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. 2013 Dec 1;305(11):E1367-74.
doi: 10.1152/ajpendo.00413.2013. Epub 2013 Oct 8.

The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors

Elizabeth G Mietlicki-Baase  1 , Pavel I Ortinski, Laura E Rupprecht, Diana R Olivos, Amber L Alhadeff, R Christopher Pierce, Matthew R Hayes
Affiliations

The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors

Elizabeth G Mietlicki-Baase et al. Am J Physiol Endocrinol Metab. .

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.

Keywords: 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid; diabetes; dopamine; glucagon-like peptide-1; glutamate; obesity; reward.

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Figures

Fig. 1.
Fig. 1.
Twenty-four-hour high-fat diet intake (A) and body weight gain (B) after intra-ventral tegmental area (VTA) pretreatment of the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin-(9–39) (Ex-9; 10 μg) or its vehicle [200 nl of artificial cerebrospinal fluid (aCSF)] in combination with intraperitoneal (ip) injection of the GLP-1R agonist Ex-4 (3 μg/kg) or its vehicle (1 ml/kg 0.9% NaCl). The reductions in food intake and body weight gain were attenuated by intra-VTA pretreatment with Ex-9. *P < 0.05 compared with aCSF/saline. All data are shown as means ± SE. C: a representative histological section showing verification of VTA cannula placement with pontamine sky blue ink injection (100 nl) is shown.
Fig. 2.
Fig. 2.
A: VTA administration of the 2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA)/kainate receptor antagonist CNQX (0.3 μg; vehicle, 100 nl of aCSF) attenuates the anorectic effect of VTA GLP-1R activation by exendin-4 (Ex-4; 0.05 μg; vehicle, 100 nl of aCSF). This effect occurs via suppression of meal size (B), with only minimal effects on meal frequency (C). *Main effect of Ex-4 (P < 0.05); formula imagemain effect of CNQX (P < 0.05); #interaction between CNQX and Ex-4 (P < 0.05). Within time bin, bars with different letters are significantly different from each other (P < 0.05). All data are shown as means ± SE.
Fig. 3.
Fig. 3.
A: VTA administration of the NMDA receptor antagonist MK-801 (0.05 μg; vehicle, 100 nl of aCSF) does not attenuate the intake-suppressive effect of VTA GLP-1R activation by Ex-4 (0.05 μg; vehicle, 100 nl of aCSF). B: VTA MK-801 does not attenuate VTA Ex-4-induced reductions in meal size. C: no effects on meal frequency were observed (all P > 0.05). *Main effect of Ex-4 (P < 0.05); formula imagemain effect of MK-801 (P < 0.05); #statistically significant interaction between MK-801 and Ex-4. Within time bin, bars with different letters are significantly different from each other (P < 0.05). All data are shown as means ± SE.
Fig. 4.
Fig. 4.
A: intra-VTA injection of Ex-4 (0.05 μg; vehicle, 100 nl of aCSF) increased VTA tyrosine hydrolase (TH; normalized to β-actin) 15 min after drug administration. B: representative immunoblots for TH and β-actin are shown. *P ≤ 0.05 compared with aCSF. Data are shown as means ± SE.
Fig. 5.
Fig. 5.
A: representative spontaneous excitatory postsynaptic current (sEPSC) traces from VTA dopamine neurons before and during Ex-4 application. B: Ex-4 increases sEPSC frequency. Effect of Ex-4 on sEPSC averages (C) is expressed as %difference from baseline recorded before Ex-4 application (D). E: Ex-4 reduces paired/pulse ratio (PPR). F: quantified PPR results (gray lines represent individual neuron responses before and during Ex-4 application; black line is the mean). Quantified data are shown as means ± SE. *P < 0.05.
Fig. 6.
Fig. 6.
A: voltage responses of a VTA dopamine neuron to a −140-pA and a +140-pA current step illustrate a slight decrease in action potential (AP) firing during Ex-4 treatment. B: quantified frequency vs. injected current (f-I) data (means ± SE) shows that the effect of Ex-4 on the f-I relationship is not significant (P > 0.05).
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