CRF system recruitment mediates dark side of compulsive eating

Cottone, Pietro; Sabino, Valentina; Roberto, Marisa; Bajo, Michal; Pockros, Lara; Frihauf, J.B.; Fekete, Éva; Steardo, Luca; Rice, Kenner C.; Grigoriadis, Dimitri E.; Conti, Bruno; Koob, George F.; Zorrilla, Eric P.

doi:10.1073/pnas.0908789106

Cited by 170 publications

(210 citation statements)

References 27 publications

Supporting

Mentioning

179

Contrasting

Unclassified

Order By: Relevance

“…The FWS used herein might exacerbate the stressful experience of opiate withdrawal in wild-type mice, thus increasing behavior aimed at obtaining palatable food in the attempt to alleviate a severe stress-like state. Accordingly, rats or mice withdrawn from palatable food diets display a stress-like state, including hypophagia, anhedonia, increased anxiety-like, and hypothalamus-pituitary-adrenal (HPA) axis responses to stressors, that can be attenuated by the CRF 1 receptor-preferring antagonist R121919 (Cottone et al, 2009;Sharma et al, 2013). Although other interpretations could be provided, several factors suggest that the stress-induced nonrewarded operant behavior observed herein in the long-term opiate-withdrawn wildtype mice reflects up-shifted motivational states.…”

Section: Summary Of the Resultsmentioning

confidence: 99%

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Morisot

Rouibi

Contarino

2015

Neuropsychopharmacol

View full text Add to dashboard Cite

Vulnerability to stressful life events is a hallmark of drug dependence that may persist long after cessation of drug intake and dramatically fuel key clinical features, such as deregulated up-shifted motivational states and craving. However, to date, no effective therapy is available for reducing vulnerability to stressful events in former drug users and drug-dependent patients, mostly because of poor knowledge of the mechanisms underlying it. In this study, we report that genetic inactivation of the stress-responsive corticotropin-releasing factor receptor-2 (CRF 2 − / − ) completely eliminates the reemergence of increased nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by ethological environmental stressors long after cessation of morphine administration in mice. Accordingly, CRF 2 receptor deficiency completely abolishes the increase in biomarkers of synthesis of major brain motivational substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala γ-aminobutyric acid (GABA) systems, associated with the stress-induced reemergence of upshifted motivational states long after opiate withdrawal. Nevertheless, neither CRF 2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF 2 receptor deficiency does not influence the locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the present results reveal an essential and specific role for the CRF 2 receptor in the stress-induced reemergence of up-shifted motivational states and related alterations in brain motivational systems long after opiate withdrawal. These findings suggest new strategies for the treatment of the severe and longlasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.

show abstract

Section: Summary Of the Resultsmentioning

confidence: 99%

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Morisot

Rouibi

Contarino

2015

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Ingestion of highly palatable food reduces the activity of the central stress response network, including CRH expression in the CeA, attenuates autonomic outflow and therefore represents a "self-treating" mechanism with which to reduce adverse effects of chronic stress (Dallman et al 2005). Further on, withdrawal from palatable food recruits anti-reward CRH -CRH1R in the extended amygdala that may be responsible for compulsive behavior and binge eating (Cottone et al 2009).…”

Section: The Integrated Stress Response-view From Crhmentioning

confidence: 99%

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

Kovács

2013

Journal of Chemical Neuroanatomy

105

View full text Add to dashboard Cite

Two major and mutually interconnected brain systems are recruited during stress reaction. One is the hypothalamic paraventricular nucleus (PVH) and the second is the extended amygdala. PVH governs the neuroendocrine stress response while CeA regulates most of the autonomic and behavioral stress reactions. The common neurohormonal mediator of these responses is the corticotropin-releasing hormone, CRH, which is expressed in both centers. CRH belongs to a larger family of neuropeptides that also includes urocortins 1, 2, and 3 all have different affinity towards the two types of CRHR receptors and have been implicated in regulation of stress and HPA axis activity. One functionally relevant aspect of CRH systems is their differential regulation by glucocorticoids. While corticosterone inhibits CRH transcription in the PVH, stress-induced glucocorticoids stimulate CRH expression in the extended amygdala. This review summarizes past and recent findings related to CRH gene regulation and its involvement in the neuroendocrine, autonomic and behavioral stress reaction.Key words: Corticotropin-releasing hormone, paraventricular nucleus, central amygdala, bed nucleus of stria terminalis, corticosterone, cAMP-response element.

show abstract

“…Ad libitum diet alternation was performed as previously described (Cottone et al, 2009a;Cottone et al, 2008Cottone et al, , 2009bIemolo et al, 2012; see scheme in Figure 1a). After acclimation, rats were divided into two groups matched for food intake, body weight and feed efficiency from the previous 4 days.…”

Section: Ad Libitum Diet Alternationmentioning

confidence: 99%

“…Rimonabant was administered immediately after the basal blood collection. Plasma levels of corticosterone-like immunoreactivity levels were quantified as previously described (Cottone et al, 2009a).…”

Section: Plasma Corticosterone Riamentioning

confidence: 99%

“…Here, we provide evidence that rimonabant may precipitate a withdrawal-like state in patients with obesity or eating disorders, analogous to the withdrawal-like state that receptor antagonists of a drug of abuse can precipitate in drug-dependent subjects. Eating disorders and obesity, similarly to drug addiction, can be conceptualized as chronic relapsing conditions with alternating periods of abstinence (eg, dieting) and relapse (compulsive overeating of palatable foods; Corwin and Grigson, 2009;Cottone et al, 2009a;Epstein and Shaham, 2010;Johnson and Kenny, 2010;Parylak et al, 2011). Chronic, intermittent drug use can result in affective dependence over repeated cycles of abuse and abstinence, culminating with the emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) when drug use ceases or is prevented ('withdrawal'; Koob and Volkow, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

Blasio

Iemolo

Sabino

et al. 2013

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB 1 ) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB 1 receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB 1 receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB 1 receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB 1 receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.

show abstract

CRF system recruitment mediates dark side of compulsive eating

Cited by 170 publications

References 27 publications

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

Contact Info

Product

Resources

About