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

R. 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. J Neurophysiol 114: 585-607, 2015. First published May 13, 2015 doi:10.1152/jn.00012.2015.-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 shortterm 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.

Anorectic efficacy and safety of the diethylpropion‐topiramate combination in rats

“…In this study, diethylpropion showed mild piloerection and hyperactivity between 10 and 30 mg/kg, meanwhile topiramate induced mild sedation between 300 and 560 mg/kg. The observed safety profiles agree with previous studies where diethylpropion induces motor stimulation (Kalyanasundar et al, ; Safta et al, ; Samanin & Garattini, ) and topiramate decreases anxiety (Abo‐Elmatty & Zaitone, ) are the main side effects in rat. Oral co‐administration of diethylpropion + topiramate only induced mild piloerection and hyperactivity at the highest tested dose at 1:1 and 3:1, but not 1:3, dose ratios, respectively.…”

“…The ED 30 value of diethylpropion in 12 hr‐food deprived rats was slightly lower, but not significant, than the ED 30 value in of nondeprived rats. Kalyanasundar et al () reported that diethylpropion produces a greater weight loss, with less tolerance and\rebound weight gain when is administered in conjunction with high fat dietary restriction and during the active phase of the day a phenomenon that id related to dopaminergic systems (Kalyanasundar et al, ).…”

“…The anorectic synergy may be explained through complementary mechanisms of both drugs. Diethylpropion increases norepinephrine and dopamine in the CNS (Bendotti et al, ; Borsini et al, ; Kalyanasundar et al, ; Samanin & Garattini, ; Samanin et al, ), which in turn activate adrenergic and dopaminergic receptors to induce anorexia (Bendotti et al, ; Kalyanasundar et al, ). Siethylpropion can also stimulate peripheral thermogenesis that may contribute to weight reduction (Lang et al, ).…”

“…Diethylpropion, like phentermine, is an effective amphetaminelike analog that reduces food intake preclinically (Bendotti, Villa, & Samanin, 1986;Wallach, Dawber, McMahon, & Rogers, 1977) and produces weight loss in humans (Cercato et al, 2009;Morín Zaragoza, Lonngi Villanueva, Ponce López, Alcaraz Ortíz, & Barragán Díaz, 2007;Soto-Molina et al, 2015;Suplicy et al, 2014). Diethylpropion exerts its anorectic effect by enhancing catecholamine release and inhibiting re-uptake (Bendotti et al, 1986;Borsini, Bendotti, Carli, Poggesi, & Samanin, 1979;Kalyanasundar et al, 2015;Samanin, Bernasconi, & Garattini, 1975;Samanin & Garattini, 1993). In addition, diethylpropion produces a peripheral thermogenic effect that contributes to weight loss in animals and humans (Lang, Danforth, & Lien, 1983).…”

“…In addition, diethylpropion produces a peripheral thermogenic effect that contributes to weight loss in animals and humans (Lang, Danforth, & Lien, 1983). Hypermotility, stereotyped movements and insomnia are the main adverse effects of diethylpropion in rats (Kalyanasundar et al, 2015;Lang et al, 1983;Safta, Cuparencu, Sirbu, & Secareanu, 1976), while dry mouth and constipation are the main adverse events in humans (Morín Zaragoza et al, 2007;Soto-Molina et al, 2015).…”