Abstract
Understanding the neurobiological processes that contribute to the establishment and expression of stress-induced regulation of cocaine use in addicted individuals is important for the development of new and better treatment approaches. It has been previously shown that rats self-administering cocaine under long-access conditions (6 h daily) display heightened susceptibility to the reinstatement of extinguished cocaine seeking by a stressor, electric footshock, or i.c.v. administration of the stressor-responsive neuropeptide, corticotropin-releasing factor (CRF). This study tested the hypothesis that adrenal responsiveness during earlier long-access cocaine self-administration (SA) is necessary for the establishment of later CRF-dependent stress-induced reinstatement. Reinstatement by footshock, but not a cocaine challenge (10 mg/kg, i.p.) following long-access SA, was blocked by i.c.v. administration of the CRF receptor antagonist, α-helical CRF9−41 (10 μg). Elimination of SA-induced adrenal responses through surgical adrenalectomy and diurnal corticosterone replacement (ADX/C) before 14 days of SA under long-access conditions had minimal impact on cocaine SA, but blocked later footshock-induced reinstatement. By contrast, ADX/C after SA, but before extinction and reinstatement testing, failed to reduce footshock-induced reinstatement. Likewise, ADX/C before 14 days long-access SA prevented later reinstatement by i.c.v. CRF (0.5 or 1.0 μg). However, significant CRF-induced reinstatement was observed when rats underwent ADX/C following SA, but before extinction and reinstatement testing, although a modest but statistically nonsignificant reduction in sensitivity to CRF's reinstating effects was observed. Taken together, these findings suggest that adrenal-dependent neuroadaptations in CRF responsiveness underlie the increased susceptibility to stress-induced relapse that emerges with repeated cocaine use.
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Acknowledgements
This work was supported by National Institute on Drug Abuse (NIDA) Grant numbers DA15758 and DA025617. We acknowledge Eric Katz, Joseph Serge, Chad Seubert and Geng Lee for their technical assistance. The authors received financial support or compensation as follows: John R Mantsch is a Founder and past Director of as well as a consultant for and stockholder in Promentis Pharmaceuticals and has served as a consultant for WIL Research (Ashland, OH). He has received research support from the NIH and the State of Wisconsin Biotechnology Alliance. He is a full-time employee of Marquette University. David A Baker is a Founder and Director as well as a consultant for and stockholder in Promentis Pharmaceuticals. He has received research support from the NIH, the State of Wisconsin Biotechnology Alliance, and the National Alliance for Research on Schizophrenia and Addiction. He is a full-time employee of Marquette University. Evan Graf, Michael Hoks, Jose Sierra, Jean Baumgardner, Colin Bohr, and Oliver Vranjkovic were employees of Marquette University at the time that these studies were completed.
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Graf, E., Hoks, M., Baumgardner, J. et al. Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats. Neuropsychopharmacol 36, 1444–1454 (2011). https://doi.org/10.1038/npp.2011.28
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