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Blockade of N-methyl-D-aspartate (NMDA) receptors in the caudal brainstem delays satiation and increases food intake. NMDA receptors are heterodimers made up of distinct, but different ion channel subunits. The NR2 subunits of the NMDA receptor contain the binding site for glutamate. About half of vagal afferents express immunoreactivity for NMDA NR2B subunit and about half of the NR2B-expressing afferents also express NMDA NR2C or NR2D subunits. This suggests that increased meal size may be evoked by interference with glutamate binding to NMDA channels containing the NR2B subunit. To test this, we measured deprivation-induced intake of 15% sucrose solution following microinjection of Conantokin-G (NR2B blocker), D-CPPene (NR2B/2A blocker) and PPDA (NR2D/C blocker) directly into the NTS. Conantokin (10ng/100nl), D-CPPene (10ng/100nl) and PPDA (1ng/100nl) increased 60-min sucrose intake significantly compared to control (Conantokin: 14.2 ± 0.3 ml vs 16.57ml ± 0.3) (D-CPPene: 11.8 ± 0.3ml vs 14.6 ± 0.3ml) (PPDA: 13.7 ± 0.2ml vs 16.3 ± 0.4ml). These results show that NTS NMDA receptor subunits NR2A/B as well as NR2D/C participate in control of meal size. NMDA receptors participate in control of food intake via vagal efferent neurons that innervate the upper gastrointestinal (GI) tract. Over 80% of vagal afferents that inervate the upper GI tract express imunoreactivity for NR2B and NR1 receptor subunits. Thus, glutamate receptors located at the peripheral vagal afferent endings may also influence food intake. To further assess peripheral NR2 receptor subunit participation in the control of food intake, we measured intake of regular food (rat chow), palatable nutrient (15% sucrose), and non-nutrient (0.2% saccharin) solutions following various doses of intraperitoneal administration of D-CPPene (0.5, 1.0, 2.0, 3.0 mg/kg). D-CPPene (2.0, 3.0 mg/kg) increased significantly 60min sucrose but not saccharin intake. It also increased 30-min chow intake at 2.0 and 4.0 mg/kg dose. To test whether D-CPPene increases feeding by interfering with postoral satiation signals such as CCK, we examined the effect of systemic (IP) administration of D-CPPene on suppression of food intake by CCK. Pretreatment with D-CPPene (2 mg/kg) completely reversed the inhibitory action of CCK and increased intake above saline, control level. Finally, to dissect the contribution of CCK in D-CPPene-sensitive vagal sensory signaling pathways, we complemented the behavioral tests with an anatomical approach that uses neuronal Fos expression in the dorsal vagal complex after stimulation by exogenous administration of CCK. Blockade of NR2B/A subunit resulted in a significant attenuation in CCK-induced Fos expression in the dorsal hindbrain (-14.08 and -13.80 from bregma). In summary, these results show that: 1) selective NMDA receptor antagonist with specificity for NR2B, NR2C and NR2D subunits applied directly to the hindbrain increase food intake; 2) systemic blockade of NMDA receptor containing NR2B/A subunits increase food intake and attenuates inhibition of food intake and Fos expression by CCK. This provides evidence that NR2 receptors subunits located on central vagal afferent terminals participate in control of food intake. They also suggest that peripheral NMDA receptors expressing the NR2B/A phenotype are involved in modulation of inhibition of food intake by gastrointestinal signals and opens the possibility of a peripheral site of action of NMDA receptors
Authors :
Guard, Douglas Brent
Contributors :
Mihai Covasa, Michael H. Green, Andras Hajnal
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Publisher :  Penn State     Type :  text     Format :  application/pdf    
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Languages :  en    
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