raclopride and Weight-Loss

Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds.

Topics: Action Potentials; Animals; Appetite Depressants; Benzazepines; Bupropion; Diethylpropion; Dopamine D2 Receptor Antagonists; Drug Interactions; Eating; Locomotion; Male; Nucleus Accumbens; Phentermine; Raclopride; Random Allocation; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Sleep Initiation and Maintenance Disorders; Stereotyped Behavior; Weight Loss

While bariatric surgery has proved highly successful at producing sustained weight loss, variability in treatment response persists. A better understanding of the pathophysiology of appetite and obesity may improve patient selection and management. Research into feeding behavior and satiety has focused on the role of dopamine in reward-based behaviors. Specifically, positron-emission computed tomography (PET) has demonstrated reduced brain dopamine receptor availability in obese subjects compared to controls. This may be due to a primary deficiency in dopamine receptors or to secondary dopamine receptor downregulation. We performed a preliminary study to investigate dopamine D2 receptor activity in obese subjects before and after laparoscopic Roux-en Y gastric bypass (LGBP).. Five female subjects, ages 20 to 38 years old with a mean body mass index of 45, underwent PET with [C-11] raclopride injection. Five regions of interest were studied: ventral striatum, anterior and posterior putamen, and anterior and posterior caudate nucleus. Repeat PET was performed at 6 weeks following LGBP. D2 receptor binding was compared within subjects pre- and post-surgery. Baseline D2 binding was also compared to historical nonobese controls.. D2 receptor availability increased 6 weeks after gastric bypass surgery. The increase in receptor availability appeared roughly proportional to the amount of weight lost. No significant difference in D2 binding was seen between the obese subjects and historical nonobese controls.. Brain available dopamine D2 binding appears to increase following GBP. This preliminary finding needs to be replicated in a larger population but suggests that diminished D2 binding in the obese may be due to D2 receptor downregulation. Changes in available dopamine receptor binding may play an important role in centrally mediated appetite suppression and resultant weight loss after LGBP.

Topics: Adult; Appetite Regulation; Basal Ganglia; Brain; Carbon Radioisotopes; Caudate Nucleus; Down-Regulation; Female; Gastric Bypass; Humans; Obesity, Morbid; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Weight Loss; Young Adult

Much evidence supports the hypothesis that A2A adenosine receptors play an important role in the expression of morphine withdrawal and that the dopaminergic system might also be involved. We have evaluated morphine withdrawal signs in wild-type and A2A receptor knockout mice and shown a significant enhancement in some withdrawal signs in the knockout mice. In addition, micro -opioid and dopamine D2 receptor autoradiography, as well as micro -opioid receptor-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]GTPgammaS) autoradiography was carried out in brain sections of withdrawn wild-type and knockout mice. No significant changes in D2 and micro -opioid receptor binding were observed in any of the brain regions analysed. However, a significant increase in the level of micro receptor-stimulated [35S]GTPgammaS binding was observed in the nucleus accumbens of withdrawn knockout mice. These data indicate that the A2A receptor plays a role in opioid withdrawal related to functional receptor activation.

Topics: Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Binding Sites; Brain; Densitometry; Diarrhea; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Knockout; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Raclopride; Receptor, Adenosine A2A; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Sulfur Isotopes; Tremor; Tritium; Urine; Weight Loss