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Extended access cocaine self-administration differentially activates dorsal raphe and amygdala corticotropin-releasing factor systems in rats

Authors

  • Eric P. Zorrilla,

    Corresponding author
    1. Committee on the Neurobiology of Addictive Disorders, La Jolla, CA, USA
    2. Harold L. Dorris Neurological Research Institute, La Jolla, CA, USA
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  • Sunmee Wee,

    1. Committee on the Neurobiology of Addictive Disorders, La Jolla, CA, USA
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  • Yu Zhao,

    1. Committee on the Neurobiology of Addictive Disorders, La Jolla, CA, USA
    2. Harold L. Dorris Neurological Research Institute, La Jolla, CA, USA
    3. Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA
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    • Present addresses: Amylin Pharmaceuticals, 9360 Towne Centre Drive, San Diego, CA, USA;

  • Sheila Specio,

    1. Committee on the Neurobiology of Addictive Disorders, La Jolla, CA, USA
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  • Benjamin Boutrel,

    1. Committee on the Neurobiology of Addictive Disorders, La Jolla, CA, USA
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    • Centre de Neurosciences Psychiatriques (CNP) & Service Universitaire de Psychiatrie de l'Enfant et de l'Adolescent (SUPEA), Site de Cery, CH −1008 Prilly-Lausanne, Tél. +41 (0)21 643 69 47, Fax: +41 (0)21 643 69 50

  • George F. Koob,

    1. Committee on the Neurobiology of Addictive Disorders, La Jolla, CA, USA
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  • Friedbert Weiss

    1. Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA
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Eric P. Zorrilla, Committee on the Neurobiology of Addictive Disorders, SP30-2400, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: ezorrilla@scripps.edu

ABSTRACT

Cocaine-induced neuroadaptation of stress-related circuitry and increased access to cocaine each putatively contribute to the transition from cocaine use to cocaine dependence. The present study tested the hypothesis that rats receiving extended versus brief daily access to cocaine would exhibit regional differences in levels of the stress-regulatory neuropeptide corticotropin-releasing factor (CRF). A secondary goal was to explore how CRF levels change in relation to the time since cocaine self-administration. Male Wistar rats acquired operant self-administration of cocaine and were assigned to receive daily long access (6 hours/day, LgA, n = 20) or short access (1 hour/day, ShA, n = 18) to intravenous cocaine self-administration (fixed ratio 1, ∼0.50 mg/kg/infusion). After at least 3 weeks, tissue CRF immunoreactivity was measured at one of three timepoints: pre-session, post-session or 3 hours post-session. LgA, but not ShA, rats showed increased total session and first-hour cocaine intake. CRF immunoreactivity increased within the dorsal raphe (DR) and basolateral, but not central, nucleus of the amygdala (BLA, CeA) of ShA rats from pre-session to 3 hours post-session. In LgA rats, CRF immunoreactivity increased from pre-session to 3 hours post-session within the CeA and DR but tended to decrease in the BLA. LgA rats showed higher CRF levels than ShA rats in the DR and, pre-session, in the BLA. Thus, voluntary cocaine intake engages stress-regulatory CRF systems of the DR and amygdala. Increased availability of cocaine promotes greater tissue CRF levels in these extrahypothalamic brain regions, changes associated here with a model of cocaine dependence.

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