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Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons

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Abstract

Exercise (physical activity) has been proposed as a treatment for drug addiction. In rodents, voluntary wheel running reduces cocaine and nicotine seeking during extinction, and reinstatement of cocaine seeking triggered by drug-cues. The purpose of this study was to examine the effects of chronic wheel running during withdrawal and protracted abstinence on extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats, and to determine a potential neurobiological correlate underlying the effects. Rats were given extended access to methamphetamine (0.05 mg/kg, 6 h/day) for 22 sessions. Rats were withdrawn and were given access to running wheels (wheel runners) or no wheels (sedentary) for 3 weeks after which they experienced extinction and reinstatement of methamphetamine seeking. Extended access to methamphetamine self-administration produced escalation in methamphetamine intake. Methamphetamine experience reduced running output, and conversely, access to wheel running during withdrawal reduced responding during extinction and, context- and cue-induced reinstatement of methamphetamine seeking. Immunohistochemical analysis of brain tissue demonstrated that wheel running during withdrawal did not regulate markers of methamphetamine neurotoxicity (neurogenesis, neuronal nitric oxide synthase, vesicular monoamine transporter-2) and cellular activation (c-Fos) in brain regions involved in relapse to drug seeking. However, reduced methamphetamine seeking was associated with running-induced reduction (and normalization) of the number of tyrosine hydroxylase immunoreactive neurons in the periaqueductal gray (PAG). The present study provides evidence that dopamine neurons of the PAG region show adaptive biochemical changes during methamphetamine seeking in methamphetamine dependent rats and wheel running abolishes these effects. Given that the PAG dopamine neurons project onto the structures of the extended amygdala, the present findings also suggest that wheel running may be preventing certain allostatic changes in the brain reward and stress systems contributing to the negative reinforcement and perpetuation of the addiction cycle.

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Acknowledgments

The study was supported by funds from the National Institute on Drug Abuse (DA022473 and DA034140 to CDM), National institute on Alcoholism and Alcohol Abuse (AA020098 and AA06420 to CDM) and Alcohol Beverage Medical Research Foundation to CDM. We appreciate the technical support of Elena Crawford for StereoInvestigator, and Robert Lintz, Ilham Polis and Yanabel Grant for assistance with intravenous self-administration studies. We thank Derrick Babb from the LSSI TSRI program and Mathew Soleiman from the independent study program at UCSD for assistance with immunohistochemistry. We thank Drs. Miranda Staples and Sucharita Somkuwar for critical reading of the manuscript. This is publication number 26041 from The Scripps Research Institute.

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Correspondence to Chitra D. Mandyam.

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J. C. Sobieraj and A. Kim have equal contribution.

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Sobieraj, J.C., Kim, A., Fannon, M.J. et al. Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons. Brain Struct Funct 221, 261–276 (2016). https://doi.org/10.1007/s00429-014-0905-7

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