Reduction of food intake by intestinal macronutrient infusion is not reversed by NMDA receptor blockade

Rats increase their intake of food, but not water, after intraperitoneal injection of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate-activated ion channels. We hypothesized that MK-801 might enhance intake by interfering with intestinal chemosensory signals. To test this hypothesis, we examined the effect of the antagonist on 15% sucrose intake after an intraduodenal infusion of maltotriose, oleic acid, or phenylalanine in both real- and sham-feeding paradigms. MK-801 (100 microg/kg) significantly increased sucrose intake regardless of the composition of the infusate during real feeding. Furthermore, MK-801 had no effect on reduction of sucrose intake by intestinal nutrient infusions in sham-feeding rats. These results indicate that MK-801 does not increase meal size and duration by interfering with signals activated by intestinal macronutrients.     

NMDA receptor participation in control of food intake by the stomach

We previously reported that MK-801 (dizocilpine), an antagonist of N-methyl-D-aspartate (NMDA)-type glutamate receptors, increased meal size and duration in rats. MK-801 did not increase sham feeding or attenuate reduction of sham feeding by intraintestinal nutrient infusions. These results suggested that the MK-801-induced increase in meal size did not depend on antagonism of postgastric satiety signals. Consequently, we hypothesized that the NMDA antagonist might increase food intake by directly antagonizing gastric mechanosensory signals or by accelerating gastric emptying, thereby reducing gastric mechanoreceptive feedback. To test this hypothesis, we recorded intake of 15% sucrose in rats implanted with pyloric cuffs that could be closed to prevent gastric emptying. Sucrose intake was increased when the pyloric cuffs were open, allowing the stomach to empty. However, intake was not increased when the pyloric cuffs were inflated, causing gastric retention of all ingested sucrose. Direct measurements of gastric emptying revealed that MK-801 accelerated the emptying of 5-ml loads of 0.9% NaCl and 15% sucrose. Furthermore, MK-801 also accelerated the rate of emptying of freely ingested sucrose regardless of the volume ingested. Taken together with our previous findings, these results indicate that blockade of NMDA receptors with MK-801 does not increase food intake by antagonizing gastric mechanosensation. Rather, it accelerates gastric emptying, and thereby may indirectly reduce gastric mechanoreceptive cues, resulting in prolongation of eating. Modulation of gastric emptying rate by NMDA receptors could play an important role in the control of meal sizes.     

Amylin receptor blockade stimulates food intake in rats

Amylin is postulated to act as a hormonal signal from the pancreas to the brain to inhibit food intake and regulate energy reserves. Amylin potently reduces food intake, body weight, and adiposity when administered systemically or into the brain. Whether selective blockade of endogenous amylin action increases food intake and adiposity remains to be clearly established. In the present study, the amylin receptor antagonist acetyl-[Asn(30), Tyr(32)] sCT-(8-32) (AC187) was used to assess whether action of endogenous amylin is essential for normal satiation to occur. Non-food-deprived rats received a 3- to 4-h intravenous infusion of AC187 (60-2,000 pmol.kg(-1).min(-1)), either alone or coadministered with a 3-h intravenous infusion of amylin (2.5 or 5 pmol.kg(-1).min(-1)) or a 2-h intragastric infusion of an elemental liquid diet (4 kcal/h). Infusions began just before dark onset. Food intake and meal patterns during the first 4 h of the dark period were determined from continuous computer recordings of changes in food bowl weight. Amylin inhibited food intake by approximately 50%, and AC187 attenuated this response by approximately 50%. AC187 dose-dependently stimulated food intake (maximal increases from 76 to 171%), whether administered alone or with an intragastric infusion of liquid diet. Amylin reduced mean meal size and meal frequency, AC187 attenuated these responses, and AC187 administration alone increased mean meal size and meal frequency. These results support the hypothesis that endogenous amylin plays an essential role in reducing meal size and increasing the postmeal interval of satiety.     

Effects of peripheral CCK receptor blockade on food intake in rats

Type A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated, in part, by CCK action at CCKARs located peripheral to the blood-brain barrier. At dark onset, non-food-deprived rats received a bolus injection of devazepide (2.5 micromol/kg iv), a 3-h infusion of A-70104 (1 or 3 micromol x kg-1 x h-1 iv), or vehicle either alone or coadministered with a 3-h infusion of CCK-8 (10 nmol x kg-1 x h-1 iv) or a 2-h intragastric infusion of peptone (1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nalpha-3-quinolinoyl-d-Glu-N,N-dipentylamide (A-65186), does not. CCK-8 inhibited 3-h food intake by more than 50% and both A-70104 and devazepide abolished this response. A-70104 and devazepide stimulated food intake and similarly attenuated the anorexic response to intragastric infusion of peptone. Thus endogenous CCK appears to act, in part, at CCKARs peripheral to the blood-brain barrier to inhibit food intake.     

Cholinergic neurotransmission in rotifers

The presence of acetylcholinesterase and choline acetyltransferase, enzymes involved in acetylcholine metabolism, has been shown in twelve species of rotifers. Both enzymes have been visualized by histochemical staining in live animals, and acetylcholinesterase was also isolated by acrylamide gel electrophoresis. All the known ganglia of rotifers as well as some sensory nerve endings have been found to contain these enzymes. Preliminary experiments aimed at the detection of norepinephrine and tyrosinase, an enzyme involved in catecholamine metabolism, were unsuccessful.     

Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat

Hindbrain administration of MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) channel blocker, increases meal size, suggesting NMDA receptors in this location participate in control of food intake. However, dizocilpine (MK-801) reportedly antagonizes some non-NMDA ion channels. Therefore, to further assess hindbrain NMDA receptor participation in food intake control, we measured deprivation-induced intakes of 15% sucrose solution or rat chow after intraperitoneal injection of either saline vehicle or D(-)-2-amino-5-phosphonopentanoic acid (AP5), a competitive NMDA receptor antagonist, to the fourth ventricular, or nucleus of the solitary tract (NTS). Intraperitoneal injection of AP5 (0.05, 0.1, 1.0, 3.0, and 5.0 mg/kg) did not alter 30-min sucrose intake at any dose (10.7 +/- 0.4 ml, saline control) (11.0 +/- 0.8, 11.2 +/- 1.0, 11.2 +/- 1.0, 13.1 +/- 2.2, and 11.0 +/- 1.9 ml, AP5 doses, respectively). Fourth ventricular administration of both 0.2 mug (16.7 +/- 0.6 ml) and 0.4 mug (14.9 +/- 0.5 ml) but not 0.1 and 0.6 mug of AP5 significantly increased 60-min sucrose intake compared with saline (11.2 +/- 0.4 ml). Twenty-four hour chow intake also was increased compared with saline (AP5: 31.5 +/- 0.1 g vs. saline: 27.1 +/- 0.6 g). Furthermore, rats did not increase intake of 0.2% saccharin after fourth ventricular AP5 administration (AP5: 9.8 +/- 0.7 ml, vs. saline: 10.5 +/- 0.5 ml). Finally, NTS AP5 (20 ng/30 nl) significantly increased 30- (AP5: 17.2 +/- 0.7 ml vs. saline: 14.6 +/- 1.7 ml), and 60-min (AP5: 19.4 +/- 0.6 ml vs. saline: 15.5 +/- 1.4 ml) sucrose intake, as well as 24-h chow intake (AP5: 31.6 +/- 0.3 g vs. saline: 26.1 +/- 1.2 g). These results support the hypothesis that hindbrain NMDA receptors participate in control of food intake and suggest that this participation also may contribute to control of body weight over a 24-h period.     

Impaired glutamine metabolism in NMDA receptor hypofunction induced by MK801

Paradoxically, glutamate receptor antagonists have neurotoxic and psychotogenic properties in addition to their neuroprotective potential during excessive glutamate release. In the present study the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK801 was used to examine glial-neuronal interactions in NMDA receptor hypofunction. Rats were given a subanesthetic dose of MK801 together with [1-13C]glucose and [1,2-13C]acetate, and brains were removed 20 min later. Analyses of extracts from cingulate, retrosplenial plus middle frontal cortices (CRFC) and temporal lobe were performed using HPLC and 13C and 1H nuclear magnetic resonance spectroscopy. Hypofunction of the NMDA receptor induced similar changes in both brain areas investigated; however, the changes were most pronounced in the temporal lobe. Generally, only labeling from [1-13C]glucose was affected by MK801. In CRFC and temporal lobe amounts of both labeled and unlabeled glutamine were increased, whereas those of aspartate were decreased. In the CRFC the decrease in labeling of aspartate was greater than the decrease in concentration, leading to decreased 13C enrichment. In temporal lobe, not in CRFC, increased concentrations of glutamate, GABA, succinate, glutathione and inositol were detected together with increased labeling of GABA and succinate from [1-13C]glucose. 13C Enrichment was decreased in glutamate and increased in succinate. The results point towards a disturbance in glutamate-glutamine cycling and thus interaction between neurons and glia, since labeling of glutamate and glutamine from glucose was affected differently.     

AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats

Resistance training is accompanied by cardiac hypertrophy, but the role of the renin-angiotensin system (RAS) in this response is elusive. We evaluated this question in 36 male Wistar rats divided into six groups: control (n=6); trained (n=6); control+losartan (10 mg.kg(-1).day(-1), n=6); trained+losartan (n=6); control+high-salt diet (1%, n=6); and trained+high-salt diet (1%, n=6). High salt was used to inhibit the systemic RAS and losartan to block the AT1 receptor. The exercise protocol consisted of: 4x12 bouts, 5x/wk during 8 wk, with 65-75% of one repetition maximum. Left ventricle weight-to-body weight ratio increased only in trained and trained+high-salt diet groups (8.5% and 10.6%, P<0.05) compared with control. Also, none of the pathological cardiac hypertrophy markers, atrial natriuretic peptide, and alphaMHC (alpha-myosin heavy chain)-to-betaMHC ratio, were changed. ACE activity was analyzed by fluorometric assay (systemic and cardiac) and plasma renin activity (PRA) by RIA and remained unchanged upon resistance training, whereas PRA decreased significantly with the high-salt diet. Interestingly, using Western blot analysis and RT-PRC, no changes were observed in cardiac AT2 receptor levels, whereas the AT1 receptor gene (56%, P<0.05) and protein (31%, P<0.05) expressions were upregulated in the trained group. Also, cardiac ANG II concentration evaluated by ELISA remained unchanged (23.27+/-2.4 vs. 22.01+/-0.8 pg/mg, P>0.05). Administration of a subhypotensive dose of losartan prevented left ventricle hypertrophy in response to the resistance training. Altogether, we provide evidence that resistance training-induced cardiac hypertrophy is accompanied by induction of AT1 receptor expression with no changes in cardiac ANG II, which suggests a local activation of the RAS consistent with the hypertrophic response.     

Opiate receptor blockade in man reduces 2-deoxy-d-glucose-induced food intake but not hunger,thirst, and hypothermia

Opioid peptides may act as neuromodulators in the central nervous system to conserve energy stores and water in mammals. To examine this hypothesis in man, the effect of opiate receptor blockade with naloxone on the hunger, thirst, and hypothermic response to 2-deoxy-D-glucose-induced glucoprivic stress was assessed. Opiate receptor blockade decreased stress-induced food intake but did not reduce marked increases in hunger produced by glucoprivation. Naloxone infusions did not change the hypercortisolemic, polydipsic, hypothermic, and thermogenic response to 2-deoxy-D-glucose. While these results do not suggest a major role for a β-endorphin modulation of stress-induced hunger, hypothermia and water conservation, the reduction of food intake could be due to augmented satiety, perhaps associated with retardation of gastric emptying during opiate receptor blockade.     

Cholinergic and glutamatergic activation reverses working memory failure by hippocampal histamine H1 receptor blockade in rats

Intrahippocampal administration of the histamine H1 receptor antagonist pyrilamine (3.2-32 ug/ side) but not the histamine H2 receptor antagonist cimetidine (1.0-10 microg/side) increased the number of errors in the working memory task with a three-panel runway setup. The increase in working memory errors induced by intrahippocampal 32 microg/side pyrilamine was significantly reduced by concurrent infusion of the histamine H1 receptor agonist 2-pyridylethylamine (3.2 and 10 microg/side). The cholinesterase inhibitor physostigmine ( 1.0 and 3.2 microg/side) and D-cycloserine (0.32 and 1.0 microg/side), the partial agonist at the glycine binding site on the NMDA receptor/channel complex, reduced the increase in working memory errors induced by intrahippocampal 32 microg/side pyrilamine. These results suggest that the hippocampal histaminergic activity via histamine H1 receptor is necessary for normal working memory processes and that the septohippocampal cholinergic activation and positive modulation of the NMDA receptor/channel through activation of the glycine site can alleviate dysfunction of hippocampal histamine H1 receptor-mediated neurotransmission involved in working memory function.     

Running inhibits osteoporosis induced by protein-deficient (PD) food intake

Running at 0.7 km/h for 10 min every day inhibited development of osteoporosis caused by protein deficient (PD) food intake. Urine alkaline phosphatase (ALP), a marker of bone formation osteoporosis, was not elevated in rats fed PD, when the osteoporosis was inhibited by running. Estrogen supplementation increased bone-breaking energy (BBE), but did not increase bone mineral density (BMD), and did not decrease urinary ALP levels.     

Elevated serum gastrin after food intake or acid blockade evokes hypocalcemia

Gastrin lowers blood Ca2+ in the rat. Recently, it was suggested that gastrin causes hypocalcemia by releasing gastrocalcin, a hypothetical peptide hormone thought to reside in the acid-producing part of the stomach. The results of the present study suggest that not only exogenous gastrin but also gastrin of endogenous origin lowers blood Ca2+. Food intake in fasted intact rats produced a transient drop in blood Ca2+, probably induced by the postprandial rise in serum gastrin. Food intake in fasted gastrectomized or fundectomized (acid-producing part extirpated) rats failed to induce any lowering of the blood Ca2+, supporting the view that the gastrin-evoked hypocalcemia is dependent upon a factor in the oxyntic mucosa. Also, the increase in serum gastrin concentration following intraperitoneal injection of the histamine H2-receptor antagonist ranitidine was associated with a drop in blood Ca2+ and also the ranitidine-evoked hypocalcemia could be prevented by gastrectomy. We suggest that endogenous gastrin evokes hypocalcemia by the same mechanism as exogenous gastrin, i.e., by mobilization of gastrocalcin from the acid-producing part of the stomach.     

Cholinergic neurotransmission and muscarinic receptors in the enteric nervous system

There is a rich knowledge of the enteric nervous system (ENS), especially the neurochemical and neurophysiological properties of enteric neurons and how they communicate in neural circuits underlying intestinal reflexes. The major pathways of excitatory transmission within the ENS are mediated by cholinergic and tachykinergic transmission, with transmitters Acetylcholine (ACh) and Tachykinins (TK), respectively, producing excitatory potentials in post-synaptic effectors. This review focuses on the cholinergic pathways of the ENS. The cholinergic circuitry of the ENS is extensive and mediates motility (muscular) and secretory (mucosal) reflexes, in addition to intrinsic sensory and vascular reflexes. The capacity of ACh to mediate multiple physiologically significant intestinal reflexes is largely due to having multiple sites of neuronal and non-neuronal release and reception within the intestine. This review will concentrate on one of two classes of ACh receptors, Muscarinic receptors (mAChr), in particular their location and function in mediating synaptic transmission within enteric circuits underlying intestinal reflexes.     

Apomorphine-induced changes in striatal and pallidal neuronal activity are modified by NMDA and muscarinic receptor blockade.

Systemic administration of apomorphine decreased the firing rate of caudate Type I neurons and increased the firing rate, presumably via disinhibition (16), of globus pallidus (GP) Type II neurons. In the present study, extracellular single-unit recording techniques were used to demonstrate that systemic administration of the NMDA antagonist dizocilpine (MK801) reduced both the inhibition of caudate neurons by apomorphine as well as the apomorphine-induced excitation of GP neurons. In addition, the muscarinic antagonists atropine and scopolamine had effects similar to dizocilpine. Thus, both glutamate and acetylcholine appear to play a role in dopaminergic modulation of striatal and GP activity.     

Increased food intake by neuropeptide Y is due to an increased motivation to eat

Neuropeptide Y (NPY), administered intracerebroventricularly, is a potent orexigenic agent. To determine if NPY-induced eating represented an increase in motivation to eat (e.g., hunger) rather than pathological or stimulus-bound eating, we determined its effect on eating in three paradigms, including lever press, appetitive passive avoidance and quinine-adulterated milk. NPY-injected mice consumed more milk when required to work for it in a lever press apparatus and tolerated shock to the tongue for drinking milk. Increasing the dose of NPY also allowed mice to overcome a taste aversion for quinine-adulterated milk. Overall, these studies support the hypothesis that NPY causes a specific increase in the motivation to eat, rather than nonspecific or stimulus-bound behavior.     

Changes in phosphorylation of the NMDA receptor in the rat hippocampus induced by status epilepticus

Systemic administration of pilocarpine preceded by lithium induces status epilepticus (SE) that results in neurodegeneration and may lead to the development of spontaneous recurrent seizures. We investigated the effect of Li/pilocarpine-induced SE on phosphorylation of the NMDA receptor in rat hippocampus. Phosphorylation of NR1 by PKC on Ser890 was decreased to 45% of control values immediately following 1 h of SE. During the first 3 h following the termination of SE, phosphorylation of Ser890 increased 4-fold before declining to control values by 24 h. Phosphorylation of NR1 by PKA was also depressed relative to controls immediately following SE and transiently increased above control values upon the termination of SE. SE was accompanied by a general increase in tyrosine phosphorylation of hippocampal proteins that lasted for several hours following the termination of seizures. Tyrosine phosphorylation of the NR2A and NR2B subunits of the NMDAR increased 3-4-fold over control values during SE, continued to increase during the first hour following SE and then declined to control levels by 24 h. SE resulted in the activation of Src and Pyk2 associated with the postsynaptic apparatus, suggesting a role for these enzymes in the SE-induced increase in tyrosine phosphorylation. Changes in phosphorylation of the NMDA receptor may play a role in the pathophysiological consequences of SE.     

Effect of increased dairy consumption on appetitive ratings and food intake

Objective: The influence of dairy product consumption on food intake and appetitive sensations was explored in a cross‐over design study with individuals who were habitually low (<1 serving/d) or high (>3 servings/d) dairy consumers. Research Methods and Procedures: Fifty‐eight participants were required to eat one portion of dairy each day (low dairy) or three portions of dairy each day (high dairy) for 7 days. After a 7‐day washout period, the opposite treatment condition was completed. Food intake and appetitive ratings were measured on each day of the treatment periods. Results: During the high‐dairy period, participants consumed 209 kcal/d more than during the low dairy period (p < 0.05). There were no significant differences in subjective appetite ratings. Habitual dairy use did not influence either the appetitive or dietary findings. Discussion: These data indicate that increasing dairy consumption may lead to increased energy intake, which could potentially cause weight gain.     

NMDA receptor blockade attenuates CCK-induced reduction of real feeding but not sham feeding

Systemic injection of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor ion channels, increases meal size and delays satiation. We examined whether MK-801 increases food intake by directly interfering with actions of cholecystokinin (CCK). Prior administration of MK-801 (100 microg/kg ip) reversed the inhibitory effects of CCK-8 (2 and 4 microg/kg ip) on real feeding of both liquid and solid foods. MK-801 alone did not alter 30-min sham intake of 15% sucrose compared with intake after saline. Furthermore, while CCK-8 (2 or 4 microg/kg ip) reduced sham intake, this reduction was not attenuated by MK-801 pretreatment. To ascertain whether MK-801 attenuation of CCK-induced reduction of real feeding was associated with attenuated inhibition of gastric emptying, we tested the effect of MK-801 pretreatment on CCK-induced inhibition of gastric emptying of 5-ml saline loads. Ten-minute gastric emptying was accelerated after MK-801 (3.9 +/- 0.2 ml) compared with saline vehicle (2.72 +/- 0.2 ml). CCK-8 (0.5 microg/kg ip) reduced 10-min emptying to 1.36 +/- 0.3 ml. Pretreatment with MK-801 did not significantly attenuate CCK-8-induced reduction of gastric emptying (0.9 +/- 0.4 ml). This series of experiments demonstrates that blockade of NMDA ion channels reverses inhibition of real feeding by CCK. However, neither inhibition of sham feeding nor inhibition of gastric emptying by CCK is attenuated by MK-801. Therefore, increased food intake after NMDA receptor blockade is not caused by a direct interference with CCK-induced satiation. Rather, increased real feeding, either in the presence or absence of CCK, depends on blockade of NMDA receptor participation in other post-oral feedback signals such as gastric sensation or gastric tone.     

High multivitamin intake by Wistar rats during pregnancy results in increased food intake and components of the metabolic syndrome in male offspring

The effect of high multivitamin intake during pregnancy on the metabolic phenotype of rat offspring was investigated. Pregnant Wistar rats (n=10 per group) were fed the AIN-93G diet with the recommended vitamin (RV) content or a 10-fold increase [high vitamin (HV) content]. In experiment 1, male and female offspring were followed for 12 wk after weaning; in experiment 2, only males were followed for 28 wk. Body weight (BW) was measured weekly. Every 4 wk, after an overnight fast, food intake over 1 h was measured 30 min after a gavage of glucose or water. An oral glucose tolerance test was performed every 3-5 wk. Postweaning fasting glucose, insulin, ghrelin, glucagon-like peptide-1, and systolic blood pressure were measured. No difference in BW at birth or litter size was observed. Food intake was greater in males born to HV dams (P<0.05), and at 28 wk after weaning, BW was 8% higher (P<0.05) and fat pad mass was 27% higher (P<0.05). Food intake reduction after the glucose preload was nearly twofold less in males born to HV dams at 12 wk after weaning (P<0.05). Fasting glucose, insulin, and ghrelin were 11%, 62%, and 41% higher in males from HV dams at 14 wk after weaning (P<0.05). Blood glucose response was 46% higher at 23 wk after weaning (P<0.01), and systolic blood pressure was 16% higher at 28 wk after weaning (P<0.05). In conclusion, high multivitamin intake during pregnancy programmed the male offspring for the development of the components of metabolic syndrome in adulthood, possibly by its effects on central mechanisms of food intake control.