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 μg/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.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00570.2003 ◽

2004 ◽

Vol 286 (5) ◽

pp. R826-R831 ◽

Cited By ~ 6

Author(s):

Mihai Covasa ◽

Robert C. Ritter ◽

Gilbert A. Burns

Keyword(s):

Gastric Emptying ◽

Ion Channels ◽

Nmda Receptor ◽

Food Intake ◽

Receptor Blockade ◽

Sham Feeding ◽

Systemic Injection ◽

Mk 801 ◽

Nmda Receptor Blockade ◽

Series Of Experiments

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 μg/kg ip) reversed the inhibitory effects of CCK-8 (2 and 4 μg/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 μg/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 μg/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 postoral feedback signals such as gastric sensation or gastric tone.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00641.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. R642-R651 ◽

Cited By ~ 19

Author(s):

Chun-Yi Hung ◽

M. Covasa ◽

R. C. Ritter ◽

G. A. Burns

Keyword(s):

Nmda Receptor ◽

Food Intake ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Intraperitoneal Injection ◽

Sucrose Solution ◽

Nmda Receptor Antagonist ◽

Saline Control ◽

Sucrose Intake ◽

Mk 801

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 μg (16.7 ± 0.6 ml) and 0.4 μg (14.9 ± 0.5 ml) but not 0.1 and 0.6 μg 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 ± 0.7ml, vs. saline: 10.5 ± 0.5ml). 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.

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Chronic neonatal NMDA receptor blockade with MK-801 alters monoamine metabolism in the adult rat

Neuroscience Letters ◽

10.1016/0304-3940(92)90307-s ◽

1992 ◽

Vol 137 (1) ◽

pp. 97-100 ◽

Cited By ~ 30

Author(s):

Jan A. Gorter ◽

Margriet H.A. Botterblom ◽

Matthijs G.P. Feenstra ◽

Gerard J. Boer

Keyword(s):

Nmda Receptor ◽

Receptor Blockade ◽

Monoamine Metabolism ◽

Mk 801 ◽

Adult Rat ◽

Nmda Receptor Blockade

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Cholinergic neurotransmission participates in increased food intake induced by NMDA receptor blockade

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00055.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. R641-R648 ◽

Cited By ~ 11

Author(s):

Mihai Covasa ◽

Robert C. Ritter ◽

Gilbert A. Burns

Keyword(s):

Gastric Emptying ◽

Nmda Receptor ◽

Food Intake ◽

Receptor Antagonist ◽

Motor Neurons ◽

Nmda Receptor Antagonist ◽

Sucrose Intake ◽

Cholinergic Mechanism ◽

Mk 801 ◽

Cholinergic Tone

MK-801, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, enhances gastric emptying while increasing food intake. Although our previously reported results implicate the vagus in MK-801's effect on feeding, it is not clear whether vagal motor fibers participate in the feeding response. Control of gastric emptying is exerted, in part, by cholinergic vagal motor neurons. Therefore, we examined the ability of MK-801 to increase meal size in the presence or absence of the muscarinic receptor antagonist atropine methyl nitrate. Both central and systemic administration of MK-801 significantly increased intake of 15% sucrose. Intraperitoneal injection of atropine abolished MK-801-induced increase in sucrose intake, whereas administration into the fourth ventricle had no effect. To determine whether augmentation of cholinergic tone produces an enhancement of food intake in the absence of MK-801, we tested the ability of cisapride, a gastric prokinetic agent that promotes acetylcholine release through an action on presynaptic serotonin (5-HT4) receptors, to increase sucrose consumption. Cisapride (500 μg/kg ip) induced a small but significant increase in 15% sucrose intake (15.5 ± 0.5 ml) compared with NaCl (13.0 ± 0.6 ml). Furthermore, when MK-801 (100 μg/kg ip) was given in combination with cisapride, intake was significantly higher (19.8 ± 0.9 ml) than following either agent given alone. Pretreatment with atropine abolished the cisapride-induced increase in intake (12.1 ± 0.9 ml) as well as the increased intake induced by combining MK-801 and cisapride. These results suggest that blockade of NMDA-gated ion channels in the hindbrain increases food intake, in part, via a peripheral muscarinic cholinergic mechanism.

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NMDA Receptor Blockade and Spinal Cord Ischemia Due to Aortic Crossclamping in the Rat Model

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100041202 ◽

1994 ◽

Vol 21 (3) ◽

pp. 227-232 ◽

Cited By ~ 18

Author(s):

F. Follis ◽

K. Miller ◽

O. U. Scremin ◽

S. Pett ◽

R. Kessler ◽

...

Keyword(s):

Spinal Cord ◽

Nmda Receptor ◽

Brain Research ◽

Spinal Cord Ischemia ◽

Intrathecal Injection ◽

Control Group ◽

Receptor Subtype ◽

Receptor Blockade ◽

Mk 801 ◽

Nmda Receptor Blockade

Abstract:Recent brain research proposes that, during ischemia, synaptically released excitatory amino acid neurotransmitters accumulate at toxic concentrations with ensuing neuronal death. Their action is mediated by the receptor subtype N-methyl-D-aspartate (NMDA). The protective effect of NMDA receptor blockade with intrathecal MgS04 and MK-801 was investigated during spinal cord ischemia induced by aortic occlusion of 12 minutes. Male Sprague-Dawley rats, 250-300g, underwent intrathecal administration of 20 μL of normal saline (SA n = 16), MgS04 1M (MG n = 16), or MK-801, 25 mM solutions (MK n = 16) in a randomized order. After 2 hours, the animals underwent occlusion of the thoracic aorta and subclavian arteries for 12 min. An additional control group (CO n = 16) underwent occlusion for 12 minutes, without intrathecal injection. The animals were scored according to their functional performance (LS = lesion score) each day for four days by a blinded observer. Mean LS were calculated for each group at a given day. Treatment and control groups were not different at day 1 (P = 0.302). Group MG was improved from groups SA (P = < 0.0039) and CO (P = < 0.0048) at day 4. This study demonstrates that although intrathecal NMDA receptor blockade with MgS04 or MK-801 does not prevent paraplegia due to spinal cord ischemia in the rat, it could however influence the rate of recovery after ischemic injury.

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Behavioral Consequences of a Combination of Gad1 Haplodeficiency and Adolescent Exposure to an NMDA Receptor Antagonist in Long-Evans Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.646088 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kazuyuki Fujihara ◽

Takumi Sato ◽

Kazuya Higeta ◽

Yoshiki Miyasaka ◽

Tomoji Mashimo ◽

...

Keyword(s):

Nmda Receptor ◽

Forced Swim Test ◽

Nmda Receptor Antagonist ◽

Receptor Blockade ◽

Novelty Preference ◽

Behavioral Consequences ◽

Mk 801 ◽

Model Studies ◽

Affective Symptoms ◽

Nmda Receptor Blockade

Glutamate decarboxylase 67-kDa isoform (GAD67), which is encoded by the GAD1 gene, is one of the key enzymes that produce GABA. The reduced expression of GAD67 has been linked to the pathophysiology of schizophrenia. Additionally, the excitatory glutamatergic system plays an important role in the development of this disorder. Animal model studies have revealed that chronic blockade of NMDA-type glutamate receptors can cause GABAergic dysfunction and long-lasting behavioral abnormalities. Based on these findings, we speculated that Gad1 haplodeficiency combined with chronic NMDA receptor blockade would lead to larger behavioral consequences relevant to schizophrenia in a rat model. In this study, we administered an NMDAR antagonist, MK-801 (0.2 mg/kg), to CRISPR/Cas9-generated Gad1+/− rats during adolescence to test this hypothesis. The MK-801 treated Gad1+/− rats showed a shorter duration in each rearing episode in the open field test than the saline-treated Gad1+/+ rats. In contrast, immobility in the forced swim test was increased and fear extinction was impaired in Gad1+/− rats irrespective of MK-801 treatment. Interestingly, the time spent in the center region of the elevated plus-maze was significantly affected only in the saline-treated Gad1+/− rats. Additionally, the MK-801-induced impairment of the social novelty preference was not observed in Gad1+/− rats. These results suggest that the synergistic and additive effects of Gad1 haplodeficiency and NMDA receptor blockade during adolescence on the pathogenesis of schizophrenia may be more limited than expected. Findings from this study also imply that these two factors mainly affect negative or affective symptoms, rather than positive symptoms.

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