Novel Highly Potent and Selective Sigma1 Receptor Antagonists Effectively Block the Binge Eating Episode in Female Rats

Cifani, Carlo; Bonaventura, Emanuela Micioni Di; Botticelli, Luca; Bello, Fabio Del; Giorgioni, Gianfabio; Pavletić, Pegi; Piergentili, Alessandro; Quaglia, Wilma; Bonifazi, Alessandro; Schepmann, Dirk; Wünsch, Bernhard; Vistoli, Giulio; Bonaventura, Maria Vittoria Micioni Di

doi:10.1021/acschemneuro.0c00456

Cited by 14 publications

(13 citation statements)

References 57 publications

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“…On day 68, 24 h after the last administration of PF‐3845, animals were subjected to elevated plus maze (EPM) paradigm, as described in previous studies (Filaferro et al, 2014; Rodi et al, 2008) and the day after (first day without treatment) animals underwent open field test (OFT), as described in Cifani, Micioni Di Bonaventura, et al (2020), Micioni Di Bonaventura et al (2012, 2020). Detailed descriptions of the behavioral tests can be found in Supporting Information Material S1.2.…”

Section: Methodsmentioning

confidence: 99%

Anxiety associated with palatable food withdrawal is reversed by the selective FAAH inhibitor PF‐3845: A regional analysis of the contribution of endocannabinoid signaling machinery

Ceglia

Bonaventura

Romano

et al. 2023

Intl J Eating Disorders

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Objective Consumption of energy‐dense palatable “comfort” food can alleviate stress and negative emotions, while abrupt withdrawal from a palatable diet can worsen these symptoms, causing difficulties with adherence to weight‐loss diets. Currently, no pharmacological treatment is effective for obesity‐related anxiety, so we investigated the endocannabinoid system (ECS), and specifically the fatty acid amide hydrolase (FAAH), as an interesting emerging target in this context because of its key role in the regulation of both energy homeostasis and emotional behavior. Methods Rats were subjected to exposure and subsequent abstinence from a palatable cafeteria diet. During abstinence period, rats were treated with the selective FAAH inhibitor PF‐3845 (10 mg/kg; intraperitoneal administration every other day). Results Abstinent rats displayed an anxiogenic‐like behavior and changes in the proteins of ECS signaling machinery in brain areas involved both in anxiety and food intake regulation. In particular, withdrawal caused a reduction of the expression of cannabinoid receptors in the nucleus accumbens and of enzymes diacylglycerol lipase alpha and monoacylglycerol lipase (MAGL) in the amygdala. Pharmacological inhibition of FAAH exerted an anxiolytic‐like effect in abstinent animals and increased both MAGL expression in amygdala and CB2 expression in prefrontal cortex. Discussion Overall, our results suggest that emotional disturbances associated with dieting are coupled with region‐specific alterations in the cerebral expression of the ECS and that the enhancement of the endocannabinoid signaling by FAAH inhibition might represent a novel pharmacological strategy for the treatment of anxiety related to abstinence from palatable food. Public Significance The present study focused on evaluating the role of the endocannabinoid system in modulating withdrawal from naturally rewarding activities that have an impact on mood, such as feeding. The variations observed in the emotional behavior of abstinent rats was linked to neuroadaptations of the ECS in specific brain areas.

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Section: Methodsmentioning

confidence: 99%

Anxiety associated with palatable food withdrawal is reversed by the selective FAAH inhibitor PF‐3845: A regional analysis of the contribution of endocannabinoid signaling machinery

Ceglia

Bonaventura

Romano

et al. 2023

Intl J Eating Disorders

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“…A detailed description of the BE model is reported in Supplementary Materials . In accordance with the higher prevalence of eating disorders among young adolescents and adult women rather than men, female rats were used [ 6 , 79 ], as in previously published works [ 80 , 81 , 82 ].…”

Section: Methodsmentioning

confidence: 99%

Endocannabinoid System Regulation in Female Rats with Recurrent Episodes of Binge Eating

Pucci

Bonaventura

Mercante

et al. 2022

IJMS

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Recurrent Binge Eating (BE) episodes characterize several eating disorders. Here, we attempted to reassemble a condition closer to BE disorder, and we analyzed whether recurrent episodes might evoke molecular alterations in the hypothalamus of rats. The hypothalamus is a brain region which is sensitive to stress and relevant in motivated behaviors, such as food intake. A well-characterized animal model of BE, in which a history of intermittent food restriction and stress induce binge-like palatable food consumption, was used to analyze the transcriptional regulation of the endocannabinoid system (ECS). We detected, in rats showing the BE behavior, an up-regulated gene expression of cannabinoid type-1 receptor (CB1), sn-1-specific diacylglycerol lipase, as well as fatty acid amide hydrolase (Faah) and monoacylglycerol lipase. A selective reduction in DNA methylation was also observed at the promoter of Faah, which is consistent with the changes in the gene expression. Moreover, BE behavior in rats was associated with an increase in anandamide (AEA) levels. Our findings support the relevant role of the ECS in the regulation of food intake in rats subjected to repeated BE episodes, and, in particular, on AEA signaling, acting via CB1 and FAAH modulation. Notably, the epigenetic regulation of the Faah gene might suggest this enzyme as a possible target for developing new therapeutical approaches.

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“…With no BED phenotype, the result demonstrates only an effect to decrease hyperphagia, not efficacy against the psychopathology of BED. Cifani et al (2020) have recently reported that sigma-1 antagonists show potential as drugs to treat BED. This result requires further replication because the fasting/stress BED model is claimed to have predictive validity partly based on the differential actions of sibutramine and topiramate (Cifani et al, 2009).…”

Section: Research Directions Into New Drugs To Treat Binge-eating Dis...mentioning

confidence: 99%

Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology

Heal¹,

Smith²

2021

J Psychopharmacol

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Background: Binge-eating disorder (BED) is a common psychiatric condition with adverse psychological and metabolic consequences. Lisdexamfetamine (LDX) is the only approved BED drug treatment. New drugs to treat BED are urgently needed. Methods: A comprehensive review of published psychopathological, pharmacological and clinical findings. Results: The evidence supports the hypothesis that BED is an impulse control disorder with similarities to ADHD, including responsiveness to catecholaminergic drugs, for example LDX and dasotraline. The target product profile (TPP) of the ideal BED drug combines treating the psychopathological drivers of the disorder with an independent weight-loss effect. Drugs with proven efficacy in BED have a common pharmacology; they potentiate central noradrenergic and dopaminergic neurotransmission. Because of the overlap between pharmacotherapy in attention deficit hyperactivity disorder (ADHD) and BED, drug-candidates from diverse pharmacological classes, which have already failed in ADHD would also be predicted to fail if tested in BED. The failure in BED trials of drugs with diverse pharmacological mechanisms indicates many possible avenues for drug discovery can probably be discounted. Conclusions: (1) The efficacy of drugs for BED is dependent on reducing its core psychopathologies of impulsivity, compulsivity and perseveration and by increasing cognitive control of eating. (2) The analysis revealed a large number of pharmacological mechanisms are unlikely to be productive in the search for effective new BED drugs. (3) The most promising areas for new treatments for BED are drugs, which augment noradrenergic and dopaminergic neurotransmission and/or those which are effective in ADHD.

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Novel Highly Potent and Selective Sigma1 Receptor Antagonists Effectively Block the Binge Eating Episode in Female Rats

Cited by 14 publications

References 57 publications

Anxiety associated with palatable food withdrawal is reversed by the selective FAAH inhibitor PF‐3845: A regional analysis of the contribution of endocannabinoid signaling machinery

Anxiety associated with palatable food withdrawal is reversed by the selective FAAH inhibitor PF‐3845: A regional analysis of the contribution of endocannabinoid signaling machinery

Endocannabinoid System Regulation in Female Rats with Recurrent Episodes of Binge Eating

Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology

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