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The role of neuronal nitric oxide synthase in cocaine place preference and mu opioid receptor expression in the nucleus accumbens

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Abstract

Rationale

There is evidence that central mu opioid receptors (MORs) are implicated in several aspects of cocaine addiction, and that MOR expression is elevated by cocaine in vitro and in the nucleus accumbens (NAc) when administered in vivo.

Objective

To understand the cellular mechanisms involved in regulating MOR expression, this study explored whether neuronal nitric oxide synthase (nNOS) modulates the neurochemical and behavioral effects of acute and repeated cocaine administration.

Methods

Male Sprague-Dawley rats received a single cocaine injection (20 mg/kg, i.p.) in combination with the selective nNOS inhibitor 7-nitroindazole (7-NI) (0, 25, or 50 mg/kg, i.p.), and the expression of MOR and nNOS messenger RNA (mRNA) and protein levels in the NAc were measured. In a separate conditioned place preference (CPP) experiment, 7-NI (0, 25, or 50 mg/kg, i.p.) was administered prior to cocaine (0 or 20 mg/kg, i.p.) conditioning sessions, and levels of MOR and nNOS mRNA and protein in the NAc were measured following CPP test.

Results

Acute cocaine administration significantly enhanced nNOS and MOR mRNA and protein expression in the NAc, and this increase in MOR expression was blocked by 7-NI. Furthermore, in 7-NI pre-treated rats, cocaine-induced CPP was not statistically significant and the increase in MOR mRNA expression in the NAc in these animals was attenuated.

Conclusions

These findings suggest that nNOS modulates MOR expression following acute cocaine administration, and that cocaine CPP and associated upregulation of MOR expression involve both nNOS-dependent and independent mechanisms. Elucidation of these molecular events may identify useful therapeutic target for cocaine addiction.

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Funding

Funding was provided by the Natural Sciences and Engineering Research Council of Canada (FL), Canadian Institutes of Health Research, Ontario Veterinary College.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Guelph (ON), Guelph, Ontario, N1G 2W1, Canada

    Rachel-Karson Thériault & Bettina Kalisch

  2. Collaborative Neuroscience Program, University of Guelph (ON), Guelph, Ontario, N1G 2W1, Canada

    Rachel-Karson Thériault, Francesco Leri & Bettina Kalisch

  3. Department of Psychology, University of Guelph (ON), Guelph, Ontario, N1G 2W1, Canada

    Francesco Leri

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  1. Rachel-Karson Thériault
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  2. Francesco Leri
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Correspondence to Bettina Kalisch.

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Thériault, RK., Leri, F. & Kalisch, B. The role of neuronal nitric oxide synthase in cocaine place preference and mu opioid receptor expression in the nucleus accumbens. Psychopharmacology 235, 2675–2685 (2018). https://doi.org/10.1007/s00213-018-4961-1

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