Bromocriptine Administration Reduces Hyperphagia and Adiposity and Differentially Affects Dopamine D2 Receptor and Transporter Binding in Leptin-Receptor-Deficient Zucker Rats and Rats with Diet-Induced Obesity

Abstract

Background: The dopamine (DA) D₂ receptor (D2R) agonist bromocriptine (BC) decreases body fat in animal and human models and increases lean muscle mass, improves glucose intolerance and insulin resistance, and reduces triglycerides and free fatty acids. We have previously shown a negative correlation between D2R and body weight in obese individuals and in rodents, and that chronic food restriction increases D2R binding in genetically obese rats. The purpose of this study was to assess whether the antiobesity and metabolic effects of BC are related to changes in midbrain DA and D2R activity by measuring D2R and DA transporter (DAT) binding in a genetic (leptin-receptor-deficient) and environmental (diet-induced) rodent obesity model. Methods: Obese (fa/fa) (leptin-receptor-deficient), lean (FA/FA) Zucker rats and rats with diet-induced obesity (DIO) were treated with 10 mg/kg BC for 4 weeks. Body weight, food intake, locomotor activity and blood glucose levels were measured along with D2R- and DAT-binding levels using in vitro receptor autoradiography. Results: BC decreased food intake and body fat and increased locomotor activity in both the (fa/fa) and DIO rats. Furthermore, BC increased D2R binding in (fa/fa) but not in DIO rats. Finally, BC increased DAT binding in DIO rats but not in the (fa/fa) rats. Conclusion: These observations are all consistent with the existence of unique leptin-DA interactions and the hypothesis that there is hyposensitivity of the DA system in obesity.

Effects of Ovariectomy and 17<i>β</i>-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

“…showing anti-obesity properties [81] [82]. On the other hand, sulpiride significantly increased food intake and body weight gain in our studies.…”

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

“…These include reduced DA concentrations, impaired response to electrically evoked accumbal DA release, decreased basal tyrosine hydroxylase and DAT expression, as well as lower levels of D 2 receptor binding (Pothos et al, 1998;Geiger et al, 2008). Correspondingly, striatal D 2 receptor binding is inversely correlated to the degree of obesity in humans (Volkow and Wise, 2005), and D 2 receptor agonists produce hypophagia and weight loss in animal models of obesity (Scislowski et al, 1999;Davis et al, 2008). In addition, mesolimbic D 3 receptor function may also have a role in obesity, as suggested by findings of D 3 receptor agonist-induced hypophagia in DIO mice and increased adiposity in D 3 receptor knockout mice (McQuade et al, 2003;McQuade et al, 2004).…”

“…Food intake and food depriviation have opposing effects on extracellular DA levels in the nucleus accumbens, as feeding stimulates DA release and turnover whereas food deprivation causes the opposite effects (Nelson and Gehlert, 2006). Several DA receptors may be effectors of increased DA availability during feeding episodes, as both D 1 , D 2 , and D 3 receptor agonists reduce food intake in animal models of obesity (Scislowski et al, 1999;McQuade et al, 2003;Davis et al, 2008).…”

Food and Drug Reward: Overlapping Circuits in Human Obesity and Addiction

“…Importantly, decreased striatal D2R availability has been linked to compulsive food intake in obese rodents (Johnson and Kenny 2010) and with decreased metabolic activity in OFC and ACC in obese humans (Volkow et al 2008b) (Fig.7 a-c). Given that dysfunction in OFC and ACC results in compulsivity [see review (Fineberg et al 2009)], this might be part of the mechanism by which low striatal D2R signaling facilitates hyperphagia (Davis et al 2009). In addition, since decreased D2R-related signaling is also likely to reduce the sensitivity to other natural rewards, this deficit in obese individuals might also contribute to compensatory overeating (Geiger et al 2008).…”