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Responses to drugs of abuse and non-drug rewards in leptin deficient ob/ob mice

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Abstract

Rationale

Although leptin receptors are found in hypothalamic nuclei classically associated with homeostatic feeding mechanisms, they are also present in brain regions known to regulate hedonic-based feeding, natural reward processing, and responses to drugs of abuse. The ob/ob mouse is deficient in leptin signaling, and previous work has found altered mesolimbic dopamine signaling and sensitivity to the locomotor activating effects of amphetamine in these mice.

Objectives

We directly assessed responses to three drugs of abuse and non-drug rewards in the leptin-deficient ob/ob mouse.

Methods

Ob/ob mice were tested in assays of sweet preference, novelty seeking, and drug reward/reinforcement.

Results

In assays of novelty seeking, novel open field activity and operant sensation seeking were reduced in ob/ob mice, although novel object interaction and novel environment preference were comparable to wild types. We also found that ob/ob mice had specific phenotypes in regard to cocaine: conditioned place preference for 2.5 mg/kg was increased, while the locomotor response to 10 mg/kg was reduced, and cocaine self-administration was the same as wild types. Ob/ob mice also acquired self-administration of the potent opioid remifentanil, but breakpoints for the drug were significantly reduced. Finally, we found significant differences in ethanol drinking in ob/ob mice that correlated negatively with body weight and positively with operant sensation seeking.

Conclusions

In conclusion, ob/ob mice displayed task-specific deficits in novelty seeking and dissociable differences in reward/reinforcement associated with cocaine, remifentanil, and ethanol.

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Acknowledgments

Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under award number K99/R00 DA026994. Research was also supported by the Medical College of Wisconsin Research Affairs Committee and the Research and Education Initiative Fund, a component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. We gratefully acknowledge the NIDA Drug Supply Program for providing cocaine. The authors wish to thank Cassie Arthur for helping with data collection. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Neuroscience Research Center and Department of Pharmacology & Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    Matthew J. Muelbl, Natalie N. Nawarawong, Patrick T. Clancy, Catherine E. Nettesheim, Yi Wei Lim & Christopher M. Olsen

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  1. Matthew J. Muelbl
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  2. Natalie N. Nawarawong
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  3. Patrick T. Clancy
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  4. Catherine E. Nettesheim
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  6. Christopher M. Olsen
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Correspondence to Christopher M. Olsen.

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Figure S1

Fluid intake during ethanol intake tests. Fluid intake of ethanol (A) and total fluid intake (B) during two-bottle choice tests. Bar: median, box: quartiles, whiskers: range. (DOC 65 kb)

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Muelbl, M.J., Nawarawong, N.N., Clancy, P.T. et al. Responses to drugs of abuse and non-drug rewards in leptin deficient ob/ob mice. Psychopharmacology 233, 2799–2811 (2016). https://doi.org/10.1007/s00213-016-4323-9

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  • DOI: https://doi.org/10.1007/s00213-016-4323-9

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