%0 Journal Article %A Shoupeng Wei %A Sarah Hertle %A Rainer Spanagel %A Ainhoa Bilbao %T NMDA receptors in accumbal D1 neurons influence chronic sugar consumption and relapse %D 2021 %R 10.1523/ENEURO.0029-21.2021 %J eneuro %P ENEURO.0029-21.2021 %X Glutamatergic input via NMDA and AMPA receptors within the mesolimbic dopamine pathway plays a critical role in the development of addictive behavior and relapse towards 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 dopamine 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 GluN1D1CreERT2mice) have altered sugar consumption in both sexes, whereas GluA1DATCreERT2 and GluN1DATCreERT2do not differ from their respective littermate controls. In terms of relapse-like behavior, female GluN1D1CreERT2mice 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.Significance StatementHere we provide evidence from various inducible and site-specific transgenic mouse models that glutamate receptors within the mesolimbic dopamine system do not play a critical role in relapse behavior in chronically sugar-drinking male and female mice. This differentiates a natural reward from drugs of abuse on the molecular level, as mesolimbic NMDA and AMPA receptors are essential for drug-induced neuroplasticity and subsequent relapse behavior. %U https://www.eneuro.org/content/eneuro/early/2021/04/26/ENEURO.0029-21.2021.full.pdf