Glutamatergic Input to the Lateral Hypothalamus Stimulates Ethanol Intake: Role of Orexin and Melanin‐Concentrating Hormone

Abstract

Background Glutamate (GLUT) in the lateral hypothalamus (LH) has been suggested to mediate reward behaviors and may promote the ingestion of drugs of abuse. The current study tested the hypothesis that GLUT in the LH stimulates consumption of ethanol and that this effect occurs, in part, via its interaction with local peptides, hypocretin/orexin (OX) and melanin-concentrating hormone (MCH). Methods In Experiments 1 and 2, male Sprague-Dawley rats, after being trained to drink 9% ethanol, were microinjected in the LH with N-methyl-D-aspartate (NMDA) or its antagonist, D-AP5, or with alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionic acid (AMPA) or its antagonist, CNQX-ds. Consumption of ethanol, chow, and water was then measured. To provide an anatomical control, a separate set of rats was injected 2 mm dorsal to the LH. In Experiment 3, the effect of LH injection of NMDA and AMPA on the expression of OX and MCH was measured using radiolabeled in situ hybridization (ISH) and also digoxigenin-labeled ISH, to distinguish effects on OX and MCH cells in the LH and the nearby perifornical area (PF) and zona incerta (ZI). Results When injected into the LH, NMDA and AMPA both significantly increased ethanol intake while having no effect on chow or water intake. The GLUT receptor antagonists had the opposite effect, significantly reducing ethanol consumption. No effects were observed with injections 2 mm dorsal to the LH. In addition to these behavioral effects, LH injection of NMDA significantly stimulated expression of OX in both the LH and PF while reducing MCH in the ZI, whereas AMPA increased OX only in the LH and had no effect on MCH. Conclusions Glutamatergic inputs to the LH, acting through NMDA and AMPA receptors, appear to have a stimulatory effect on ethanol consumption, mediated in part by increased OX in LH and PF and reduced MCH in ZI.

Glutamate Signaling in Alcohol Abuse and Dependence

“…These conflicting results may arise partly from competing effects of receptor-selective compounds on different brain systems when injected peripherally. For example, injection of glutamatergic agonists into the lateral hypothalamus enhanced ethanol intake, whereas glutamatergic antagonists reduced drinking (Chen, Barson, Chen, Hoebel, & Leibowitz, 2013). Administration of topiramate that may antagonize certain AMPA/kainate receptors also reduced ethanol consumption in C57BL/6 J mice without affecting food consumption (Nguyen, Malcolm, & Middaugh, 2007).…”

Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

“…For example, NMDA and AMPA infused into the lateral hypothalamus can both increase 2BC consumption 14 . However, GluN antagonists and glycine B site blockade can importantly reduce motor coordination to achieve these effects 13– 16 .…”

Hypothalamic neuropeptide signaling in alcohol addiction

“…Manipulations that make rats drink more alcohol, including injections of D1 and glutamatergic agonists into the LH, increase gene expression of OX in this brain region (Chen et al, 2013a; Chen et al, 2014b). Conversely, manipulations that make rats drink less alcohol, like LH injection of a D2 agonist or oral gavage of a triglyceride-lowering drug, decrease OX expression in the LH (Barson et al, 2009; Chen et al, 2014b).…”

“…Our laboratory has shown that outbred Sprague-Dawley rats predicted to drink higher levels of alcohol due to their novelty-induced locomotor activity and fat-induced triglyceride levels show no difference in levels of MCH mRNA from non-prone rats (Barson et al, 2013). Moreover, manipulations that make rats drink more alcohol, including injections of D1 and glutamatergic agonists into the LH, fail to significantly affect gene expression of MCH in this brain region (Chen et al, 2013a; Chen et al, 2014b). Thus, it is possible that MCH endogenously promotes alcohol intake only in limited scenarios.…”