OR30-4 MC3R is expressed in the VTA and is required for dopamine-dependent behaviors and total VTA dopamine content in female mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR30-Central Regulation of Appetite & Feeding
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 304 (Moscone Center)
Rachel N. Lippert*, Kate L.J. Ellacott and Roger D Cone
Vanderbilt University Medical Center, Nashville, TN
Both homeostatic and hedonic drives play a critical role in the control of food intake. Our laboratory is focused on the contribution of central melanocortin system in these processes. The MC4R is well understood to be the key regulator of energy homeostasis; however, less is understood about the function of the MC3R, both within the hypothalamus and in other brain regions. Using the MC3R-GFP mouse model, we demonstrated a very high level of expression of the MC3R in the ventral tegmental area (VTA) of the midbrain. This data is in agreement with previous in situ hybridization data from our laboratory, indicating this high expression in this region known to be critical for reward signaling. Interestingly, approximately 75% of all MC3R-GFP expressing neurons in this brain region co-expressed tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis and a marker of dopaminergic neurons. Furthermore, MC3R deficient mice showed a significant 60% increase in VTA dopamine content, as measured by HPLC, but only in female mice. VTA dopamine signaling is known to regulate sucrose intake and preference in a choice paradigm. This led us to hypothesize that MC3R deficient female mice may have a defect in sucrose intake and preference as compared to WT females and this effect would not be noted in the MC3R deficient male mice which show comparable dopamine levels in this region to WT controls. In support of our hypothesis MC3R deficient female mice showed a statistically significant decrease in total sucrose consumption and in overall sucrose preference when compared to WT female mice. As predicted, this difference was not seen in the male animals. Combined, this data suggests a potential interaction between of ovarian hormones and the MC3R in controlling central dopamine synthesis and/or signaling. Indeed, the increase in VTA dopamine content in the MC3R female mice was reversed by surgical ovariectomy. On a gene expression level, there was no change in tyrosine hydroxylase, dopamine transporter, estrogen receptor alpha, or estrogen receptor beta in the VTA of female MC3R deficient mice compared with WT mice; as such, the mechanism which causes this alteration in dopamine remains to be elucidated.  In summary our data demonstrate a sexual dimorphism in the regulation of VTA dopamine expression and related behaviors in MC3R deficient mice which may reflect an interaction between ovarian hormones and MC3R signaling in these animals.

Nothing to Disclose: RNL, KLJE, RDC

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Sources of Research Support: This work was supported by NIH grants DK078850 and T32 DK07563.