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μ-Opioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in Long-Evans rats: a delayed effect of ethanol

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Abstract

Rationale

Naltrexone, a non-selective opioid antagonist, decreases the euphoria and positive subjective responses to alcohol in heavy drinkers. It has been proposed that the μ-opioid receptor plays a role in ethanol reinforcement through modulation of ethanol-stimulated mesolimbic dopamine release.

Objectives

To investigate the ability of naltrexone and β-funaltrexamine, an irreversible μ-opioid specific antagonist, to inhibit ethanol-stimulated and morphine-stimulated mesolimbic dopamine release, and to determine whether opioid receptors on mesolimbic neurons contribute to these mechanisms.

Methods

Ethanol-naïve male Long Evans rats were given opioid receptor antagonists either intravenously, subcutaneously, or intracranially into the ventral tegmental area (VTA), followed by intravenous administration of ethanol or morphine. We measured extracellular dopamine in vivo using microdialysis probes inserted into the nucleus accumbens shell (n = 114).

Results

Administration of naltrexone (intravenously) and β-funaltrexamine (subcutaneously), as well as intracranial injection of naltrexone into the VTA did not prevent the initiation of dopamine release by intravenous ethanol administration, but prevented it from being as prolonged. In contrast, morphine-stimulated mesolimbic dopamine release was effectively suppressed.

Conclusions

Our results provide novel evidence that there are two distinct mechanisms that mediate ethanol-stimulated mesolimbic dopamine release (an initial phase and a delayed phase), and that opioid receptor activation is required to maintain the delayed-phase dopamine release. Moreover, μ-opioid receptors account for this delayed-phase dopamine response, and the VTA is potentially the site of action of this mechanism. We conclude that μ-opioid receptors play different roles in the mechanisms of stimulation of mesolimbic dopamine activity by ethanol and morphine.

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Acknowledgments

This work was supported by a grant from NIH/NIAAA (AA11852). The authors thank the NIDA drug supply program for supplying morphine and β-funaltrexamine. John Valenta, Martin Job, Regina Mangieri, Christina Schier, and Elaina Howard were supported by a training grant T32 AA07471 from NIH/NIAAA. Martin Job and Elaina Howard were also supported by predoctoral fellowships from NIH/NIAAA (F31 AA016741, F31 A016874, respectively). Regina Mangieri was supported by a postdoctoral fellowship from NIH/NIAAA (F32 AA018252). The authors acknowledge the excellent technical assistance of Shannon Zandy, James Reno, Woojung Lee and Jessica Hunter. A portion of the data in this manuscript was previously presented at the Society for Neuroscience meeting (2008, 2011).

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. College of Pharmacy, Department of Pharmacology, University of Texas at Austin, 2409 University Avenue, Stop A1900, Austin, TX, 78712-1113, USA

    John P. Valenta, Martin O. Job, Regina A. Mangieri, Christina J. Schier, Elaina C. Howard & Rueben A. Gonzales

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  1. John P. Valenta
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  2. Martin O. Job
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  3. Regina A. Mangieri
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  4. Christina J. Schier
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  5. Elaina C. Howard
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  6. Rueben A. Gonzales
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Corresponding author

Correspondence to Rueben A. Gonzales.

Additional information

John Valenta and Martin Job contributed equally to this work and should be considered co-first authors.

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Valenta, J.P., Job, M.O., Mangieri, R.A. et al. μ-Opioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in Long-Evans rats: a delayed effect of ethanol. Psychopharmacology 228, 389–400 (2013). https://doi.org/10.1007/s00213-013-3041-9

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