of ghrelin are not limited to food intake, but can also include alterations in water intake.     

Ghrelin stimulates growth hormone secretion and food intake in aged rats

Age-related decreases in energy expenditure have been associated with the loss of skeletal muscle and decline of food intake, possibly through a mechanism involving changes of growth hormone (GH) secretion and feeding behavior. Age-related declines of growth hormone secretion and food intake have been termed the somatopause and anorexia of ageing, respectively. Ghrelin, a 28-amino-acid peptide, was isolated from human and rat stomachs as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin stimulates growth hormone release and food intake when peripherally administered to rodents and humans. Here, we investigate the relationship between age-related decline of growth hormone secretion and/or food intake and ghrelin function. Ghrelin (10 nmol/kg body weight) was administered intravenously to male 3-, 12-, 24-and 27-month-old Long-Evans rats, after which growth hormone concentrations and 2 h food intake were measured. An intravenous administration of ghrelin to rats increased food intake in all generations. In addition, to orexigenic effect by ghrelin, intravenous administration of ghrelin elicited a marked increase in plasma GH levels, with the peak occurring 15 min after administration. These findings suggest that the aged rats maintain the reactivity to administered exogenous ghrelin.     

Effect of the N-methyl-d-aspartate receptor antagonist on locomotor activity and cholecystokinin-induced anorexigenic action in a goldfish model

We have previously identified that peripherally administered cholecystokinin (CCK) exerts an anorexigenic action via the vagal afferent, and subsequently the brain melanocortin- and corticotropin-releasing hormone-neuronal pathways in goldfish. N-Methyl-d-aspartate (NMDA) receptors have been shown to be involved in the regulations of locomotor activity and food intake in mammals. Although several neuropeptides and other factors exert similar effects in fish and mammals, the role of NMDA receptor in the control of locomotor activity and feeding behavior in fish is still unclear. In the present study, we examined the effect of the NMDA receptor antagonist, MK-801, on locomotor activity and food intake in the goldfish. Intraperitoneal (IP) injection of MK-801 at 0.15 nmol/g body weight (BW) increased locomotor activity, but did not affect food consumption. IP injection of MK-801 at same dose attenuated peripheral CCK (100 pmol/g BW)-induced anorexigenic, but not peripheral acyl ghrelin (10 pmol/g BW)-induced orexigenic actions. These data show for the first time that the NMDA receptor-signaling pathway is involved in the regulation of locomotor activity and feeding behavior through modulation of the peripheral CCK-induced satiety signal, but not the orexigenic effect of ghrelin.     

6-Hydroxydopamine lesions of the ventral tegmental area suppress ghrelin's ability to elicit food-reinforced behavior

While past research suggests that ghrelin stimulates appetite through an action on hypothalamic signaling, recent evidence indicates that the peptide acts via mesotelencephalic dopamine neurons to alter appetitive motivation. In the present study, rats were trained to operantly respond for food on a progressive ratio PR5 schedule until stable breakpoints were established. Ghrelin (30-300 pmol) was then injected directly into the ventral tegmental area (VTA) and the 300 pmol dose was observed to increase breakpoint. The dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA, 6 μg) was subsequently administered into the VTA resulting in a significant depletion of striatal dopamine. Stable breakpoints were then re-established. When ghrelin's effects were reassessed, the peptide's ability to alter operant responding for food was reliably reduced. Our findings demonstrate that ghrelin induces food-reinforced behavior in the mesotelencephalic reward pathway and that this effect is dependent on intact dopaminergic signaling. We conclude that the metabolic peptide ghrelin interacts with dopamine, within reward circuitry, to modulate appetitive behavior.     

Peripheral ghrelin selectively increases Fos expression in neuropeptide Y - synthesizing neurons in mouse hypothalamic arcuate nucleus

Ghrelin, a peptide isolated from the rat stomach, is the endogenous ligand of the growth hormone-secretagogue receptor and also known to have orexigenic effect. We examined the influence of intraperitoneal (i.p.) injection of ghrelin on food intake and brain neuronal activity in freely fed mice. Ghrelin (3, 10 or 30 microg/mouse) dose-dependently increased food intake by 0.8-, 1.6- and 2.6-fold, respectively, at 30 min post injection. Ghrelin (10 microg/mouse) induces Fos expression selectively in the ventromedial part of the hypothalamic arcuate nucleus (Arc). No change in Fos expression was observed in other hypothalamic and hindbrain nuclei. About 90% of the Fos-positive neurons in the Arc expressed neuropeptide Y (NPY) messenger RNA. These data indicate that NPY neurons in the Arc are likely the primary target mediating i.p. ghrelin induced orexigenic effect.     

Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents

Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food.     

The role of GABAergic system on the inhibitory effect of ghrelin on food intake in neonatal chicks

Ghrelin is a gut-brain peptide that has a stimulatory effect on food intake in mammals. In contrast, this peptide decreases food intake in neonatal chicks when injected intracerebroventricularly (ICV). In mammals, neuropeptide Y (NPY) mediates the orexigenic effect of ghrelin whereas in chicks it appears that corticotrophin releasing factor (CRF) is partially involved in the inhibitory effect of ghrelin on food intake. Gamma aminobutyric acid (GABA) has a stimulatory effect on food intake in mammals and birds. In this study we investigated whether the anorectic effect of ghrelin is mediated by the GABAergic system. In Experiment 1, 3 h-fasted chicks were given an ICV injection of chicken ghrelin and picrotoxin, a GABA_A receptors antagonist. Picrotoxin decreased food intake compared to the control chicks indicating a stimulatory effect of GABA_A receptors on food intake. However, picrotoxin did not alter the inhibitory effect of ghrelin on food intake. In Experiment 2, THIP hydrochloride, a GABA_A receptor agonist, was used in place of picrotoxin. THIP hydrochloride appeared to partially attenuate the decrease in food intake induced by ghrelin at 30 min postinjection. In Experiment 3, the effect of ICV injection of chicken ghrelin on gene expression of glutamate decarboxylase (GAD)₁ and GAD₂, GABA synthesis enzymes in the brain stem including hypothalamus, was investigated. The ICV injection of chicken ghrelin significantly reduced GAD₂ gene expression. These findings suggest that ghrelin may decrease food intake in neonatal chicks by reducing GABA synthesis and thereby GABA release within brain feeding centers.     

Effects of manipulations of glucoregulation on feeding in the ground squirrel

Insulin and 2-deoxy-D-glucose (2-DG) stimulate feeding in rats, while glucagon inhibits feeding. We report here their effects on food intake in the 13-lined ground squirrel (Spermophilus tridecumlinectus). These hibernating animals are an interesting model for studying appetite regulation because of the marked seasonal variations in food consumption. Food intake reached a peak of 286 +/- 7 g/kg/day in mid July, decreasing to 16.1 +/- 3 g/kg/day in September. Studies during the hyperphagic period showed that glucagon (0.5 to 1 mg/kg) decreased feeding 30 minutes post injection (p less than 0.01) whereas at 4 hours glucagon produced a 37% increase in feeding (p less than 0.05). During the hypophagic period, glucagon failed to alter food consumption. Insulin (5-100 Units/kg) produced no effect on feeding in hyperphagic animals despite a decrease in glucose from 193 +/- 10 mg/dl to 55 +/- 4 mg/dl after 100 Units/kg. However, insulin (50 and 100 Units/kg) resulted in significant increases in food consumption at 2 and 4 hours (p less than 0.01 and 0.05, respectively) when administered while the animals were hypophagic. 2-DG (250-750 mg/kg) increased food consumption (hyperphagic phase) by 76% at 20 hours (p less than 0.01) with significant increases being present as early as 4 hours, although when 2-DG was given to hypophagic animals it resulted in decreased food intake at 4 hours (p less than 0.05). We conclude that the effects of glucoregulatory manipulations on food consumption are markedly influenced by the circannual rhythm of feeding in the 13-lined ground squirrel.     

Ghrelin and the short- and long-term regulation of appetite and body weight

Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients. Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood-brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.     

SKF 83566 attenuates the effects of ghrelin on performance in the object location memory task

Increasing research implicates ghrelin, a metabolic signaling peptide, in memory processes including acquisition, consolidation, and retention. The present study investigated the effects of ghrelin on spatial memory acquisition by utilizing the object location memory task paradigm. Given the co-expression of ghrelin and dopamine D₁ receptors within hippocampal neurons, we examined a potential interaction between these two systems on memory performance. When injected into the dorsal third ventricle (D3V) of male Sprague-Dawley rats, proximal to hippocampal tissue, ghrelin (500 pmol) increased the amount of time spent with objects in novel locations. This effect was completely reversed by the D₁ antagonist SKF 83566 (100 μg/kg IP), although when administered alone, the antagonist had no effect on task performance (10-100 μg/kg). We also examined the feeding effects of D3V ghrelin and found that the peptide reliably increased food intake (500 pmol) but that this effect was not blocked by SKF 83566 (100 μg/kg). When given alone, SKF 83566 did not alter food intake (10-100 μg/kg). Our findings indicate that, in addition to an orexigenic effect, ghrelin improves acquisition of spatial location memories. Furthermore, D₁ receptor activation is necessary for ghrelin to improve the encoding of spatial memories but does not impact the increase in food intake elicited by the peptide.     

Centrally administered ghrelin potently inhibits water intake induced by angiotensin II and hypovolemia in rats

Ghrelin is a potent, centrally acting orexigenic hormone. Recently, we showed that centrally administered ghrelin is a potent antidipsogenic hormone in 24-h water deprived rats. In this study, we examined the effect of intracerebroventricular (icv) injection of ghrelin on angiotensin II (AII)-induced water intake in rats. We also examined the effects of icv injection of ghrelin on drinking induced by intraperitoneal injection of an isotonic polyethylene glycol (PEG) solution that causes isotonic hypovolemia. Water intake induced by the icv injection of AII or ip injection of PEG was significantly reduced after icv injection of ghrelin, although food intake was stimulated by the hormone. The drinking induced by AII was also inhibited by the icv administration of 4α-phorbol 12, 13-didecanoate, an agonist of the osmosensitive TRPV4 channel. This study showed that ghrelin is a potent antidipsogenic peptide by antagonizing general dipsogenic mechanisms including those activated by AII and hypovolemia in rats.     

A role of the histaminergic system for the control of feeding by orexigenic peptides

A considerable number of neuropeptides are involved in the hypothalamic regulation of feeding behavior. We previously reported that leptin, the ob gene product, expressed its anorectic effect though the histaminergic system via histamine H(1) receptors. However, the interactions among the orexigenic neuropeptides, such as orexin-A, neuropeptide Y (NPY), and ghrelin, and the histaminergic system have not yet been clarified. In this study, we investigated the effect of the neuropeptides on the hypothalamic histamine release in rats, and on food intake and locomotor activity in H(1)-receptor knockout (H1R-KO) mice. Orexin-A increased the histamine release and locomotor activity, but not food intake, suggesting that the histaminergic system participates in arousal rather than feeding by orexin-A. NPY also increased histamine release, but its effect was not immediate. NPY-injected H1R-KO mice consumed more food than the wild-type mice; thus, the histaminergic system may act as a feedback factor downstream of NPY. Ghrelin did not affect histamine release, and it increased food intake, even in H1R-KO mice. Thus, ghrelin expresses its action in a histamine-independent manner.     

Central administration of ghrelin preferentially enhances fat ingestion

Ghrelin, a brain-gut peptide discovered from the stomach, stimulates growth hormone release, food intake, adiposity, and weight gain. Circulating ghrelin levels are modulated under conditions of positive and negative energy balance, however its effect on macronutrient selection is not known. The present experiment investigates the effect of ghrelin on single and two-diet feeding paradigms in high-carbohydrate (HC) and high-fat (HF) preferring rats. In the macronutrient selection test in which rats were given free access to either high-carbohydrate or high-fat diet, an intracerebroventricular (i.c.v.) administration of ghrelin potently enhanced fat intake over carbohydrate intake in both HC- and HF-preferring rats. In the diet preference test in which rats were given free access to both high-carbohydrate and high-fat diets simultaneously, an i.c.v. administration of ghrelin also preferentially enhanced fat consumption over carbohydrate in both HF- and HC-preferring rats. Intracerebroventricular administrations of galanin and neuropeptide Y enhanced fat and carbohydrate ingestion, respectively. Centrally administered ghrelin enhanced fat ingestion. These results provide further insights for the role of ghrelin in feeding behavior and the development of obesity.     

Peripheral ghrelin enhances sweet taste food consumption and preference, regardless of its caloric content

Aims

Ghrelin is one of the most potent orexigens known to date. While the prevailing view is that ghrelin participates in the homeostatic control of feeding, the question arose as to whether consummatory responses evoked by this compound could be related to search for reward. We therefore attempted to delineate the involvement of ghrelin in the modulation of non-caloric but highly rewarding consumption.

Methods

We tested the effect of intraperitoneally injected ghrelin on the acceptance and preference for a 0.3% saccharin solution using single bottle tests and free-choice preference test procedures in C57BL6/J mice, as well as in mice lacking the ghrelin receptor (GHSR1a −/−) and their wild-type (WT) littermates.

Results

In the single bottle tests, peripheral ghrelin consistently increased the consumption of saccharin, independently of availability of caloric food. In the free-choice preference test procedures, ghrelin increased the preference for saccharin in WT mice, while it did had not effect in GHSR1a −/−animals, indicating that the ghrelin receptor pathway is necessary to mediate this parameter.

Conclusions

Peripheral ghrelin enhances intake and preference for a sweet food, regardless of whether the food has caloric content. This effect, mediated through the ghrelin receptor pathway, may serve as additional enhancers of energy intake.     

Modulation of the satiating effect of amylin by central ghrelin, leptin and insulin

Amylin is a pancreatic hormone that is considered to be a satiating signal acting on neurons of the area postrema (AP) in the hindbrain. The adiposity signals leptin and insulin act in the hypothalamus to influence feeding. They also enhance the hindbrain's responsivity to satiating signals, e.g. cholecystokinin (CCK). The orexigenic hormone ghrelin is thought to use the same hypothalamic pathways as leptin and insulin, with opposite actions on feeding behaviour. In fact, CCK and ghrelin also seem to interact in the control of feeding. Because CCK's anorectic effect depends on endogenous amylin, the aim of this study was therefore to evaluate a possible functional interaction between amylin and these hormones on short-term food intake in rats. The experiments were performed with male Wistar rats. Intracerebroventricular injection (i3vt) of an orexigenic dose of ghrelin (5 ng/5 microl) reduced but did not completely reverse the intraperitoneal amylin (5 microg/kg)-induced inhibition of food intake. In comparison, administration of a sub-threshold dose of ghrelin (3 ng/5 microl) did not affect the anorexigenic action of peripheral amylin. Leptin administered into the third ventricle (i3vt; 3.5 microg/5 microl) and intraperitoneal amylin (5 microg/kg) synergistically reduced food intake in chow-fed rats. I3vt insulin, administered at a sub-threshold dose (0.5 mU/5 microl), significantly enhanced the response to peripheral amylin. These results indicate that the lipostatic signals leptin and insulin may synergize with amylin to reduce food intake. In contrast, under the conditions tested, the orexigenic hormone ghrelin does not seem to influence the feeding response to peripheral amylin.     

Oxytocin inhibits food and fluid intake in rats

Increasing evidence indirectly suggests a role for oxytocinergic neurons in the control of ingestive behaviors. The present study was aimed at directly investigating a possible effect of oxytocin on food and water intake in rats. Oxytocin, whether administered intracerebroventricularly (ICV) (1-10 micrograms/rat) or intraperitoneally (IP) (375-3,000 micrograms/kg) dose dependently inhibited food intake in freely feeding animals; in schedule-fed animals fasting for 21 h, oxytocin not only reduced food intake but also reduced the time spent eating and increased the latency to first meal. On the other hand, oxytocin antagonist d(CH2)5Tyr(Me)-[Orn8]-vasotocin, ICV injected at the dose of 10 micrograms/rat, increased food intake and time spent eating and reduced the latency to first meal; moreover, it completely prevented the effect of oxytocin. Water intake was studied both in freely drinking animals and in three different models of thirst (water deprivation, hypertonic saline administration, angiotensin II injection). In all cases, oxytocin dose dependently inhibited water intake, in a dose range of 0.1-10 micrograms/rat (ICV) or 93-750 micrograms/kg (IP). In the water deprivation model, ICV pretreatment with d(CH2)5Tyr(Me)-[Orn8]-vasotocin completely prevented the antidipsogenic effect of oxytocin. In conclusion, these data show that oxytocin directly inhibits food and water intake in rats, the effect being specifically mediated by brain oxytocin receptors. This may support the idea that the brain oxytocinergic system plays an important role in the regulation of ingestive behaviors.     

Ghrelin、melanotan-Ⅱ以及胆囊收缩素对下丘脑双侧室旁核损伤大鼠摄食的影响

目的探讨大鼠下丘脑双侧室旁核(PVN)损伤引起的过食和肥胖的产生机制。方法 Wistar雄性大鼠36只,通过电损伤下丘脑双侧PVN使大鼠产生过食和肥胖,检测ghrelin、melanotan-II(MT-II,一种合成的α-黑色素细胞刺激素——α-MSH的结构同源体)以及胆囊收缩素-8(CCK-8)摄食作用的改变。结果双侧PVN损伤后大鼠的体重和摄食量明显增加,显示出过食和肥胖,手术后1周,外周给与Ghrelin,3～4h后PVN损伤组比伪损伤组的摄食量增加明显,Ghrelin显示出更强的刺激摄食的作用;中枢给予MT-Ⅱ可明显抑制24h节食大鼠的食物摄取,然而PVN损伤后MT-II对24h节食大鼠摄食的抑制作用减弱甚至消失;外周给予CCK-8可明显抑制大鼠各时间段的摄食作用,PVN损伤组和伪损伤组之间未见明显差异。结论大鼠下丘脑双侧PVN损伤引起的过食和肥胖可能与增强的ghrelin对摄食的刺激作用和(或)α-MSH受体的破坏有关。     

Effect of the diazepam-binding inhibitor-derived peptide, octadecaneuropeptide, on food intake in goldfish

An endogenous ligand of central-type benzodiazepine receptors (CBR), the endozepine octadecaneuropeptide (ODN), is a very potent inhibitor of food intake in rodents. Although endozepines have been localized and characterized in the trout hypothalamus, so far, the action of these neuropeptides on feeding behavior has never been investigated in fish. In the present study, we have examined the effect of i.c.v. administration of synthetic rat ODN, its C-terminal octapeptide (OP) and the head-to-tail cyclic analog cyclo(1-8)OP (cOP) on feeding behavior in the goldfish model. i.c.v. injection of graded doses of ODN (2.5-10 pmol/g body weight (BW)) induced a dose-dependent inhibition of food intake, a significant decrease in cumulative food intake during the 60-min period after feeding being observed at doses of 5 and 10 pmol/g BW. The inhibitory effect of a 10 pmol/g BW dose of ODN on food consumption (-39%) was mimicked by an equimolar dose of OP (-42%) and cOP (-53%). The food intake-suppressing activity of ODN (10 pmol/g BW) was not affected by pre-injection of the CBR antagonist flumazenil (200 pmol/g BW). In contrast, the anorexigenic effect of ODN (10 pmol/g BW) was totally suppressed by a selective antagonist of metabotropic endozepine receptors, cyclo(1-8)[dLeu(5)]OP. These data indicate that, in goldfish as in rodents, ODN is a potent inhibitor of food consumption, and that the anorexigenic effect of ODN is not mediated through CBR but through the metabotropic endozepine receptor.     

Phentolamine stimulates insulin release and glucose clearance and suppresses food ingestion

In Experiment One, phentolamine (PTA), an alpha-adrenergic blocker, was injected in rats at doses of 0, 50, 100, 200, and 300 micrograms/kg following a 4-hr fast. Measurement of food intake 1-hr postinjection revealed that 300 micrograms/kg PTA reduced food intake. Experiment Two evaluated the potential aversiveness of 300 micrograms/kg PTA. Four-hour fasted rats were adapted to a milk diet as the only food source during a 1-hr intake measurement period. After the 15-day adaptation period, three separate groups of animals (n = 8 per group) received the milk with cherry flavoring added and infections of either 1% body weight 0.9 NaCl, isosmotic LiCl or 300 micrograms/kg PTA. Only those subjects that had received LiCl injections developed a reliable aversion to the cherry-flavored milk. The final experiments subdivided the 1-hr feeding period into three 20-min segments and, in separate animals, food intake or plasma insulin and glucose changes were assessed. The animals were assigned to one of two groups receiving either 300 micrograms/kg PTA or equivolume 0.9% NaCl. PTA-injected subjects showed an immediate modest enhancement of insulin release during the first 20-min feeding segment following injection, compared to controls, while blood glucose levels decreased but never differed reliably between groups. Food intake was reliably suppressed in the second and third 20-min segments for the PTA-injected rats. We advance that PTA by enhancing glucose clearance may be reducing ingestion.     

Ghrelin injected into the paraventricular nucleus of the hypothalamus of male rats induces feeding but not penile erection

The effect of ghrelin, a recently characterized endogenous receptor agonist for growth hormone (GH) secretagogue receptors, on feeding and penile erection was compared with that of EP 80661, a peptide analogue of the GH secretagogue hexarelin, previously identified for its pro-erectile activity when injected into the paraventricular nucleus of the hypothalamus of male rats. Ghrelin (0.01-1 microg), but not EP 80661 (0.02-1 microg), was found to be particularly effective in enhancing feeding. The minimal effective dose of ghrelin was 0.1 microg, which increased food intake by 88%, while the maximal response (355% above control values) was found with 1 microg of the peptide. The enhancing effect of ghrelin on feeding was prevented by the prior administration of the neuropeptide Y Y5 receptor antagonist (DTyr(2), DThr(32)) neuropeptide Y (NPY, 10 microg), but not by the GH-RH receptor antagonist MZ-4-71 (10 microg), or by EP 91073, a hexarelin analogue that antagonizes the pro-erectile effect of EP 80661 (10 microg), given into the lateral ventricles. In contrast, ghrelin failed to induce penile erection at all doses tested, while EP 80661 induced penile erection in a dose-dependent manner. The pro-erectile effect of EP 80661 was prevented by EP 91073 (10 microg), but not by (DTyr(2), DThr(32)) NPY (10 microg) or by the GH-RH receptor antagonist MZ 4-71 (10 microg), given into the lateral ventricles. The present results provide further support to the hypothesis that the GH secretagogue receptors mediating feeding are different from those mediating penile erection and activated by pro-erectile EP peptides.