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Dissociable role of tumor necrosis factor alpha gene deletion in methamphetamine self-administration and cue-induced relapsing behavior in mice

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Abstract

Rationale

During the development of addiction, addictive drugs induce transient and long-lasting changes in the brain including expression of endogenous molecules and alteration of morphological structure. Of the altered endogenous molecules, some facilitate but others slow the development of drug addiction. Previously, we have reported that tumor necrosis factor alpha (TNF-α) is a critical molecule among endogenous anti-addictive modulators using animal models of drug-conditioned place preference and drug discrimination.

Objectives

Does targeted deletion of the TNF-α gene in mice affect methamphetamine (METH) self-administration, motivation to self-administer METH, cue-induced reinstatement of METH-seeking behavior, and food reinforcement or seeking behavior?

Methods

Both METH self-administration and reinstatement of drug-seeking behavior and food self-delivery and food-seeking behavior were measured in TNF-α (−/−) and wild-type mice.

Results

There were an upward shift of dose responses to METH self-administration under a fixed ratio schedule of reinforcement and higher breaking points under a progressive ratio schedule of reinforcement in TNF-α knockout (TNF-α (−/−)) mice as compared with wild-type mice. There was no significant difference in cue-induced reinstatement of METH-seeking behavior, food-maintained operant behavior, motivation to natural food, and cue-induced food-seeking behavior between TNF-α (−/−) and wild-type mice.

Conclusion

TNF-α affects METH self-administration and motivation to self-administer METH but contributes to neither METH-associated cue-induced relapsing behavior nor food reward and food-seeking behavior. TNF-α may be explored for use as a diagnostic biomarker for the early stage of drug addiction.

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Acknowledgments

We thank Drs. Mizoguchi Hiroyuki, Tsuneyuki Yamamoto, and Masayuki Nadai for their technical assistance in the establishment of a mouse model of self-administration in our laboratory. We also appreciate Mr. Yaroslaw Pryslawsky’s assistance in the three-way statistical analyses of data. This study was supported by grants-in-aid for Scientific Research (A) (22248033), Scientific Research (B)(20390073)(21390045), and Exploratory Research(19659017)(22659213); by the joint research project under the Japan–Korea basic scientific corporation program from the Japan Society for the promotion of science; by the ‘Academic Frontier’ Project for private universities (2007–2011); by the Regional Joint Research Program supported by grants to private universities to cover current expenses from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); by the Research on Regulatory Science of Pharmaceuticals and Medical Devices; by the Research on Risk of Chemical Substances, Health and Labour Science research grants from the Ministry of Health, Labour and Welfare (MHLW); and by the New Energy and Industrial Technology Development Organization (NEDO) (Translational Research Promotion Project).

Disclosure/conflicts of interest

The authors of this manuscript report no conflicts of interest.

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Authors and Affiliations

  1. Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Nagoya, 466-8560, Japan

    Yijin Yan, Atsumi Nitta, Kiyofumi Yamada & Toshitaka Nabeshima

  2. Department of Pharmaceutical Therapy & Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2639 Sugitani, Toyama, 930-0194, Japan

    Atsumi Nitta

  3. Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya, 468-8503, Japan

    Takenao Koseki & Toshitaka Nabeshima

  4. Comparative Cognitive Science Institutes, Meijo University, Nagoya, 468-8503, Japan

    Toshitaka Nabeshima

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  1. Yijin Yan
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  2. Atsumi Nitta
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  3. Takenao Koseki
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  4. Kiyofumi Yamada
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Correspondence to Toshitaka Nabeshima.

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Yan, Y., Nitta, A., Koseki, T. et al. Dissociable role of tumor necrosis factor alpha gene deletion in methamphetamine self-administration and cue-induced relapsing behavior in mice. Psychopharmacology 221, 427–436 (2012). https://doi.org/10.1007/s00213-011-2589-5

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  • DOI: https://doi.org/10.1007/s00213-011-2589-5

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