Abstract
Rational
Caloric restriction increases the risk of relapse in abstinent drug users. Hormones involved in the regulation of energy balance and food intake, such as leptin and ghrelin, are implicated in drug-related behaviors.
Objectives
We investigated the role of leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction.
Methods
Rats self-administered heroin (0.1 mg/kg/infusion) for 10 days followed by 14 days of drug withdrawal. During withdrawal, rats were food restricted to 90% of their original body weight or were given free access to food. In experiment 1, we measured the plasma concentrations of leptin and ghrelin following heroin self-administration and withdrawal. In experiment 2, leptin was administered centrally (2.0 or 4.0 μg; i.c.v.) prior to a heroin-seeking test under extinction conditions. High density of both leptin and ghrelin receptors was previously identified in the ventral tegmental area (VTA), suggesting a direct effect on reward and motivation. Hence, we administered leptin (experiment 3; 0.125 or 0.250 μg/side), or ghrelin receptor antagonist JMV 2959 (experiment 4; 2.0 or 10.0 μg/side) directly into the VTA prior to the heroin-seeking test.
Results
Chronic food restriction significantly decreased plasma levels of leptin and elevated plasma levels of ghrelin. Central administration of leptin had no statistically significant effect on heroin seeking. Intra-VTA administration of either leptin or JMV 2959 dose-dependently and selectively decreased heroin seeking in the food-restricted rats.
Conclusions
Leptin and ghrelin transmission in the VTA can modulate the augmentation of heroin seeking induced by chronic food restriction.
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Acknowledgments
The authors wish to thank Melissa Russo, Soraya le Noble, Damaris Rizzo, and Emilie Daoud for invaluable technical assistance throughout this project.
Funding
This work was supported by the Natural Sciences & Engineering Council Discovery Program (US: 298915), the Fonds de recherche du Quebec - Santé (CSBN), the Canada Research Chairs program (US), and a CIHR grant and FRQS research scholar award to SF.
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D’Cunha, T.M., Chisholm, A., Hryhorczuk, C. et al. A role for leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction. Psychopharmacology 237, 787–800 (2020). https://doi.org/10.1007/s00213-019-05415-9
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DOI: https://doi.org/10.1007/s00213-019-05415-9