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Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior

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An Erratum to this article was published on 24 October 2003

Abstract

Rationale

Withdrawal from non-contingent exposure to psychostimulants increases the activity of midbrain dopamine cells and impairs the function of impulse-regulating dopamine autoreceptors. It is unclear whether these neuroadaptations play an important role in withdrawal-associated drug seeking.

Objectives

We determined whether cocaine self-administration modifies the impulse activity of midbrain dopamine neurons and dopamine autoreceptor function, and whether experimentally induced reduction in dopamine cell activity (by autoreceptor activation) could influence drug-seeking behavior.

Methods

Animals were trained to self-administer saline or cocaine (500 µg/kg per infusion) for 7 days. At different withdrawal periods, we used single-unit extracellular recordings to measure impulse activity of dopamine cells and administered the D2/D3 dopamine receptor agonist quinpirole to determine autoreceptor sensitivity. In a separate set of experiments, we determined the effects of autoreceptor-selective doses of quinpirole on drug-seeking behavior (non-reinforced responding in the absence of cocaine) during an extinction/reinstatement task.

Results

Cocaine self-administration induced a short-lived increase in the mean firing rate and bursting activity of midbrain dopamine cells. This effect was greatest at early withdrawal and was paralleled by decreased ability of quinpirole to inhibit dopamine cell firing rate and drug-seeking behavior. Changes in dopamine cell activity dissipated over time; at late withdrawal, when both impulse activity and autoreceptor sensitivity returned to control values, quinpirole dramatically decreased drug-seeking behavior.

Conclusions

These results show that inhibiting dopamine cell impulse activity, by activation of dopamine autoreceptors, reduces drug-seeking behavior. This suggests that the impulse activity of midbrain dopamine cells could be an important factor contributing to relapse.

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Acknowledgements

This work was supported by United States Public Health Service Grant DA04093 and Senior Scientist Award DA 00456 from the National Institute on Drug Abuse to F.J.W. M.M. was supported by a NARSAD young investigator award. We are indebted to Dr. Muriel Koehl for invaluable discussions and advice. We thank Jake Battle for help with the writing of the burst analysis program.

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Authors and Affiliations

  1. Department of Cellular and Molecular Pharmacology, Finch University of Health Sciences, The Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064, USA

    Michela Marinelli

  2. Department of Neuroscience, Finch University of Health Sciences, The Chicago Medical School, 3333 Green Bay Rd., North Chicago, IL 60064, USA

    Donald C. Cooper, Lorinda K. Baker & Francis J. White

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  1. Michela Marinelli
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  2. Donald C. Cooper
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Correspondence to Michela Marinelli.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-003-1674-9

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Marinelli, M., Cooper, D.C., Baker, L.K. et al. Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior. Psychopharmacology 168, 84–98 (2003). https://doi.org/10.1007/s00213-003-1491-1

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