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Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet-induced obesity

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Abstract

Rationale

Basal and diet-induced differences in mesolimbic function, particularly within the nucleus accumbens (NAc), may contribute to human obesity; these differences may be more pronounced in susceptible populations.

Objectives

We examined differences in cocaine-induced behavioral plasticity in rats that are susceptible vs. resistant to diet-induced obesity and basal differences in striatal neuron function in adult and in adolescent obesity-prone and obesity-resistant rats.

Methods

Susceptible and resistant outbred rats were identified based on “junk-food” diet-induced obesity. Then, the induction and expression of cocaine-induced locomotor sensitization, which is mediated by enhanced striatal function and is associated with increased motivation for rewards and reward-paired cues, were evaluated. Basal differences in mesolimbic function were examined in selectively bred obesity-prone and obesity-resistant rats (P70–80 and P30–40) using both cocaine-induced locomotion and whole-cell patch clamping approaches in NAc core medium spiny neurons (MSNs).

Results

In rats that became obese after eating junk-food, the expression of locomotor sensitization was enhanced compared to non-obese rats, with similarly strong responses to 7.5 and 15 mg/kg cocaine. Without diet manipulation, obesity-prone rats were hyper-responsive to the acute locomotor-activating effects of cocaine, and the intrinsic excitability of NAc core MSNs was enhanced by ∼60 % at positive and negative potentials. These differences were present in adult, but not adolescent rats. Post-synaptic glutamatergic transmission was similar between groups.

Conclusions

Mesolimbic systems, particularly NAc MSNs, are hyper-responsive in obesity-prone individuals, and interactions between predisposition and experience influence neurobehavioral plasticity in ways that may promote weight gain and hamper weight loss in susceptible rats.

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Acknowledgments

Technical assistance was provided by Cameron W. Nobile, and helpful comments during the preparation of this manuscript were provided by Drs. Peggy Gnegy and Paul Meyer.

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  1. Department of Pharmacology, University of Michigan, 1150 W. Medical Center Drive, MSRB III 1301, Ann Arbor, MI, 48109, USA

    Max F. Oginsky, Joel D. Maust, John T. Corthell & Carrie R. Ferrario

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  1. Max F. Oginsky
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  2. Joel D. Maust
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  3. John T. Corthell
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  4. Carrie R. Ferrario
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Correspondence to Carrie R. Ferrario.

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Funding and disclosures

Cocaine was provided by the NIDA drug supply program. This work was supported by R01DK106188 and by a Brain and Behavior Research Foundation NARSAD Young Investigator Award to CRF. MFO was supported by NIDA T32DA007268.

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Oginsky, M.F., Maust, J.D., Corthell, J.T. et al. Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet-induced obesity. Psychopharmacology 233, 773–784 (2016). https://doi.org/10.1007/s00213-015-4157-x

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