Regulation of Sweetened Alcohol Drinking Behaviors in Rats by Melanin-Concentrating Hormone Activation

Alcohol Use Disorder (AUD) is a prevalent motivational disorder among adults and adolescents. One reason as to why this may be is due to the increase market availability of alcoholic drinks that contain sugar. While these ready to drink cocktails are assumed to be popular is because of their high palatability, potentially leading to the development of AUD. However, this ignores the ability of some commonly available sugars, like glucose, to pass directly into the brain and impact the firing of glucose-sensitive neurons. One such population of these glucose includes are the Melanin-Concentrating Hormone (MCH) neurons which project from the lateral hypothalamus (LH) to other regions in the brain. These neurons are implicated in feeding, energy regulation, and most importantly, alcohol drinking, which may be why this neuronal circuit may be implicated in alcohol cocktail drinking, and ultimately AUD. MCH neurons are particularly sensitive to high extracellular glucose concentrations in the brain, meaning that there is a possibility that glucose, especially in alcoholic drinks, may be playing a role in facilitating AUD-like behavior. We therefore hypothesize that rats will drink more alcohol when glucose is added, compared to an equally caloric but less brain penetrant sugar like fructose. We further hypothesize that MCH neuron activation facilitates glucose-alcohol drinking. This study intends to measure alcohol consumption patterns and differences in rat behavior when different concentrations of alcohol are used, and the study will directly compare rats drinking alcohol cocktails containing glucose and fructose sugars as a comparison. Sex differences will also be measured between male and female rats to analyze if sex is a biological factor between alcohol consumption. The study will use adult age matched Wistar male and female rats that are either intracranially infused with viral vectors delivering Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to LH MCH neurons or a control virus. Then they will be trained to self-administer either 10% glucose or 10% fructose alcohol cocktail solutions. During the experiment, the concentration and type of sugar will remain the same but during training the concentration of alcohol will be increase weekly from 1.25%, 2.5%, 5%, to 10%. Once trained, they will be given access to different weekly alcohol concentrations in a Latin Square Design. They will be pretreated during one session each week with clozapine-n-oxide (0.3 mg/kg, i.p.) or vehicle to test the effect of activating the DREADD. The behavioral measurement will include the amount of solution drank (measured as both change in bottle weight and total licks), patterns of licking behavior (lick number, lick per time unit) and pauses in licking (pause number, pause length).