raclopride and Obesity

Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine system in ventral tegmental area and striatum, key areas implicated in reward. We hypothesized that dopamine and opioid receptor availabilities correlate in vivo and that this correlation is altered in obesity, a disease with altered reward processing. Twenty lean females (mean BMI 22) and 25 non-binge eating morbidly obese females (mean BMI 41) underwent two positron emission tomography scans with [(11)C]carfentanil and [(11)C]raclopride to measure the MOR and dopamine D2 receptor (DRD2) availability, respectively. In lean subjects, the MOR and DRD2 availabilities were positively associated in the ventral striatum (r=0.62, p=0.003) and dorsal caudate nucleus (r=0.62, p=0.004). Moreover, DRD2 availability in the ventral striatum was associated with MOR availability in other regions of the reward circuitry, particularly in the ventral tegmental area. In morbidly obese subjects, this receptor interaction was significantly weaker in ventral striatum but unaltered in the caudate nucleus. Finally, the association between DRD2 availability in the ventral striatum and MOR availability in the ventral tegmental area was abolished in the morbidly obese. The study demonstrates a link between DRD2 and MOR availabilities in living human brain. This interaction is selectively disrupted in mesolimbic dopamine system in morbid obesity. We propose that interaction between the dopamine and opioid systems is a prerequisite for normal reward processing and that disrupted cross-talk may underlie altered reward processing in obesity.

Topics: Adult; Body Mass Index; Caudate Nucleus; Female; Fentanyl; Humans; Middle Aged; Obesity; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Opioid, mu; Reward; Ventral Striatum

Chronic overeating of obesogenic diets can lead to obesity, reduced dopamine signaling, and increased consumption of added sugars to compensate for blunted reward. However, the specific role of diet composition yet remains unknown. To study this, Sprague-Dawley male rats were fed a high-energy diet with high fat and low carbohydrate content (HFHE), a fat-sugar combination high-energy diet (FCHE), or standard chow for 24 weeks. We found that both high-energy diets produced substantial body weight gain compared to chow-fed controls. To investigate dopamine control of short (2-h) intake of palatable sucrose or fructose solutions, rats were pretreated peripherally (IP) with equimolar doses (0-600 nmol/kg) of the dopamine D1 (SCH23390) and D2 (raclopride) subtype-specific receptor antagonists. The results showed an overall increase in the efficacy of D1 and D2 receptor antagonists on suppression of intake in obese rats compared to lean rats, with effects differing based on diets and test solutions. Specifically, SCH23390 potently reduced both sucrose and fructose intake in all groups; however, lower doses were more effective in HFHE rats. In contrast, raclopride was most effective at reducing fructose intake in the obese FCHE rats. Thus, it appears that obesity due to the consumption of combinations of dietary fat and sugar rather than extra calories from dietary fat alone may result in reduced D2 receptor signaling. Furthermore, such deficits seem to preferentially affect the control of fructose intake. These findings demonstrate for the first time a plausible interaction between diet composition and dopamine control of carbohydrate intake in diet-induced obese rats. It also provides additional evidence that sucrose and fructose intake is regulated differentially by the dopamine system.

Topics: Adiposity; Animals; Body Weight; Dietary Fats; Dopamine; Dopamine Antagonists; Eating; Energy Intake; Fructose; Male; Obesity; Raclopride; Rats; Rats, Sprague-Dawley; Sucrose

Dopamine (DA) regulates food intake by modulating food reward and motivation but its involvement in obesity is much less understood. Recent evidence points to the involvement of leptin in the DA-related modulation of food intake. Here we assess DA D2 receptors (D2R) in a genetic rodent obesity model characterized by leptin-receptor deficiency and assess the influence of food restriction on these receptors.. We compared D2R levels between Zucker Obese (fa/fa) and Lean (Fa/Fa) rats at 1 and 4 months of age and in two different feeding conditions (restricted and unrestricted food access) using in-vivo muPET imaging ([11C] raclopride, which is a method sensitive to competition with endogenous DA) and in-vitro ([3H] spiperone washed to ensure no competition with endogenous DA) autoradiography (ARG).. Both ARG and muPET showed that D2R were higher at 1 month than at 4 months of age and that food restricted animals had higher D2R than unrestricted animals. However there were significant differences in the results obtained at 4 months between ARG and muPET. ARG showed that at 1 month and at 4 months unrestricted lean rats (Le U) had significantly higher D2R binding than obese unrestricted rats (Ob U) but showed no differences between restricted obese (Ob R) and restricted lean rats (Le R). It also showed that D2R decline between 1 and 4 months of age was significantly attenuated in food restricted rats [both obese and lean]. In contrast, muPET showed that at 4 months of age, Ob U showed greater D2R availability than Le U rats but like ARG showed no differences between Ob R and Le R rats.. The lower D2R binding in Ob U than Le U rats observed with ARG most likely reflects decreases in striatal D2 receptors levels whereas the increased availability observed with muPET is likely to reflect reduced DA release (resulting in decreased competition with endogenous DA). Lack of a significant difference between Ob R and Le R suggests that the differences in dopamine activity and D2R levels between Ob and Le Zucker rats are modulated by access to food. The ARG finding of an attenuation of the age-related loss of D2R binding corroborates previous studies of the salutary effects of food restriction in the aging process. Because [11C] raclopride is sensitive to competition with endogenous DA, the higher D2R binding in obese rats with raclopride despite the lower D2R levels shown with spiperone could reflect lower extracellular DA in the Ob rats and merits further investigation.

Topics: Age Factors; Animals; Apomorphine; Appetite Regulation; Autoradiography; Brain; Disease Models, Animal; Dopamine; Dopamine Agonists; Eating; Food Deprivation; In Vitro Techniques; Male; Motor Activity; Obesity; Positron-Emission Tomography; Raclopride; Rats; Rats, Zucker; Receptors, Dopamine D2; Receptors, Leptin; Spiperone; Tritium