NMDA Receptors in Accumbal D1 Neurons Influence Chronic Sugar Consumption and Relapse.

Glutamatergic input via NMDA and AMPA receptors within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior and relapse toward drugs of abuse. Although well-established for drugs of abuse, it is not clear whether glutamate receptors within the mesolimbic system are involved in mediating chronic consumption and relapse following abstinence from a non-drug reward. Here, we evaluated the contribution of mesolimbic glutamate receptors in mediating chronic sugar consumption and the sugar-deprivation effect (SDE), which is used as a measure of relapse-like behavior following abstinence. We studied four inducible mutant mouse lines lacking the GluA1 or GluN1 subunit in either DA transporter (DAT) or D1R-expressing neurons in an automated monitoring system for free-choice sugar drinking in the home cage. Mice lacking either GluA1 or GluN1 in D1R-expressing neurons (GluA1D1CreERT2 or GluN1D1CreERT2 mice) have altered sugar consumption in both sexes, whereas GluA1DATCreERT2 and GluN1DATCreERT2 do not differ from their respective littermate controls. In terms of relapse-like behavior, female GluN1D1CreERT2 mice show a more pronounced SDE. Given that glutamate receptors within the mesolimbic system play a critical role in mediating relapse behavior of alcohol and other drugs of abuse, it is surprising that these receptors do not mediate the SDE, or in the case of female GluN1D1CreERT2 mice, show an opposing effect. We conclude that a relapse-like phenotype of sugar consumption differs from that of drugs of abuse on the molecular level, at least with respect to the contribution of mesolimbic glutamate receptors.

Female mice are more prone to develop an addictive-like phenotype for sugar consumption.

The concept of "sugar addiction" is gaining increasing attention in both the lay media and scientific literature. However, the concept of sugar addiction is controversial and only a few studies to date have attempted to determine the "addictive" properties of sugar using rigorous scientific criteria. Here we set out to systematically test the addictive properties of sugar in male and female mice using established paradigms and models from the drug addiction field. Male and female C57BL/6N (8-10 weeks old) were evaluated in 4 experimental procedures to study the addictive properties of sugar: (i) a drinking in the dark (DID) procedure to model sugar binging; (ii) a long-term free choice home cage drinking procedure measuring the sugar deprivation effect (SDE) following an abstinence phase; (iii) a long-term operant sugar self-administration with persistence, motivation and compulsivity measures and (iv) intracranial self-stimulation (ICSS). Female mice were more vulnerable to the addictive properties of sugar than male mice, showing higher binge and long-term, excessive drinking, a more pronounced relapse-like drinking following deprivation, and higher persistence and motivation for sugar. No sex differences were seen in a compulsivity test or reward sensitivity measured using ICSS following extended sugar consumption. This study demonstrates the occurrence of an addictive-like phenotype for sugar in male and female mice, similar to drugs of abuse, and suggests sex-dependent differences in the development of sugar addiction.

Endocannabinoid LTD in Accumbal D1 Neurons Mediates Reward-Seeking Behavior.

The nucleus accumbens (NAc) plays a key role in drug-related behavior and natural reward learning. Synaptic plasticity in dopamine D1 and D2 receptor medium spiny neurons (MSNs) of the NAc and the endogenous cannabinoid (eCB) system have been implicated in reward seeking. However, the precise molecular and physiological basis of reward-seeking behavior remains unknown. We found that the specific deletion of metabotropic glutamate receptor 5 (mGluR5) in D1-expressing MSNs (D1miRmGluR5 mice) abolishes eCB-mediated long-term depression (LTD) and prevents the expression of drug (cocaine and ethanol), natural reward (saccharin), and brain-stimulation-seeking behavior. In vivo enhancement of 2-arachidonoylglycerol (2-AG) eCB signaling within the NAc core restores both eCB-LTD and reward-seeking behavior in D1miRmGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses.