GLP-1 analog attenuates cocaine reward

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Molecular Psychiatry (Impact Factor: 14.5). 10/2012; 18(9). DOI: 10.1038/mp.2012.141
Source: PubMed


Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment

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    • "The present data add to the growing evidence that physiological state variables, including stress (Heilig and Koob, 2007) and feeding-related hormonal signals (Aston-Jones et al, 2010; Carroll et al, 1979; Dickson et al, 2011; Graham et al, 2013), can influence the motivation for drug-seeking in drug-experienced individuals. They are consistent with the emerging view that the compulsive overeating of sweet and high-fat foods is under the influence of some of the same mechanisms as are involved in addiction (Kenny, 2011; Volkow and Wise, 2005; Wise, 1988; Wise, 2001). "
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    ABSTRACT: Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats: First, we report that cocaine and the expectancy of cocaine each depress plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates (i) the ability of cocaine to elevate dopamine levels in nucleus accumbens (ii) the ability of cocaine to establish a conditioned place preference, and (iii) the ability of cocaine-predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus while leptin represents an endogenous antagonist of the habit-forming and habit-sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine.Neuropsychopharmacology accepted article preview online, 05 August 2015. doi:10.1038/npp.2015.230.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2015; DOI:10.1038/npp.2015.230 · 7.05 Impact Factor
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    • "In addition to alcohol, GLP-1 receptors appear to be important for reward induced by addictive drugs. Indeed, exendin-4 attenuates amphetamine-induced locomotor stimulation and cocaine-induced conditioned place preference in rodents [115, 116]. In support are the recent data showing that exendin-4, attenuates the reinforcing properties of cocaine as well as amphetamine as measured by locomotor stimulation, accumbal dopamine release and conditioned place preference in mice [117]. "
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    ABSTRACT: Food intake and appetite are regulated by various circulating hormones including ghrelin and glucagon-like-peptide 1 (GLP-1). Ghrelin, mainly released from the stomach, increases food intake, induces appetite, enhances adiposity as well as releases growth hormone. Hypothalamic "ghrelin receptors" (GHS-R1A) have a critical role in food intake regulation, but GHS-R1A are also expressed in reward related areas. GLP-1 is produced in the intestinal mucosa as well as in the hindbrain in response to nutrient ingestion. This gut-brain hormone reduces food intake as well as regulates glucose homeostasis, foremost via GLP-1 receptors in hypothalamus and brain stem. However, GLP-1 receptors are expressed in areas intimately associated with reward regulation. Given that regulation of food and drug intake share common neurobiological substrates, the possibility that ghrelin and GLP-1 play an important role in reward regulation should be considered. Indeed, this leading article describes that the orexigenic peptide ghrelin activates the cholinergic-dopaminergic reward link, an important part of the reward systems in the brain associated with reinforcement and thereby increases the incentive salience for motivated behaviors via this system. We also review the role of ghrelin signaling for reward induced by alcohol and addictive drugs from a preclinical, clinical and human genetic perspective. In addition, the recent findings showing that GLP-1 controls reward induced by alcohol, amphetamine, cocaine and nicotine in rodents are overviewed herein. Finally, the role of several other appetite regulatory hormones for reward and addiction is briefly discussed. Collectively, these data suggest that ghrelin and GLP-1 receptors may be novel targets for development of pharmacological treatments of alcohol and drug dependence.
    CNS Drugs 06/2014; 28(10). DOI:10.1007/s40263-014-0178-y · 5.11 Impact Factor
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    • "Albeit previous studies have shown that Ex4, at a dose range similar to what was used in the present study, induces a condition taste aversion [47] the possibility that our results are due to aversion rather than reduced reward appears however less likely. Thus, repeated Ex4 treatment does not induce a conditioned place aversion in rodents [18,42], indicating that the Ex4 dose used is not aversive or induces nausea [48]. Moreover, Ex4 targets reward related parameters such as locomotor stimulation, accumbal dopamine release, CPP and locomotor sensitization not only for nicotine as shown in the present study, but also for alcohol, amphetamine and cocaine as shown elsewhere [18,19,41,42]. "
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    ABSTRACT: The gastrointestinal peptide glucagon-like peptide 1 (GLP-1) is known to regulate consummatory behavior and is released in response to nutrient ingestion. Analogues of this peptide recently emerged as novel pharmacotherapies for treatment of type II diabetes since they reduce gastric emptying, glucagon secretion as well as enhance glucose-dependent insulin secretion. The findings that GLP-1 targets reward related areas including mesolimbic dopamine areas indicate that the physiological role of GLP-1 extends beyond food intake and glucose homeostasis control to include reward regulation. The present series of experiments was therefore designed to investigate the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on established nicotine-induced effects on the mesolimbic dopamine system in mice. Specifically, we show that treatment with Ex4, at a dose with no effect per se, attenuate nicotine-induced locomotor stimulation, accumbal dopamine release as well as the expression of conditioned place preference in mice. In accordance, Ex4 also blocks nicotine-induced expression of locomotor sensitization in mice. Given that development of nicotine addiction largely depends on the effects of nicotine on the mesolimbic dopamine system these findings indicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for nicotine cessations in humans.
    PLoS ONE 10/2013; 8(10):e77284. DOI:10.1371/journal.pone.0077284 · 3.23 Impact Factor
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