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

Abstract

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 (GluA1^D1CreERT2 or GluN1^D1CreERT2 mice) have altered sugar consumption in both sexes, whereas GluA1^DATCreERT2 and GluN1^DATCreERT2 do not differ from their respective littermate controls. In terms of relapse-like behavior, female GluN1^D1CreERT2 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 GluN1^D1CreERT2 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.

Keywords: addictive phenotypes; glutamate receptors; mesolimbic system; mice; sugar; transgenic models.

Figure 1.

Characterization of chronic sugar drinking, SDE, and locomotor activity in male and female GluN1^DATCreERT2 mice. A, G, Baseline sugar intake in g/kg/d after free-choice access to a bottle containing a sugar solution (5% w/v) and a bottle with tap water in the homecage for eight weeks in wild-type male (n = 26), female (n = 25), and GluN1^DATCreERT2 male (n = 25) and female (n = 24) mice. B, H, Baseline locomotor activity after eight weeks of free-choice sugar drinking. C, I, Diurnal drinking pattern during baseline sucrose consumption and during the SDE. D, J, Diurnal activity pattern during baseline sucrose consumption and during the SDE. E, K, Relapse behavior measured in % change from baseline during the first 4 h of the SDE. F, L, Relative change in locomotor activity during the first 4 h of the SDE in relation to baseline activity; * indicates significant changes (p < 0.001) in sucrose consumption or activity during the SDE when compared with baseline; # indicates significant (p < 0.05) genotype differences.

Figure 2.

Characterization of chronic sugar drinking, SDE, and locomotor activity in male and female GluN1^D1CreERT2 mice. A, G, Baseline sugar intake in g/kg/d after free-choice access to a bottle containing a sugar solution (5% w/v) solution and a bottle with tap water in the homecage for eight weeks in wild-type male (n = 19), female (n = 20), and GluN1^D1CreERT2 male (n = 21) and female (n = 19) mice. B, H, Baseline locomotor activity after eight weeks of free-choice sugar drinking. C, I, Diurnal drinking pattern during baseline sucrose consumption and during the SDE. D, J, Diurnal activity pattern during baseline sucrose consumption and during the SDE. E, K, Relapse behavior measured in % change from baseline during the first 4 h of the SDE. F, L, Relative change in locomotor activity during the first 4 h of the SDE in relation to baseline activity; * indicates significant changes (p < 0.05) in sucrose consumption or activity during the SDE when compared with baseline; # indicates significant (p < 0.05 or p < 0.01 for A, G, L, K, respectively) genotype differences.

Figure 3.

Characterization of chronic sugar drinking, SDE, and locomotor activity in male and female GluA1^DATCreERT2 mice. A, G, Baseline sugar intake in g/kg/d after free-choice access to a bottle containing a sugar solution (5% w/v) solution and a bottle with tap water in the homecage for eight weeks in wild-type male (n = 26), female (n = 25), and GluA1^DATCreERT2 male (n = 26) and female (n = 27) mice. B, H, Baseline locomotor activity after eight weeks of free-choice sugar drinking. C, I, Diurnal drinking pattern during baseline sucrose consumption and during the SDE. D, J, Diurnal activity pattern during baseline sucrose consumption and during the SDE. E, K, Relapse behavior measured in % change from baseline during the first 4 h of the SDE. F, L, Relative change in locomotor activity during the first 4 h of the SDE in relation to baseline activity; * indicates significant changes (p < 0.01) in sucrose consumption or activity during the SDE when compared with baseline.

Figure 4.

Characterization of chronic sugar drinking, SDE, and locomotor activity in male and female GluA1^D1CreERT2 mice. A, G, Baseline sugar intake in g/kg/d after free-choice access to a bottle containing a sugar solution (5% w/v) solution and a bottle with tap water in the homecage for eight weeks in wild-type male (n = 19), female (n = 20), and GluA1^D1CreERT2 male (n = 18) and female (n = 20) mice. B, H, Baseline locomotor activity after eight weeks of free-choice sugar drinking. C, I, Diurnal drinking pattern during baseline sucrose consumption and during the SDE. D, J, Diurnal activity pattern during baseline sucrose consumption and during the SDE. E, K, Relapse behavior measured in % change from baseline during the first 4 h of the SDE. F, L, Relative change in locomotor activity during the first 4 h of the SDE in relation to baseline activity; * indicates significant changes (p < 0.05) in sucrose consumption or activity during the SDE when compared with baseline; # indicates significant (p < 0.05) genotype differences.