A comparison between the <i>in vivo</i> and <i>in vitro</i> activity of five potent and competitive NMDA antagonists

Lodge, David; Davies, Stephen N.; Jones, Martyn G.; Millar, John D.; Manallack, David T.; Ornstein, Paul L.; Verberne, Anthony J.M.; Young, Nicole A.; Beart, Philip M

doi:10.1111/j.1476-5381.1988.tb11726.x

Cited by 44 publications

(29 citation statements)

References 25 publications

(22 reference statements)

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“…However, increased feeding was not evoked when AP5 was injected systemically. Although previous reports indicate that AP5 is a highly specific NMDA receptor antagonist (20,53), peripheral AP5 activity appears to be limited. Our previous work shows that the central site is well established for the feeding effects of MK-801, and the current findings also indicate that AP5 only works centrally, since peripheral administration of AP5 at doses as high as 5 mg/kg did not increase food intake.…”

Section: Discussionmentioning

confidence: 81%

“…D-(-)-2-Amino-5-phosphonopentanoic acid (AP5) is a potent and selective competitive NMDA-type glutamate receptor antagonist (20,53). In this study, we tested the hypothesis that blockade of NMDA receptors by AP5 would increase food intake.…”

Section: Satiation; Nucleus Of the Solitary Tract; N-methyl-d-aspartamentioning

confidence: 99%

“…Unlike MK-801, competitive NMDA antagonists compete directly with glutamate for binding on the ion channel. Therefore, competitive NMDA receptor antagonists not only are more selective for NMDA receptors than their noncompetitive cogeners, but interpretation of their pharmacological effects is more straightforward.D-(-)-2-Amino-5-phosphonopentanoic acid (AP5) is a potent and selective competitive NMDA-type glutamate receptor antagonist (20,53). In this study, we tested the hypothesis that blockade of NMDA receptors by AP5 would increase food intake.…”

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confidence: 99%

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

Hung¹,

Covașă²,

Ritter³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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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 Ϯ 0.4 ml, saline control) (11.0 Ϯ 0.8, 11.2 Ϯ 1.0, 11.2 Ϯ 1.0, 13.1 Ϯ 2.2, and 11.0 Ϯ 1.9 ml, AP5 doses, respectively). Fourth ventricular administration of both 0.2 g (16.7 Ϯ 0.6 ml) and 0.4 g (14.9 Ϯ 0.5 ml) but not 0.1 and 0.6 g of AP5 significantly increased 60-min sucrose intake compared with saline (11.2 Ϯ 0.4 ml). Twenty-four hour chow intake also was increased compared with saline (AP5: 31.5 Ϯ 0.1 g vs. saline: 27.1 Ϯ 0.6 g). Furthermore, rats did not increase intake of 0.2% saccharin after fourth ventricular AP5 administration (AP5: 9.8 Ϯ 0.7ml, vs. saline: 10.5 Ϯ 0.5ml). Finally, NTS AP5 (20 ng/30 nl) significantly increased 30-(AP5: 17.2 Ϯ 0.7 ml vs. saline: 14.6 Ϯ 1.7 ml), and 60-min (AP5: 19.4 Ϯ 0.6 ml vs. saline: 15.5 Ϯ 1.4 ml) sucrose intake, as well as 24-h chow intake (AP5: 31.6 Ϯ 0.3 g vs. saline: 26.1 Ϯ 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. satiation; nucleus of the solitary tract; N-methyl-d-aspartate channel blockerN-METHYL-D-ASPARTATE (NMDA)-type glutamate receptors are expressed in many neurons in the central nervous system (4, 24, 33, 52), as well as by some peripheral neurons, including primary vagal afferents (1) and the intrinsic neurons of the gastrointestinal tract (7,19,52). Over the past decade, evidence of NMDA receptor participation in meal termination has steadily accumulated. Studies from our laboratory (6), as well as others (17), have demonstrated that intraperitoneal administration of dizocilpine (MK-801), a noncompetitive antagonist of NMDA receptors, increases intake of both solid chow and palatable food, but not water, in rats after overnight food deprivation. Administration of MK-801 into the fourth ventricle or directly into the caudal medial nucleus of the solitary tract (NTS) increases the size of a 15% sucrose meal (49). Furthermore, lesions of the dorsal vagal complex abolish increased meal size evoked by systemic administration of MK-801 (50). Finally, systemic MK-801 administration increases only nutritive sucrose but not nonnutritive saccharin solution (5), indicating that blockade of NMDA receptors by MK-801 delays me...

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Section: Discussionmentioning

confidence: 81%

Section: Satiation; Nucleus Of the Solitary Tract; N-methyl-d-aspartamentioning

confidence: 99%

mentioning

confidence: 99%

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

Hung¹,

Covașă²,

Ritter³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Differential roles of AMPARs and kainate receptors are not understood in IC. To block NMDARs, CPP is both highly selective and more potent than alternatives such as AP-5 (Lodge et al, 1988). A previous in vivo study of glutamate receptor function in IC used these same receptor antagonists (Zhang and Kelly, 2001).…”

Section: Methodsmentioning

confidence: 99%

Contribution of NMDA and AMPA Receptors to Temporal Patterning of Auditory Responses in the Inferior Colliculus

Sanchez¹,

Gans²,

Wenstrup³

2007

J. Neurosci.

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“…Therefore, increased food intake following hindbrain administration of the NMDA receptor could be the result of these antagonists acting presynaptically on gastrointestinal vagal afferent terminals expressing heterometric NR2B and NR2C NMDA receptors. Electrophysiological results suggest that transmitter release by primary somatosensory afferent terminals in the spinal cord can be modulated by presynaptic NMDA receptors in the terminals of these neurons in the spinal cord (36). Unfortunately, there are currently no functional experiments to link increased food intake evoked by NR2B or NR2C.…”

Section: Discussionmentioning

confidence: 98%

Blockade of hindbrain NMDA receptors containing NR2 subunits increases sucrose intake

Guard

Swartz²,

Ritter³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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We have previously shown that blockade of N-methyl-d-aspartate (NMDA) receptors in the caudal brain stem 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 food intake 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 fourth ventricle and intra-nucleus of the solitary tract (intra-NTS) injections of Conantokin G (Con G; NR2B blocker), d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene; NR2B/2A blocker), and (+/-)-cis-1-(phenanthren-2yl-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA; NR2D/C blocker). Fourth ventricular administration of Con G (5, 20, 40, 80 ng), d-CPPene (3.0, 6.25, 12.5, 25, 50, 100 ng), and PPDA (300, 400 ng) increased sucrose intake significantly compared with control. Likewise, injections of Con G (10 ng), d-CPPene (5 ng, 10 ng), and PPDA (0.5, 1.0, 2.5, 5.0 ng) directly into the NTS significantly increased sucrose intake. These results show that hindbrain injection of competitive NMDA antagonists with selectivity or preference for the NMDA receptor NR2B or NR2C subunits increases food intake.

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A comparison between the in vivo and in vitro activity of five potent and competitive NMDA antagonists

Cited by 44 publications

References 25 publications

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

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

Contribution of NMDA and AMPA Receptors to Temporal Patterning of Auditory Responses in the Inferior Colliculus

Blockade of hindbrain NMDA receptors containing NR2 subunits increases sucrose intake

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