Lateral hypothalamic NMDA receptor subunits NR2A and/or NR2B mediate eating: immunochemical/behavioral evidence

Abstract

Cells within the lateral hypothalamic area (LHA) are important in eating control. Glutamate or its analogs, kainic acid (KA) and N-methyl-d-aspartate (NMDA), elicit intense eating when microinjected there, and, conversely, LHA-administered NMDA receptor antagonists suppress deprivation- and NMDA-elicited eating. The subunit composition of LHA NMDA receptors (NMDA-Rs) mediating feeding, however, has not yet been determined. Identifying this is important, because distinct second messengers/modulators may be activated by NMDA-Rs with differing compositions. To begin to address this, we detected LHA NR2A and NR2B subunits by immunoblotting and NR2B subunits by immunohistochemistry using subunit-specific antibodies. To help determine whether NMDA-Rs mediating feeding might contain these subunits, we conducted behavioral studies using LHA-administered ifenprodil, an antagonist selective for NR2A- and/or NR2B-containing NMDA-Rs at the doses we used (0.001–100 nmol). Ifenprodil maximally suppressed NMDA- and deprivation-elicited feeding by 63 and 39%, respectively, but failed to suppress KA-elicited eating, suggesting its actions were behaviorally specific. Collectively, these results suggest that LHA NMDA-Rs, some of which contribute to feeding control, are composed of NR2A and/or NR2B subunits, and implicate NR2A- and/or NR2B-linked signal transduction in feeding behavior.

Projections from bed nuclei of the stria terminalis, dorsomedial nucleus: Implications for cerebral hemisphere integration of neuroendocrine, autonomic, and drinking responses

“…8C'; Peterson, 1966;Duan and Ju, 1998;Khan et al, 1999). PHAL-labeled axons penetrate through these magnocellular neurosecretory neuron clusters and display many boutons (Fig.…”

“…In contrast, the BSTdm projections to the supraoptic nucleus are found caudally and ventrally, where vasopressinergic neuronal cell bodies predominate-as well as rostrally and dorsally where oxytocinergic cell bodies predominate. The BSTdm also densely innervates several clusters of magnocellular neurons forming part of the accessory supraoptic nucleus, where complex mixtures of oxytocinergic and vasopressinergic neurons may be found (Peterson, 1966;Duan and Ju, 1998;Khan et al, 1999).…”

“…They include a) the ventrolateral preoptic nucleus, with GABA/galaninergic neurons that are active during sleep (Sherin et al, 1996(Sherin et al, , 1998Gaus et al, 2002;Lu et al, 2002); b) the ventral tuberomammillary nucleus, with GABA/histaminergic neurons that promote wakefulness (see Köhler et al, 1985;Scammell et al, 2000); c) the dorsal region of the lateral hypothalamic area, with its separate populations of melanin-concentrating hormone containing and hypocretin/orexin-containing neurons modulating the sleep-wake cycle and arousal in ways that remain to be fully characterized (see Broberger et al, 1998;Elias et al, 1998;Chemelli et al, 1999;Saper et al, 2001;Willie et al, 2001;Taheri et al, 2002); and d) the supramammillary and posterior hypothalamic nuclei, which play an important role in modulating hippocampal theta rhythm, which in turn is present during exploratory behavior and the rapid eye movement stage of sleep (see Vertes and Kocsis, 1997). The general region of the lateral hypothalamic area mentioned in c) also appears to play an important role in the expression of eating and drinking behaviors (e.g., Yamamoto et al, 1989;Elias et al, 1999;Khan et al, 1999;Stratford and Kelley, 1999;Watts et al, 1999;Petrovich et al, 2002).…”

Catecholaminergic Control of Mitogen-Activated Protein Kinase Signaling in Paraventricular Neuroendocrine NeuronsIn VivoandIn Vitro: A Proposed Role during Glycemic Challenges

“…anesthesia, each rat was stereotaxically fitted with a unilateral, stainless-steel indwelling guide cannula [26 gauge; outer diameter (o.d. ), 0.46 mm] targeted toward the PVH, using the general stereotaxic procedure described by Khan et al (1999). With the incisor bar 3.3 mm below the ear bars, stereotaxic coordinates (Paxinos and Watson, 1998) were as follows: 6.8 mm anterior to the interaural line, 0.4 mm lateral to the midsagittal sinus, and either 6.4 or 7.2 mm ventral to the surface of the skull.…”

Adverse Effects of Antiepileptic Drugs

“…The effect of glutamate antagonists on feeding has been variable, depending on the site tested and the type of glutamate receptor blocked (72)(73)(74). Currently, there are insufficient data about the effects of these drugs on the hypothalamus or other areas of the brain that mediate feeding and hunger to know how these drugs reduce weight.…”