Food Intake In Non-deprived Rats Research Articles

Effects of the GABAB receptor agonist baclofen administered orally on normal food intake and intraperitoneally on fat intake in non-deprived rats.

It has been previously reported that the GABAB receptor agonist baclofen decreases food intake after oral administration and fat intake after intraperitoneal administration. The aim of the study was to investigate the effects of baclofen (1–4mg/ kg) administered orally (Experiment 1) on food intake in non-deprived rats (n=6) and intraperitoneally (Experiment 2) on fat intake in non-deprived rats (n=8) that were naïve to baclofen (1st set of trials) and in the same group of rats after they were sub-chronically exposed to baclofen (2nd set of trials). The results from Experiment 1 show that baclofen had no effects on food intake during the 1st set of trials, but the 2 and 4mg/kg doses significantly increased food consumption during the 2nd set of trials. Baclofen produced sedation during the 1st set of trials, but tolerance occurred to this effect and was not apparent during the 2nd set of trials. These observations suggest that the motor effects may have competed with the hyperphagic effects of baclofen during the 1st set of trials. The data from Experiment 2 show that baclofen had no effects on fat intake during either the 1st or 2nd set of trials. The results of the study thus indicate that orally administrated baclofen increases food intake and intraperitoneal administration has no effect on fat intake in non-deprived rats under the conditions used in this study. These findings may have important implications for research on the use of baclofen in studies concerned with ingestive behaviours.

Injections of muscimol into the paraventricular thalamic nucleus, but not mediodorsal thalamic nuclei, induce feeding in rats

The paraventricular thalamic nucleus (PVT) is a component of the midline thalamic group that is interconnected with several brain regions known to play important roles in the control of food intake, including the lateral hypothalamus and nucleus accumbens shell, suggesting that the PVT itself may be involved in mediating feeding behavior. In the current study, we examined whether inhibition of cells in the PVT with the GABAA agonist muscimol could alter food intake in non-deprived rats. To control for possible spread of the drug, we also observed food intake after injections of muscimol into the overlying ventricle or laterally adjacent mediodorsal thalamic nuclei (MD). We found that muscimol injections into the central PVT dose-dependently increased food intake. In contrast, intra-MD injections of muscimol resulted in a potent dose-dependent suppression of food intake, while those into the overlying ventricle had no effect. These results support the proposal that the PVT is a component of the neural circuitry controlling feeding behavior.

Effects of intraperitoneal administration of the GABAB receptor positive allosteric modulator 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) on food intake in non-deprived rats

γ-Aminobutyric acid-B (GABAB) receptor positive allosteric modulators (PAMs) act on an allosteric site on the GABAB receptor to potentiate the effects of GABA and GABAB receptor agonists. It has previously been demonstrated that the GABAB receptor agonist baclofen increases food intake in non-deprived rats. The aim of this study was to investigate whether the GABAB receptor PAM 2,6-di tert-butyl-4-(2-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) would (i) increase food intake, and (ii) potentiate the hyperphagic effects of baclofen in rats. In Experiment 1, the effects of intraperitoneal (i.p.) administration of CGP7930 (1, 6 and 12mg/kg) was investigated on food intake in non-deprived male Wistar rats. The 12mg/kg dose of CGP7930 significantly increased cumulative food intake 30, 60 and 120min (P<0.05, in each case) after administration. The 1 and 6mg/kg doses were without effect. In Experiment 2, the effects of pretreatment with CGP7930 (6mg/kg; i.p.) 5min prior to administration of baclofen (2mg/kg, i.p.) was investigated on 30min cumulative food intake in non-deprived male Wistar rats. Baclofen (2mg/kg) significantly increased food intake compared with vehicle treatment (P<0.01). CGP7930 (6mg/kg) had no effect on feeding. However, pretreatment with CGP7930 (6mg/kg) significantly potentiated the hyperphagic effects of baclofen (2mg/kg) (P<0.01). These findings show that CGP7930 increases food intake and enhances the hyperphagic effects of baclofen, and are consistent with in vitro studies that suggest that it potentiates the effects of endogenous GABA and GABAB receptor agonists by allosteric modulation of the GABAB receptor.

Effects of intraperitoneal administration of the GABAB receptor agonist baclofen on food intake in rats measured under different feeding conditions

The effects of intraperitoneal (i.p.) administration of the GABAB receptor agonist baclofen were assessed in rats under different feeding conditions. In Experiment 1, it was observed that baclofen (1–4mg/kg) significantly (at least, P<0.05) increased cumulative food intake in non-deprived rats during the 120min measurement period during the early light phase of the light-dark cycle. By contrast, during the early dark phase of the light-dark cycle in non-deprived rats, the 1mg/kg doses of baclofen significantly increased cumulative feeding at 30, 60 and 120min (at least P<0.05), the 2mg/kg dose significantly increased feeding at 30 and 60min (at least P<0.05) and the 4mg/kg dose had no effects on feeding. In Experiment 2, baclofen (1–4mg/kg) was found to produce no significant effects on food intake in rats that were food-deprived for 22h. In Experiment 3, the effects of baclofen were investigated on food intake in 16h food-deprived rats that had received an oral preload for 2h prior to drug administration. Baclofen (1–4mg/kg) significantly increased cumulative food consumption (at least, P<0.05) only during the first 30min after administration in these animals. The results of this study indicate that the effects of baclofen on food intake may be related to the state of hunger or satiety of the animals and the time during the light-dark cycle when the drug is administered.

The effect of intraperitoneal administration of leptin on short-term food intake in rats

The effects of intraperitoneal (i.p.) injection of leptin (1, 5, and 10 μg/kg) were investigated on the food consumption during a 60 min test meal in 21 h fasted rats. All doses of leptin produced significant reductions in cumulative food intake during the first 15 min and 30 min (at least, P < 0.05) after administration. Similarly, i.p., but not subcutaneous (s.c.), administration of leptin (25 μg/kg) reduced food intake in 21 h fasted rats. Leptin (10 and 25 μg/kg, i.p.) did not reduce water intake in 16 h water-deprived rats, nor did leptin (25 μg/kg) produce aversion in a two-bottle conditioned taste aversion test indicating that the hypophagic effect of leptin is (i) behaviourally specific for food and not water intake, and (ii) not due to drug-induced malaise. Moreover, leptin (10 and 25 μg/kg, i.p.) did not significantly alter food intake in non-deprived rats when measured at 30 min intervals over a period of 24 h. Chemical vagotomy with capsaicin abolished the inhibitory effects of leptin (25 μg/kg, i.p) on food intake in fasted rats and suggest that the hypophagic effect is dependent on intact vagal afferent nerves. Furthermore, the hypophagia induced by leptin (10 μg/kg, i.p.) in fasted rats was not attenuated by systemic administration of the peripherally acting cholecystokinin 1 receptor antagonist, 2-naphthalenesulphanyl- l-aspartyl-2-(phenethyl) amide (2-NAP; 2 mg/kg, i.p.), indicating that the suppressant effects of leptin on food consumption are not secondary to the release of endogenous peripheral cholecystokinin.

Effects of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APA) on food intake in rats

It has previously been demonstrated that central administration of the GABAB agonist baclofen increases food intake in non-deprived or satiated animals by action at the central GABAB receptors. It has also been shown that systemic administration of baclofen increases food intake in non-deprived rats. Although baclofen crosses the blood brain barrier from systemic circulation to enter the brain, it is conceivable that it may increase food intake by a peripheral mode of action. This possibility was examined in the present study. The effects of intraperitoneal (i.p.) administration of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APA) were investigated on food intake in non-deprived rats. 3-APA is a potent GABAB agonist that does not penetrate the blood brain barrier. The results show that while baclofen (1-4 mg/kg) increases food intake in a dose-related manner, 3-APA (0.5-2 mg/kg) has no effects on food consumption. The results indicate that a peripheral GABAB mechanism is not involved in the hyperphagia elicited by systemic administration of baclofen and suggests that the drug increases food intake by a central mode of action.

Intraperitoneal administration of baclofen increases consumption of both solid and liquid diets in rats

It has previously been demonstrated that systemic administration of the GABA B receptor agonist baclofen increases food intake but decreases water intake in rats. In the present study, the effects of baclofen (2–4 mg/kg i.p.) were investigated on food intake in non-deprived rats given access to either pelleted food ( n = 8) or a palatable liquid diet ( n = 8). Baclofen (2–4 mg/kg i.p.) significantly increased the consumption of both the pelleted and the liquid foods. The increased intake of the liquid diet (i) argues against the involvement of non-specific gnawing in the increased consumption of the solid food by baclofen, and (ii) suggests that the inhibition of water intake produced by baclofen is not due to interference with the mechanical aspects of drinking, such as licking on a drinking spout, or the swallowing of liquid.

Effects of the 5HT1A agonist, 8-OH-DPAT, on operant food intake in non-deprived rats.

The aim of the present study was to determine whether the hyperphagia produced by systemic administration of 8-OH-DPAT is independent of drug-induced chewing or gnawing behaviour. The effects of 8-OH-DPAT (15.625-500 micrograms kg-1, s.c.) were therefore investigated on operant food intake in non-deprived rats. Low doses (i.e. 15.625-62.5 micrograms kg-1) increased operant food intake. Drug-induced stereotypy disrupted operant responding at the higher doses. The results thus suggest that 8-OH-DPAT-induced hyperphagia is independent of chewing or gnawing behaviour.

Dopamine receptor blockade in nucleus accumbens or caudate nucleus differentially affects feeding induced by 8-OH-DPAT injected into dorsal or median raphe

The 5-hydroxytryptamine (5-HT) 1A receptor agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) elicits a variety of behaviours including feeding in rats. These effects are accompanied by a reduction in 5-HT neurotransmission resulting from activation of somatodendritic 5-HT receptors located in the midbrain raphe nuclei. Previous work showing that dopamine receptor antagonists attenuate 8-OH-DPAT-induced feeding indicates that a facilitation of dopamine activity, secondary to reduced 5-HT activity, is involved in the expression of this effect. Microinjection studies were conducted to explore further the nature of this 5-HT-dopamine interaction. Injection of 8-OH-DPAT (0.125–2 μg) into either dorsal or median raphe induced dose-dependent increases in 1 h food intake in non-deprived rats. Pretreatment with haloperidol (0.05 and 0.1 mg/kg s.c.) attenuated the effect induced by median raphe 8-OH-DPAT (0.5 μg) complementing previous results with dorsal raphe 8-OH-DPAT. The feeding resulting from dorsal raphe (1 μg) or median raphe (0.5 μg) 8-OH-DPAT was attenuated by α-flupenthixol (1.25 and 2.5 μg) injected into the nucleus accumbens. α-Flupenthixol in either the dorsolateral or ventrolateral aspects of the caudate nucleus attenuated also the feeding response to dorsal raphe, but not median raphe, 8-OH-DPAT. However, α-flupenthixol in the dorsomedial caudate failed to alter feeding resulting from dorsal raphe 8-OH-DPAT. The results confirm the involvement of dopamine in mediating the effects on feeding of 8-OH-DPAT and suggest that overlapping but different mechanisms are involved in the expression of the feeding resulting from dorsal and median raphe injection of 8-OH-DPAT. Thus, while the nucleus accumbens appears to be involved in both effects, the caudate nucleus is involved only in the effect derived from the dorsal raphe. The nucleus accumbens has been implicated in reward processes, whereas dopamine in the lateral caudate appears to facilitate sensorimotor integration. It is possible that these processes may underlie 8-OH-DPAT feeding. In a broader context these results may have important implications for understanding the diversity of motivated behaviours which can be elicited by 8-OH-DPAT and a reduction in 5-HT function.

Reversal of the anorectic effect of (+)‐fenfluramine in the rat by the selective cholecystokinin receptor antagonist MK‐329

1. Experiments were conducted to determine whether or not the effect of (+)-fenfluramine (3.0 mg kg-1, i.p.) on food intake can be antagonized by the selective cholecystokinin receptor antagonist MK-239 (formerly L364,718; (3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1-H-1,4-benzodiazepin++ +-3-yl)-1H- indole-2-carboxamide). Two feeding paradigms were employed. In the first, non-deprived rats were familiarized with eating a highly palatable, sweetened mash in a 30 min test. In the second, freely-feeding rats were trained to consume powdered chow in their home-cages, and their intake was monitored over the first 6 h of the night-period. 2. In doses of 30.0 and 100.0 micrograms kg-1, s.c., MK-329 almost completely blocked the anorectic effect of (+)-fenfluramine in the palatable food intake test. These doses of MK-329 have previously been reported to antagonize the anorectic effect produced by exogenous cholecystokinin-octapeptide (CCK8) in rats. Both doses of MK-329 were also effective in significantly attenuating the anorectic effect of (+)-fenfluramine in nocturnal free-feeding animals over a 6 h-period. 3. MK-329 (10.0-100.0 micrograms kg-1, s.c.) failed to antagonize the anorectic effect of either the specific dopamine D2-receptor agonist quinpirole (0.3 mg kg-1, s.c.) or the beta-carboline FG 7142 (10.0 mg kg-1, i.p.) in the palatable food intake test. 4. MK-329 (10.0-300.Opgkg-1, s.c.) had no effect, when administered alone, on the level of palatable food intake in non-deprived rats, even when substantial satiation was produced by a pre-feeding procedure. Furthermore, MK-329 had no effect, when administered alone, on nocturnal food intake in freelyfeeding rats. 5. In conclusion, not only was MK-329 a potent antagonist of the effect of CCK8 on food intake, it also blocked the effect of (+)-fenfluramine to a significant degree. The effect of MK-329 was selective in that the anorectic effects of either quinpirole or FG 7142 remained unaffected. Administered alone, MK-329 did not affect food intake, indicating that its reversal of (+ -fenfluramine-induced anorexia was not secondary to an intrinsic hyperphagic effect. The results provide some evidence that the depressant effect of (+ )-fenfluramine on food intake depends on the activity of endogenous CCK.

The kappa agonists PD117302 and U50488 produce a biphasic effect on 24 hour food intake in the rat

The effects of the selective kappa opioid receptor agonists PD 117302 [(±) trans- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl-]benzo-[b]-thiophene-4-acetamide] and U50488 ( trans-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide) were investigated on food intake in non-deprived rats over a 24 hr period following subcutaneous administration. At doses of 2.5 mg/kg and 5 mg/kg, both PD 117302 and U50488 initially increased food intake. Between 6–24 hr, however, PD117302 (2.5–10 mg/kg) and U50488 (2.5 mg/kg and 5 mg/kg) caused a reduction in food intake. The largest doses of PD117302 and U50488 also reduced total 24 hr food intake. The reduction in food intake produced by PD117302 (5 mg/kg) was selective, since the intake of water was not affected. It is concluded that the kappa agonists PD117302 and U50488 produce a biphasic effect on 24 hr food intake, with an initial hyperphagia followed by a decrease in food intake.

The stimulation of food intake by selective agonists of mu, kappa and delta opioid receptors

It is known that under some conditions the administration of opioid agonists will stimulate food intake. However, the lack of receptor selectivity of some of the agonists which produce this effect leaves open the question of which receptor types are actually involved. In the experiments presented here, rats were given intracerebroventricular injections of Dynorphin 1–17 (DYN), [D-ala 2 6MePhe 4, GlGly-ol 5] enkephalin (DAGO), and [D-ser 2, leu 5]enkephalin-thr (DSLET); these peptides are thought to be selective agonists at kappa, mu and delta opioid receptors, respectively. All three peptides stimulated food intake in non-deprived rats at doses in the 3 – 10 nmol range; water intake was also increased in some cases. Generally, DYN stimulated feeding at a lowet dose than DAGO or DSLET and the magnitude of the effect tended to be greater. On the other hand, DAGO more consistently increased water intake. In some cases, DYN also caused episodes of “barrel-rolling” and postural abnormalities, whereas DAGO had sedative and/or cataleptic effects. These results are interpreted as an involvement of more than one opioid receptor types in the regulation of appetite, possibly with separate opioid systems contributing to food and water intake.