NPY Y1 receptor antagonist prevents NPY-induced torpor-like hypothermia in cold-acclimated Siberian hamsters

Siberian hamsters (Phodopus sungorus) undergo bouts of daily torpor during which body temperature decreases by as much as 20 degrees C and provides a significant savings in energy expenditure. Natural torpor in this species is normally triggered by winterlike photoperiods and low ambient temperatures. Intracerebroventricular injection of neuropeptide Y (NPY) reliably induces torporlike hypothermia that resembles natural torpor. NPY-induced torporlike hypothermia is also produced by intracerebroventricular injections of an NPY Y1 receptor agonist but not by injections of an NPY Y5 receptor agonist. In this research, groups of cold-acclimated Siberian hamsters were either coinjected with a Y1 receptor antagonist (1229U91) and NPY or were coinjected with a Y5 receptor antagonist (CGP71683) and NPY in counterbalanced designs. Paired vehicle + NPY induced torporlike hypothermia in 92% of the hamsters, whereas coinjection of Y1 antagonist + NPY induced torporlike hypothermia in 4% of the hamsters. In contrast, paired injections of vehicle + NPY and Y5 antagonist + NPY induced torporlike hypothermia in 100% and 91% of the hamsters, respectively. Although Y5 antagonist treatment alone had no effect on body temperature, Y1 antagonist injections produced hyperthermia compared with controls. Both Y1 antagonist and Y5 antagonist injections significantly reduced food ingestion 24 h after treatment. We conclude that activation of NPY 1 receptors is both sufficient and necessary for NPY-induced torporlike hypothermia.     

Bimodal effect of neuropeptide Y on feeding, and its antagonism by receptor blocking agents in rats.

Satiated rats received intracerebroventricular (icv.) injections of several doses of neuropeptide Y (NPY) and the food intake was measured in the following 4 h. The peptide exerted a dose-dependent biphasic effect; the 100 dose significantly suppressed the food intake, but doses of 1 microgram and 5 micrograms stimulated feeding. After the injection of 2 microliters NPY-antiserum (icv., 1:50 dilution), the cumulative food intake decreased significantly in the first 24 h. From the drugs tested the alpha-1-antagonist prazosine (4 micrograms icv.) and the opiate antagonist naloxone (NX, 0.5 micrograms, icv.) selectively inhibited the feeding-stimulatory effect a high icv. dose of NPY. The alpha-2-antagonist yohimbine (4 micrograms icv.) and the non-selective beta-antagonist propranolol (5 micrograms icv.) did not influence either effect of NPY on feeding. The results suggest the involvement of alpha-1-adrenergic and opiate receptors in the food intake-stimulatory effect of a large icv. dose of NPY. The food intake-inhibitory effect of a low icv. peptide dose was not selectively antagonized by the receptor blocking agents used.     

Effects of neuropeptide Y on forskolin, alpha 2- and beta-adrenoceptor-regulated cAMP levels in the rat brain slice.

Neuropeptide Y (10(-6) M) significantly attenuated forskolin-stimulated cAMP levels in slices of the medulla oblongata from WKY rats. No effect of NPY was observed on basal levels of cAMP in this region. Pretreatment with pertussis toxin (2 micrograms and 5 micrograms) IC prevented the reduction of forskolin-stimulated cAMP levels elicited by NPY in the medulla oblongata, suggesting that NPY is acting through an inhibitory guanine nucleotide binding protein to reduce cAMP accumulation. Moxonidine, an alpha 2-adrenoceptor agonist, was observed to reduce forskolin-stimulated cAMP levels in medullary slices. This inhibitory response was attenuated in the presence of NPY (10(-6) M). The beta-adrenoceptor agonist isoprenaline also elevated cAMP levels in the medulla oblongata; however, NPY did not alter this response. It is therefore proposed that the previously reported hemodynamic actions of NPY in the medulla oblongata, an area of cardiovascular significance, may be mediated via a reduction in cAMP levels. Moreover, an interaction between NPY and alpha 2-adrenoceptors, but not beta-adrenoceptors, on cAMP production in the medulla slice preparation was evident.     

Characterization of alpha-adrenoceptors involved in central thermoregulation in rabbits

Intracerebroventricular (icv) injection of methyldopa induced body temperature changes in the rabbits. The dose of 100 micrograms/kg did not produce any significant change on body temperature whereas 250 micrograms/kg of the drug induced hyperthermia. Higher dose of 500 micrograms/kg produced initial hypothermia which was followed by hyperthermia. On further increase of the dose to 1 mg/kg, consistent hypothermia was evident. Prazosin, a specific post-synaptic alpha 1 adrenoceptor blocker, induced hypothermia whereas piperoxan (presynaptic alpha 2 antagonist) produced hyperthermia. The pretreatment with prazosin, blocked the hyperthermic response of methyldopa. The initial hypothermia by 500 micrograms/kg of methyldopa was also potentiated. The pretreatment with piperoxan completely blocked the hypothermia but had no effect on hyperthermic response of methyldopa. Pretreatment of rabbits with both prazosin and piperoxan completely blocked the hypothermia as well as hyperthermic response of methyldopa. Thus it appeared that both presynaptic alpha 2 and postsynaptic alpha 1 adrenoceptors are involved in central thermoregulation in rabbits.     

Beta-endorphin-(1-27) antagonizes beta-endorphin-induced hypothermia in mice

The effects of beta-endorphin and beta-endorphin-(1-27) on the body temperature of mice was studied at an ambient temperature of 10 degrees C. Intracerebroventricular injection of beta-endorphin (0.25-4 micrograms) and beta-endorphin-(1-27) (0.61 to 10 micrograms) caused a dose-related hypothermia. The duration of hypothermia induced by beta-endorphin-(1-27) was shorter than that induced by beta-endorphin. The hypothermia induced by 2 micrograms of beta-endorphin was attenuated by 5 micrograms of beta-endorphin-(1-27). Our results indicated that beta-endorphin-(1-27) is a partial agonist which produces a small degree of hypothermia and an antagonist which blocks the beta-endorphin-induced hypothermia.     

Effects of neuropeptide Y, NPY analog (norleucine4-NPY), galanin and neuropeptide K on LH release in ovariectomized (ovx) and ovx estrogen, progesterone-treated rats

We studied the effects on plasma LH levels of intracerebroventricular (ICV) administration of neuropeptide Y (NPY), NPY analog (NPY-A), galanin (GAL) and neuropeptide K (NPK) in ovariectomized (ovx) and in ovx rats pretreated with estradiol benzoate (EB) and progesterone (P). Plasma LH levels were estimated in blood drawn from an intrajugular cannula before (0 min) and at 10, 20, 30 and 60 min after the ICV injection of either saline (3 microliter) or one of the neuropeptides in saline. The three classes of peptides elicited different LH responses in the two experimental paradigms. NPY and NPY-A (0.5 or 2 micrograms) decreased LH release in ovx rats and stimulated LH release in EBP ovx rats. However, GAL (0.5, 2 or 10 micrograms) failed to suppress LH release in ovx rats, but it readily increased plasma LH levels in a dose-related fashion in EBP ovx rats. In contrast, NPK readily decreased LH release in ovx rats in a time-related fashion for up to 60 min, but was mildly effective in EBP ovx rats as only a high dose of 10 micrograms produced a small significant increase. Collectively, our results show that (1) NPY can differentially effect LH release in ovx and EBP ovx rats but this property is not equally shared by the neuropeptides that have a similar anatomical disposition in the hypothalamus and (2) the excitatory effects of GAL are demonstrable in the steroid-primed rats and the inhibitory effects of NPK are apparent in the steroid-unprimed ovx rats. Since NPK induced a long-lasting marked suppression with little evidence of LH excitation at low doses, we speculate that either NPK alone or in conjunction with other peptides may mediate the suppression of LH release induced by gonadal steroids.     

Effects of neuropeptide Y on LH, FSH and TSH release in male rats

These experiments were undertaken to investigate the effects of systemically administered neuropeptide Y (NPY) on gonadotropin secretion in the intact male rat and to determine whether the effects observed might be mediated by a direct action of NPY alone on the anterior pituitary gland (APG). Subcutaneous administration of 10 micrograms of NPY caused a greater than 2-fold increase in serum luteinizing hormone (LH) concentration at 15 min after injection but was without effect on serum follicle-stimulating hormone (FSH) or thyrotropin-stimulating hormone (TSH) levels. The addition of NPY (final concentrations of 10(-8) to 10(-11) M) or the structurally similar neuropeptide, rat pancreatic polypeptide, to culture medium containing hemi-APG did not alter the release of LH, FSH, or TSH. The results indicate that systemically administered NPY can elevate serum LH concentration in intact male rats. This effect does not appear to be due to NPY acting alone at the level of the APG.     

Robust feeding following central administration of neuropeptide Y or peptide YY in chicks, Gallus domesticus

Neuropeptide Y (NPY) and peptide YY (PYY) were injected intracerebroventricularly (ICV) in broiler chicks. Both NPY and PYY markedly increased food intake during the first hour post-injection compared to saline (SAL) controls. Food intake doubled in chicks given 5 micrograms NPY. A response surface analysis suggested that following ICV injection of NPY, maximum food intake occurred, using a dose of 9 micrograms. In contrast, an estimated dose between one and 5 micrograms PYY resulted in maximum food intake, giving the latter a slightly higher potency. Time spent drinking was not significantly different among NPY, PYY and SAL groups. Chicks given NPY or PYY also spent significantly less time standing while those given PYY spent significantly less time preening compared to controls.     

Effects of Neuropeptide Y (NPY) on the release of anterior pituitary hormones in the rat

Neuropeptide Y (NPY) has been recently localized in several hypothalamic nuclei in the mammalian brain. In order to investigate the possible role of NPY on neuroendocrine function, we have investigated the effects of the peptide on the release of anterior pituitary hormones in the rat. Both intravenous (300 μg) or intraventricular (2 to 15 μg) injection of NPY produced in gonadectomized male rats a significant and long-lasting decrease of plasma LH levels. A short duration stimulating effect on prolactin plasma levels was also observed after the intravenous but not after the intraventricular injection of NPY. Plasma levels of the other pituitary hormones were not significantly modified after NPY injection. When incubated in vitro with anterior pituitary cells in monolayer culture, NPY produced no significant change in release of pituitary hormones. Thus NPY seems to exert a selective effect on LH release. Since this effect can be observed after both intravenous and intraventricular injection, it might be hypothesized that NPY could affect LHRH release in two areas which lack blood-brain barrier: the organum vasculosum of the lamina terminalis (OVLT) which contains LHRH cell bodies and NPY fibers and the median eminence which contains both LHRH and NPY fibers. The effect on prolactin release needs to be carefully evaluated in different experimental conditions.     

Central actions of neuropeptide-Y may provide a neuromodulatory link between nutrition and reproduction.

Central injection of neuropeptide-Y (NPY) has been shown to attenuate secretion of LH in ovariectomized rats, rabbits, and monkeys. Several investigators have reported elevated concentrations of NPY in the central nervous system of undernourished animals. The relationship between nutrition and reproduction positions NPY as a potential neuromodulator involved in nutritionally induced changes in secretion of LH. Three experiments were conducted with the following objectives: 1) to examine the effects of NPY on secretion of LH in ovariectomized (OVX) ewes and the influence of estradiol-17 beta (E) on these effects; 2) to determine whether NPY may act through direct effects on the pituitary to influence secretion of LH; and 3) to determine changes in concentrations of NPY in laterocerebro-spinal fluid (CSF) of food-restricted ewes compared to well-fed ewes. In Experiment 1, OVX ewes with s.c. implants of E (OVX + E, n = 4) or no steroid treatment (OVX, n = 4) were fitted with intracerebroventricular (i.c.v.) and jugular cannulae. One of 4 doses of porcine NPY (pNPY; 0, 0.5, 5, or 50 micrograms) was injected i.c.v. and blood samples were collected every 10 min for 4 h prior to and following i.c.v. injection. Blood serum was assayed for LH. The experiment was replicated four times such that each ewe received each dose of pNPY. Mean concentrations of LH as well as frequency and amplitude of pulses of LH were attenuated in response to i.c.v. injection of pNPY in a dose-related manner in both OVX and OVX + E ewes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuropeptide Y depresses reflex urinary bladder contractions in rats and modifies central activity of opioid agonists

The 36 amino acid peptide neuropeptide Y (NPY) has been found distributed in central structures associated with nociception and the actions of opioid analgesics. We therefore studied its central actions on reflex bladder contractions which we have shown to be inhibited by supraspinal and spinal opioid administrations in urethane anesthetized rats. Neuropeptide Y produced a dose related (0.5-2 micrograms per rat) inhibition of bladder contractions following intracerebroventricular (ICV) and spinal intrathecal (IT) administrations. These effects could not be antagonized by naloxone (2 micrograms, ICV or IT) or by ICI 174,864 [N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib = alpha-aminoisobutyric acid] (3 micrograms, ICV or IT). NPY (0.5-1 micrograms) reduced the ICV and IT effects of morphine but potentiated the action of the selective delta-receptor ligand [2-D-penicillamine, 5-L-penicillamine] enkephalin (DPLPE). The effect of the mu-selective opioid ligand [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAGO) were unaffected as were the submaximal ICV and IT actions of noradrenaline. It was concluded that NPY-induced inhibition of bladder activity was not due to a direct opioid receptor interaction. However since NPY consistently changed the activity of opioids (morphine and DPLPE), this suggested a possible physiological role in the regulation of opioid receptors, central neural excitability and thereby visceral activity.     

ICV NPY Y1 receptor agonist but not Y5 agonist induces torpor-like hypothermia in cold-acclimated Siberian hamsters

The reduced metabolism derived from daily torpor enables numerous small mammals, including Siberian hamsters, to survive periods of energetic challenge. Little is known of the neural mechanisms underlying the initiation and expression of torpor. Hypothalamic neuropeptide Y (NPY) contributes to surviving energetic challenges by both increasing food ingestion and reducing metabolic expenditure. Intracerebroventricular injections of NPY in cold-acclimated Siberian hamsters induce torpor-like hypothermia comparable to natural torpor. Multiple NPY receptor subtypes have been identified, and the Y1 receptor and Y5 receptor both contribute to the orexigenic effect of NPY. The purpose of this research was to compare and contrast the effects of Y1 receptor activation by a specific Y1 agonist ([D-Arg25]-NPY) or Y5 receptor activation by a specific Y5 agonist ([D-Trp34]-NPY) on body temperature and subsequent food intake in cold-acclimated Siberian hamsters. Intracerebroventricular injections of Y1 agonist produced torporlike hypothermia closely resembling that induced by intracerebroventricular NPY. The intracerebroventricular Y5 agonist infrequently produced hypothermia reaching criterion for torpor and that failed to resemble either NPY-induced or natural torpor. Combined injections of Y1 and Y5 agonists resulted in hypothermia comparable to Y5 agonist treatments alone, negating the mimicry of NPY treatment seen with Y1 agonist alone. Prior treatment with Y1 agonist or Y5 agonist surprisingly had lingering effects on NPY-induced torpor expression, Y1 agonist enhanced and Y5 agonist inhibited the effect of NPY. The ability of NPY to induce torporlike hypothermia, especially its initiation, most likely involves activation of the NPY Y1 receptor subtype.     

Analysis of neuropeptide Y-induced feeding: dissociation of Y1 and Y2 receptor effects on natural meal patterns.

To differentiate NPY receptor subtypes, Y₁ and Y₂, in terms of their impact on feeding behavior, the intact molecule NPY(1–36) and the 3 fragments, NPY(2–36), the Y₁ agonist [Leu³¹,Pro³⁴]NPY, and the Y₂ agonist NPY(13–36), were injected (100 pmol/0.3 μl) into the hypothalamic paraventricular nucleus (PVN) of freely feeding rats. A computer-automated data acquisition system was employed in these experiments to permit a detailed analysis of feeding over the 12-h nocturnal cycle, in animals maintained on pure macronutrient diets. The results demonstrate that: 1) NPY(1–36) potentiates feeding behavior, primarily carbohydrate ingestion, by increasing the size and duration of the first meal after injection, rather than by affecting meal number or feeding rate, suggesting that NPY acts through mechanisms of satiety. The potentiation of carbohydrate intake occurs in association with a suppression of protein intake, which is strongest during the second meal after injection and which further increases the proportion of carbohydrate in the diet. No changes in fat ingestion are seen. 2) NPY(2–36), with the N-terminal tyrosine residue deleted, is equally potent to NPY(1–36) in potentiating carbohydrate intake and increasing meal size; however, it is less selective than NPY(1–36), producing an additional, smaller increase in consumption of protein. 3) The stimulatory effect of these peptides on carbohydrate intake and meal size is similarly observed, with somewhat reduced potency, after PVN injection of the selective Y₁ agonist [Leu³¹,Pro³⁴]NPY which, like NPY(1–36), also reduces protein intake. 4) The Y₂ receptor agonist, NPY(13–36), causes a decrease in the ingestion of carbohydrate, a smaller decline in protein intake, and a reduction in meal size. It is proposed that hypothalamic Y₁ receptors mediate the stimulatory effect of NPY on carbohydrate intake and meal size, while Y₂ receptors have the opposite effect of suppressing carbohydrate intake, possibly by altering presynaptic release of monoamines known to influence nutrient ingestion.     

Neuropeptides and thermoregulation: the interactions of bombesin, neurotensin, TRH, somatostatin, naloxone and prostaglandins

In this study we have examined the interactions of bombesin (1 microgram ICV), neurotensin (1 microgram ICV), TRH (10 micrograms ICV), somatostatin (10 micrograms ICV), PGE2 (10 micrograms ICV) and naloxone (10 mg/kg SC) on thermoregulation in the rat at room temperature (20 +/- 1 degree C). Given alone, bombesin, neurotensin, somatostatin and naloxone all produced hypothermia (bombesin greater than neurotensin greater than somatostatin congruent to naloxone). PGE2 was hyperthermic, and TRH had no effect. Bombesin and PGE2 neutralized one another's effects. Neurotensin had no effect on PGE2-induced hyperthermia. Naloxone enhanced the hypothermic effect of bombesin and somatostatin enhanced the rate of onset of hypothermia after bombesin. TRH had no effect on bombesin-induced hypothermia. TRH, somatostatin and naloxone had no effect on neurotensin-induced hypothermia. TRH antagonized the hypothermia due to naloxone and somatostatin.     

Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats

It has been shown that centrally administered neuropeptide Y (NPY) delays gastric emptying. To determine the receptor subtypes of NPY mediating the inhibitory effects on gastric emptying, effects of intracerebroventricular injection of NPY, [Leu31,Pro34]NPY (a Y1 agonist) and NPY-(3-36) (a Y2 agonist) on solid gastric emptying and postprandial antropyloric motility were studied in conscious rats. Intracerebroventricular injection of NPY and NPY-(3-36), but not [Leu31,Pro34] NPY, delayed solid gastric emptying in a dose-dependent manner (0.03-3 nmol). After the feeding (40 min), contractions with low frequency and high amplitude of the antrum were frequently observed, and the peak contraction of the antrum occurred most often 3-6 s before the peak contraction of the pylorus. Intracerebroventricular injection of NPY and NPY-(3-36) (3 nmol), but not [Leu31,Pro34]NPY, significantly reduced antral contractions and the number of antropyloric coordination events. It is suggested that centrally administered NPY impairs postprandial antral contractions and antropyloric coordination via Y2 receptors, resulting in delayed gastric emptying.     

Neuropeptide Y (NPY)-induced feeding behavior in female rats: comparison with human NPY ([Met17]NPY), NPY analog ([norLeu4]NPY) and peptide YY

Porcine neuropeptide Y (pNPY) administered into the third ventricle of the brain is known to elicit a powerful feeding response in steroid-treated ovariectomized and intact male rats. The present study compared the effects of pNPY and 3 structurally related peptides, human NPY (hNPY), an analog of NPY (NPY-A, [norLeu4]NPY) and peptide YY (PYY) on feeding behavior in intact female rats. Intraventricular administration of pNPY, hNPY, NPY-A and PYY over a dose range of 0.5 to 10 micrograms evoked feeding behavior to a varying extent. Cumulative food intake during 60 and 120 min was increased in a dose-related fashion at 0.5 and 2.0 microgram for the 4 peptides. Whereas the 10-micrograms dose of pNPY evoked a feeding response smaller than that seen after 2 micrograms, the responses to either 10 micrograms hNPY or 10 micrograms PYY were similar to that seen after 2 micrograms. The effects of these peptides on the time spent eating were quite different: while pNPY increased the time spent eating, this effect was not dose-related, whereas hNPY, NPY-A and PYY produced dose-related increments in the time spent eating. The most dramatic increment in local eating rate was observed after 2.0 micrograms pNPY, with lesser increments seen after 2.0 microgram hNPY and NPY-A. This increased local eating was apparently responsible for the highest cumulative food intake observed. These results demonstrate that (a) 2 micrograms pNPY is equally effective in stimulating feeding behavior in intact female rats as it is in steroid-primed ovariectomized female and intact male rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ghrelin induces time-dependent modulation of thermoregulation in the cold

Fasted mice show torpor-like hypothermia in the cold in their inactive phase. The aim of the present study was to elucidate whether leptin and/or ghrelin are involved in this reaction and to identify its neurophysiological mechanisms. In ob/ob mice, which lack leptin, metabolic heat production (oxygen consumption, Vo(2)) was suppressed in 20°C cold in both the light and dark phases, resulting in hypothermia. When wild-type mice received a systemic injection of 8 μg ghrelin in the early light phase, followed by a 2-h cold exposure to 10°C, their core body temperature (T(b)) decreased by 1.7°C, and they displayed a less marked increase in Vo(2) compared with vehicle-injected mice. However, ghrelin injection in the early dark phase resulted in the maintenance of T(b) and increased Vo(2) in the mice, which was similar to the result observed in the vehicle-injected mice. The number of doubly labeled neurons with cFos and neuropeptide Y (NPY) in the suprachiasmatic nucleus was greater in the light phase in the ghrelin-injected mice, which may suggest that ghrelin activates NPY neurons. On the contrary, in the paraventricular nucleus, the counts became greater only when they were exposed to the cold in the dark phase. These results indicate that ghrelin plays an important role in inducing time-dependent changes in thermoregulation in the cold via hypothalamic pathways.     

Pertussis toxin inhibits neuropeptide Y-induced feeding in rats

Neuropeptide Y (NPY) is the most powerful peptide drug stimulating feeding in rats. Rats with paraventricular hypothalamic (PVH) cannulae were used to investigate the mechanisms involved in NPY-induced feeding. Consistent with previous reports, injection of 2 μg of NPY into the PVH significantly increased the cumulative food intake over 1-, 2- and 4-hr periods. Ad lib feeding decreased significantly two days after pertussis toxin (PT) administration, but recovered to nearly normal levels on the fourth day. PT had no immediate effect on NPY-induced feeding; however, four days after PT was injected NPY (2 μg) did not increase the food intake compared to control. In vitro investigations showed that isoproterenol-stimulated adenylate cyclase activity in the hypothalamus of control rats was inhibited by NPY. In PT-treated rats, however, no inhibition of cAMP production was observed. These results suggest that cAMP may mediate NPY-induced feeding and that a PT-sensitive G protein may be involved in this signal transduction.     

The effects of adrenergic, opioid and pancreatic polypeptidergic compounds on feeding and other behaviors in neonatal leghorn chicks

The present study examined the effects of intracerebral (IC) administration of pancreatic polypeptide (PP), neuropeptide Y (NPY), norepinephrine (NE), dynorphin and naloxone on food intake in 2-day-old Leghorn chicks. Of the compounds studied, only PP (20 micrograms) and naloxone (10 and 20 micrograms) elevated food intake significantly as compared to saline injections. NPY, a potent orexigenic agent in mammals, did not elevate consumption significantly in a dose-related fashion. This latter finding was attributed to the occurrence of tonic-clonic convulsions following NPY administration. However, for those chicks which did not exhibit behavioral convulsions, food intake appeared to be elevated by 1, 5 and 10 micrograms of NPY. Similarly, NE did not elevate food intake but instead induced sedation and narcolepsy, a behavioral response which could be distinguished from the convulsions observed after NPY. In a separate group of chicks, the effect of NPY on cortical activity was examined. Bipolar electrodes were used to record EEG activity before and after IC injections of saline, NPY or NE. The behavioral convulsions induced by NPY corresponded with an increase in high amplitude sharp-wave activity, which persisted for up to 30 min post-injection. Collectively, these results suggest that the neurochemical substrates for feeding in 2-day-old Leghorn chicks are distinct from those underlying food intake in adult mammals.     

Role of hypothalamic neuropeptide Y (NPY) in the change of feeding behavior induced by repeated treatment of amphetamine

Neuropeptide Y (NPY), an orexigenic peptide, is involved in the control of food intake. Repeated administration of amphetamine (AMPH), an anorectic agent, results in an anorectic effect on day 1 and a tolerant anorectic effect on the followings. In an attempt to know the role of hypothalamic NPY in these effects of AMPH, contents of hypothalamic NPY were determined by radioimmunoassay at first. In AMPH-treated groups, the contents of hypothalamic NPY decreased rapidly on day 1 but restored gradually to the normal level on the following days as observed in repeated AMPH. An involvement of hypothalamic NPY in the feeding change of repeated AMPH can thus be considered. Moreover, daily injection of NPY antisense oligonucleotide into brain (10 microg/10 microl/day, i.c.v.) to inhibit the gene expression of hypothalamic NPY were performed at 1 hour before daily 2 mg/kg AMPH. The reversion of food intake from the anorectic level to the normal level (tolerant anorexia) was abolished by this antisense pretreatment. It is suggested that hypothalamic NPY may play a role in the change of feeding behavior induced by repeated AMPH administration.