Abstract
Binge eating disorder (BED) is the most frequent eating disorder, for which current pharmacotherapies show poor response rates and safety concerns, thus highlighting the need for novel treatment options. The lipid-derived messenger oleoylethanolamide (OEA) acts as a satiety signal inhibiting food intake through the involvement of central noradrenergic and oxytocinergic neurons. We investigated the anti-binge effects of OEA in a rat model of binge-like eating, in which, after cycles of intermittent food restrictions/refeeding and palatable food consumptions, female rats show a binge-like intake of palatable food, following a 15-min exposure to their sight and smell (“frustration stress”). Systemically administered OEA dose-dependently (2.5, 5, and 10 mg kg−1) prevented binge-like eating. This behavioral effect was associated with a decreased activation (measured by mapping the expression of c-fos, an early gene widely used as a marker of cellular activation) of brain areas responding to stress (such as the nucleus accumbens and amygdala) and to a stimulation of areas involved in the control of food intake, such as the VTA and the PVN. These effects were paralleled, also, to the modulation of monoamine transmission in key brain areas involved in both homeostatic and hedonic control of eating. In particular, a decreased dopaminergic response to stress was observed by measuring dopamine extracellular concentrations in microdialysates from the nucleus accumbens shell, whereas an increased serotonergic and noradrenergic tone was detected in tissue homogenates of selected brain areas. Finally, a decrease in corticotropin-releasing factor (CRF) mRNA levels was induced by OEA in the central amygdala, while an increase in oxytocin mRNA levels was induced in the PVN. The restoration of a normal oxytocin receptor density in the striatum paralleled the oxytocinergic stimulation produced by OEA. In conclusion, we provide evidence suggesting that OEA might represent a novel potential pharmacological target for the treatment of binge-like eating behavior.
Highlights
Binge eating disorder (BED) is the most frequent eating disorder occurring in 2–5% of the adult population, with a higher prevalence among women than men [1,2,3]
OEA treatment selectively prevented binge-like eating in a dosedependent manner We found that acute treatment with OEA, systemically administered to rats 1 h before giving access to highly palatable food (HPF) (Fig. 1b, EXP. 1), selectively prevented binge-like eating of R + S rats (Fig. 1c), without altering feeding behavior in the other experimental groups (Fig. 1d–f)
OEA treatment affected corticotropin-releasing factor (CRF) and oxytocin mRNA levels in bingeing rats We previously demonstrated a crucial role of oxytocinergic neurotransmission in mediating the hypophagic effect of OEA [29], as well as the pivotal role played by CRF system in sustaining binge eating behavior in the experimental model used in the present study [47]
Summary
Binge eating disorder (BED) is the most frequent eating disorder occurring in 2–5% of the adult population, with a higher prevalence among women than men [1,2,3]. A large body of evidence suggests that the neurobiological mechanisms of BED converge on the activation of the mesocorticolimbic dopamine (DA) system [7, 8], as well as on brain serotonin (5-HT) and noradrenaline (NA) signaling [9,10,11,12]. Lisdexamfetamine, a prodrug of d-amphetamine, is the first medication approved for BED treatment in the United States that acts primarily by enhancing brain dopaminergic and noradrenergic neurotransmission [13]. Other treatments tested for BED lack sufficient efficacy, and are complicated by high relapse rates and a wide range of side effects [17, 18]
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