The orexin1 receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats

Jupp, Bianca; Krivdic, Bedrija; Krstew, Elena; Lawrence, Andrew J

doi:10.1016/j.brainres.2011.03.045

Cited by 128 publications

(140 citation statements)

References 30 publications

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“…Recent reports support a role for OX signaling in the neurobehavioral and motivational effects of drugs of abuse (Harris et al, 2005;Borgland et al, 2006;Jupp et al, 2011; for a review, see Bonci and Borgland, 2009;Martin-Fardon et al, 2010). Thus, blockade of OX 1 R decreases ethanol (Lawrence et al, 2006) and nicotine self-administration (Hollander et al, 2008), inhibits cue-induced reinstatement of ethanol- (Lawrence et al, 2006), cocaine- , and morphine-seeking (Harris et al, 2005), and attenuates stress-induced reinstatement of cocaine- (Boutrel et al, 2005) and ethanol-seeking (Richards et al, 2008).…”

Section: Introductionmentioning

confidence: 96%

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Piccoli

Bonaventura

Cifani

et al. 2012

Neuropsychopharmacol

144

102

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Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865, a dual OX 1 /OX 2 R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX 1 R mechanisms in BE, suggesting that selective antagonism at OX 1 R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.

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Section: Introductionmentioning

confidence: 96%

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Piccoli

Bonaventura

Cifani

et al. 2012

Neuropsychopharmacol

144

102

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“…Rats (n = 6) were trained to self-administer sucrose (0.7-2% wt/vol) with an FR3 in a similar manner to alcohol, such that the number of lever presses was matched to alcohol-trained rats (51). Following training, rats underwent surgery for i.c.v.…”

Section: Methodsmentioning

confidence: 99%

Relaxin-3/RXFP3 system regulates alcohol-seeking

Ryan

Kastman

Krstew

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

114

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Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased selfadministration of alcohol in a dose-related manner and attenuated cue-and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/ RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of rewardseeking. addiction | dependenceA lcohol abuse is a major cause of morbidity and mortality worldwide, accounting for an estimated 3.8% of all global deaths and 4.6% of the global burden of disease and injury (1). Excessive alcohol use may also lead to alcohol dependence (also termed "alcohol addiction") (2, 3), which has a lifetime prevalence of ∼12.5% (4). Economic costs due to alcohol abuse were in the order of $235 billion in the United States in 2007, or ∼2.7% of GDP (1, 5). Despite the huge impact of alcohol use disorders on society, current first-line therapeutic agents, such as naltrexone and acamprosate, are far from adequate, with high relapse rates during treatment and problems with compliance (6-8). New therapeutic agents are clearly required, particularly for the reduction of hazardous drinking and prevention of relapse (9). To this end, a major goal in addiction neuroscience is to understand the neurobiology and neurocircuitry affected by alcohol use disorders and to identify factors implicated in these conditions, which may lead to improved and more targeted therapies (7-10). Here we investigate the neuropeptide relaxin-3 for its involvement in rodent models of alcohol-seeking and consumption.Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein-coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11-16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels ...

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“…Thus, a novel and interesting approach for targeting hypocretin for the development of novel antipsychotic medications remains to be elucidated. [10,55]. The tight regulation of the sleep/wake cycle is critical for mental well-being and drugs that acts in this cycle could have a place in psychiatry.…”

Section: Other Psychiatric Disorders Regulated By Hypocretinsmentioning

confidence: 99%

“…The tight regulation of the sleep/wake cycle is critical for mental well-being and drugs that acts in this cycle could have a place in psychiatry. Significant progress has been made in the knowledge of the contribution of the orexin system to mental health; for example, several studies indicate that orexin antagonists, in particular selective OXR1 antagonist, can reduce drug seeking [4,55].…”

Section: Other Psychiatric Disorders Regulated By Hypocretinsmentioning

confidence: 99%

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Neurobiological Role of Hypocretin in Regulation of Psychiatric Disorders

Monteiro

Paes

et al. 2018

Sleep Vigilance

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Hypocretins are hypothalamic neuropeptides acting on the regulation of several physiological functions, the most important being the control of arousal. Hypocretin 1 and hypocretin 2 are derived from the same precursor and both bind to the orexin receptors. The hypocretinergic system has been a target of several studies that try to understand its function on the regulation of mood and behavior. The hypocretinergic system has a direct relationship with the pathways related to emotions and reward system, besides the interaction with the stress circuit. This article aims to analyze the relationship of hypocretins with anxiety, stress and depression, through a review of the existing literature.

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The orexin1 receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats

Cited by 128 publications

References 30 publications

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Relaxin-3/RXFP3 system regulates alcohol-seeking

Neurobiological Role of Hypocretin in Regulation of Psychiatric Disorders

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