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Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats

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Abstract

Rationale

The investigation of rodent cocaine self-administration (SA) under conditions that promote escalating patterns of intake may provide insight into the loss of control over drug use that is central to human addiction.

Objective

This study examines the effects of daily long-access (LgA) SA of high or low cocaine doses on drug intake, extinction, reinstatement, and brain mRNA levels.

Methods

Three groups of male Sprague-Dawley rats were trained to self-administer cocaine during multiple-dose sessions. Short-access (ShA) rats were tested daily for multi-dose SA then remained in the chambers for 7 h with no cocaine available. LgA rats had access to low (0.5 mg/kg per infusion; LgA-LD) or high (2.0 mg/kg per infusion; LgA-HD) cocaine doses for 7 h after multi-dose SA. After 14 days, responding was extinguished, cocaine-induced reinstatement was determined, and preproenkephalin (ppENK), preprodynorphin (ppDYN), corticotropin releasing factor (CRF) and dopamine D2 receptor (D2R) mRNA levels were measured in various brain regions using a quantitative solution hybridization RNase protection assay.

Results

Whereas SA was not altered in ShA rats and only increased during the “loading phase” in LgA-LD rats, a general escalation of intake was found in LgA-HD rats. LgA, particularly LgA-HD, rats were more susceptible to reinstatement than ShA rats. Caudate-putamen ppENK and nucleus accumbens D2R mRNA levels were elevated in LgA-HD rats. Overall, D2R mRNA levels were positively correlated with reinstatement.

Conclusions

The escalation of cocaine SA under LgA conditions is dose-dependent and is associated with heightened susceptibility to drug-induced relapse. The characterization of neurobiological alterations that accompany escalated SA should facilitate the identification of mechanisms underlying the onset of human addiction.

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Acknowledgements

The authors would like to thank Drs. R.C. Thompson (University of Michigan) for the CRF cDNA, which was subcloned by Dr. Y. Zhou (The Rockefeller University), Dr. O. Civelli (University of California-Irvine) for the ppDYN cDNA, Dr. S. Sabol (National Institute of Heart, Lung and Blood) for the ppENK cDNA, and Drs. T. Nilsen and P. Maroney (Case Western University) for the 18S cDNA. This work was supported by National Institute on Drug Abuse (NIDA) Research Center Grant DA-P50-05130 and NIDA Research Scientist Award DA-K05–00049, awarded to Dr. Mary Jeanne Kreek.

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Authors and Affiliations

  1. The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, N.Y., USA

    John R. Mantsch, Vadim Yuferov, Anne-Marie Mathieu-Kia, Ann Ho & Mary Jeanne Kreek

  2. Department of Biomedical Sciences, Schroeder Health Complex, Marquette University, Room 426, PO Box 1881, Milwaukee, WI, 53201-1881, USA

    John R. Mantsch

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  1. John R. Mantsch
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  2. Vadim Yuferov
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  3. Anne-Marie Mathieu-Kia
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  4. Ann Ho
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  5. Mary Jeanne Kreek
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Correspondence to John R. Mantsch.

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Mantsch, J.R., Yuferov, V., Mathieu-Kia, AM. et al. Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats. Psychopharmacology 175, 26–36 (2004). https://doi.org/10.1007/s00213-004-1778-x

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