Dopamine D2 Receptor Signaling in the Nucleus Accumbens Comprises a Metabolic–Cognitive Brain Interface Regulating Metabolic Components of Glucose Reinforcement

Abstract

Appetitive drive is influenced by coordinated interactions between brain circuits that regulate reinforcement and homeostatic signals that control metabolism. Glucose modulates striatal dopamine (DA) and regulates appetitive drive and reinforcement learning. Striatal DA D2 receptors (D2Rs) also regulate reinforcement learning and are implicated in glucose-related metabolic disorders. Nevertheless, interactions between striatal D2R and peripheral glucose have not been previously described. Here we show that manipulations involving striatal D2R signaling coincide with perseverative and impulsive-like responding for sucrose, a disaccharide consisting of fructose and glucose. Fructose conveys orosensory (ie, taste) reinforcement but does not convey metabolic (ie, nutrient-derived) reinforcement. Glucose however conveys orosensory reinforcement but unlike fructose, it is a major metabolic energy source, underlies sustained reinforcement, and activates striatal circuitry. We found that mice with deletion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) exclusively in D2R-expressing cells exhibited preferential D2R changes in the nucleus accumbens (NAc), a striatal region that critically regulates sucrose reinforcement. These changes coincided with perseverative and impulsive-like responding for sucrose pellets and sustained reinforcement learning of glucose-paired flavors. These mice were also characterized by significant glucose intolerance (ie, impaired glucose utilization). Systemic glucose administration significantly attenuated sucrose operant responding and D2R activation or blockade in the NAc bidirectionally modulated blood glucose levels and glucose tolerance. Collectively, these results implicate NAc D2R in regulating both peripheral glucose levels and glucose-dependent reinforcement learning behaviors and highlight the notion that glucose metabolic impairments arising from disrupted NAc D2R signaling are involved in compulsive and perseverative feeding behaviors.

Dopamine D2 receptor overexpression in the nucleus accumbens core induces robust weight loss during scheduled fasting selectively in female mice

“…Glucose tolerance refers to the clearing of glucose from the bloodstream after a meal or glucose administration, while glucose intolerance reflects an inability or delay in the clearance of elevated blood glucose 28 . Our finding that D2R-OE NAc mice exhibit glucose intolerance is consistent with recent evidence suggesting that striatal dopamine regulates energy homeostasis 28 , 46 , 47 .…”

“…Glucose tolerance refers to the clearing of glucose from the bloodstream after a meal or glucose administration, while glucose intolerance reflects an inability or delay in the clearance of elevated blood glucose 28 . Our finding that D2R-OE NAc mice exhibit glucose intolerance is consistent with recent evidence suggesting that striatal dopamine regulates energy homeostasis 28 , 46 , 47 . In particular, Michaelides et al (2017) recently showed that mice lacking dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) exclusively in D2R-expressing cells exhibit glucose intolerance and upregulation of D2R mRNA selectively in the NAc 28 , and that direct infusion of the D2R agonist bromocriptine into the NAc of normal mice increases glucose intolerance 28 .…”

“…We performed the intraperitoneal glucose tolerance test (IGTT) as described previously 28 . Briefly, mice were fasted for 8 h. Then approximately 2 hours into their dark cycle, mice received IP injections of either vehicle or 10 mg/kg of the D2R agonist bromocriptine.…”

Sex‐dependent alterations of dopamine receptor and glucose transporter density in rat hypothalamus under long‐term clozapine and haloperidol medication

“…D2R is involved not only in schizophrenia, but also in elevated levels of blood glucose in schizophrenic patients (Lawford et al., 2016). Glucose modulates striatal dopamine in mice, whereas striatal D2R regulates peripheral glucose levels and is implicated in glucose‐related metabolic disorders (Michaelides et al, 2017). Mice lacking D2R are glucose intolerant and have abnormal insulin secretion (Lopez Vicchi et al, 2016).…”

“…whereas striatal D2R regulates peripheral glucose levels and is implicated in glucose-related metabolic disorders (Michaelides et al, 2017). Mice lacking D2R are glucose intolerant and have abnormal insulin secretion (Lopez Vicchi et al, 2016).…”