title: D1 and D2 antagonists reverse the effects of appetite suppressants on weight loss, food intake, locomotion, and rebalance spiking inhibition in the rat NAc shell.
abstract: 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.
authors.affiliation: Laboratory of Neurobiology of Appetite, Department of Pharmacology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico;
authors.forename: B
authors.initials: B
authors.lastname: Kalyanasundar
authors.affiliation: Laboratory of Neurobiology of Appetite, Department of Pharmacology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico;
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Perez
authors.affiliation: Laboratory of Neurobiology of Appetite, Department of Pharmacology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico; Department of Bioelectronics, CINVESTAV, Mexico City, Mexico;
authors.forename: Alvaro
authors.initials: A
authors.lastname: Luna
authors.affiliation: Laboratory of Neurobiology of Appetite, Department of Pharmacology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico;
authors.forename: Jessica
authors.initials: J
authors.lastname: Solorio
authors.affiliation: Laboratory of Neurobiology of Appetite, Department of Pharmacology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico;
authors.forename: Mario G
authors.initials: MG
authors.lastname: Moreno
authors.affiliation: Department of Bioelectronics, CINVESTAV, Mexico City, Mexico;
authors.forename: David
authors.initials: D
authors.lastname: Elias
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Sidney A
authors.initials: SA
authors.lastname: Simon
authors.affiliation: Laboratory of Neurobiology of Appetite, Department of Pharmacology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico; ranier@cinvestav.mx.
authors.forename: Ranier
authors.initials: R
authors.lastname: Gutierrez
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D016642:Bupropion / Q000009:adverse effects / Q000494:pharmacology; D004053:Diethylpropion / Q000009:adverse effects / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology*; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects / Q000502:physiology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D010645:Phentermine / Q000009:adverse effects / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
chemical_list: D001067:Appetite Depressants; D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C534628:SCH 23390; D016642:Bupropion; D020891:Raclopride; D010645:Phentermine; D004053:Diethylpropion
keywords: amphetamine; anorexigenic; appetite; dopamine; nucleus accumbens