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Diet-induced obesity and diet-resistant rats: differences in the rewarding and anorectic effects of d-amphetamine

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Abstract

Rationale

Obesity is a leading public health problem worldwide. Multiple lines of evidence associate deficits in the brain reward circuit with obesity.

Objective

Whether alterations in brain reward sensitivity precede or are a consequence of obesity is unknown. This study aimed to investigate both innate and obesity-induced differences in the sensitivity to the effects of an indirect dopaminergic agonist.

Methods

Rats genetically prone to diet-induced obesity (DIO) and their counterpart diet-resistant (DR) were fed a chow diet, and their response to d-amphetamine on intracranial self-stimulation and food intake were assessed. The same variables were then evaluated after exposing the rats to a high-fat diet, after DIO rats selectively developed obesity. Finally, gene expression levels of dopamine receptors 1 and 2 as well as tyrosine hydroxylase were measured in reward-related brain regions.

Results

In a pre-obesity state, DIO rats showed innate decreased sensitivity to the reward-enhancing and anorectic effects of d-amphetamine, as compared to DR rats. In a diet-induced obese state, the insensitivity to the potentiating effects of d-amphetamine on intracranial self-stimulation (ICSS) threshold persisted and became more marked in DIO rats, while the anorectic effects were comparable between genotypes. Finally, innate and obesity-induced differences in the gene expression of dopamine receptors were observed.

Conclusions

Our results demonstrate that brain reward deficits antedate the development of obesity and worsen after obesity is fully developed, suggesting that these alterations represent vulnerability factors for its development. Moreover, our data suggests that the reward-enhancing and anorectic effects of d-amphetamine are dissociable in the context of obesity.

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Acknowledgments

We thank Aditi R. Narayan, Jina Kwak, and Aditya Khedkar for technical assistance, and Andrew Kim, Jeffrey Santos, and Angela Tung for editorial assistance. This publication was made possible by grant numbers DA030425, MH091945, and MH093650A1 from the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH), and by the Peter Paul Career Development Professorship (P.C.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. We gratefully acknowledge Dr. Timothy R. Nagy, Maria S. Johnson, and the UAB Small Animal Phenotyping Core for performing the rat carcass analysis, which was founded by grant numbers P30DK056336 (NORC) and P60DK079626 (DRTC).

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The authors declare that they have no competing interests.

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    Authors and Affiliations

    1. Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, 72 E Concord St, R-612 or R-618, Boston, MA, 02118, USA

      Marta Valenza, Pietro Cottone & Valentina Sabino

    2. Section of Pharmacology, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy

      Marta Valenza

    3. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

      Luca Steardo

    4. Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA

      Marta Valenza

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    1. Marta Valenza
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    Correspondence to Pietro Cottone or Valentina Sabino.

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    Pietro Cottone and Valentina Sabino contributed equally to this work.

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    Valenza, M., Steardo, L., Cottone, P. et al. Diet-induced obesity and diet-resistant rats: differences in the rewarding and anorectic effects of d-amphetamine. Psychopharmacology 232, 3215–3226 (2015). https://doi.org/10.1007/s00213-015-3981-3

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