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N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement

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Abstract

Rationale

Chronic exposure to drugs of abuse changes glutamatergic transmission in human addicts and animal models. N-acetylcysteine (NAC) is a cysteine prodrug that indirectly activates cysteine-glutamate antiporters. In the extrasynaptic space, NAC restores basal glutamate levels during drug abstinence and normalizes increased glutamatergic tone in rats during reinstatement to drugs of abuse. In initial clinical trials, repeated NAC administration seems to be promising for reduced craving in cocaine addicts.

Objective

In this study, NAC-amide, called AD4 or NACA, was examined in intravenous cocaine self-administration and extinction/reinstatement procedures in rats. We investigated the behavioral effects of AD4 in the olfactory bulbectomized (OBX) rats, considered an animal model of depression. Finally, we tested rats injected with AD4 or NAC during 10-daily extinction training sessions to examine subsequent cocaine seeking.

Results

AD4 (25–75 mg kg−1) given acutely did not alter the rewarding effects of cocaine in OBX rats and sham-operated controls. However, at 6.25–50 mg kg−1, AD4 decreased dose-dependently cocaine seeking and relapse triggered by cocaine priming or drug-associated conditioned cues in both phenotypes. Furthermore, repeated treatment with AD4 (25 mg kg−1) or NAC (100 mg kg−1) during daily extinction trials reduced reinstatement of drug-seeking behavior in sham-operated controls. In the OBX rats only, AD4 effectively blocked cocaine-seeking behavior.

Conclusions

Our results demonstrate that AD4 is effective at blocking cocaine-seeking behavior, highlighting its potential clinical use toward cocaine use disorder.

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Acknowledgments

This study was supported by the statutory funds of the Institute of Pharmacology Polish Academy of Sciences in Krakow (J.J., M.Fr., M.F..F.) and by the H. L. Lauterbach Foundation (D.A.).

Author contributions

J.J., M.Fr., and M.F. participated in research design, performed the experiments, and data analysis. J.J., M.Fr., M.F., and D.A. wrote or contributed to writing of the manuscript. All authors critically reviewed the content and approved the final version for publication.

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Authors and Affiliations

  1. Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Joanna Jastrzębska, Malgorzata Frankowska & Malgorzata Filip

  2. Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

    Daphne Atlas

Authors
  1. Joanna Jastrzębska
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  2. Malgorzata Frankowska
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  3. Malgorzata Filip
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  4. Daphne Atlas
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Corresponding author

Correspondence to Malgorzata Filip.

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The authors declare that they have no conflicts of interest.

Additional information

Joanna Jastrzębska and Malgorzata Frankowska contributed equally to the work.

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Jastrzębska, J., Frankowska, M., Filip, M. et al. N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement. Psychopharmacology 233, 3437–3448 (2016). https://doi.org/10.1007/s00213-016-4388-5

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  • DOI: https://doi.org/10.1007/s00213-016-4388-5

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