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Research ArticleBehavioral Pharmacology

Orexin-1 Receptor Mediation of Cocaine Seeking in Male and Female Rats

Luyi Zhou, Shannon M. Ghee, Clifford Chan, Li Lin, Michael D. Cameron, Paul J. Kenny and Ronald E. See
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 801-809; DOI: https://doi.org/10.1124/jpet.111.187567
Luyi Zhou
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Shannon M. Ghee
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Clifford Chan
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Li Lin
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Michael D. Cameron
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Paul J. Kenny
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Ronald E. See
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Abstract

Previous studies have shown that female rats exhibit enhanced cocaine seeking during multiple phases of cocaine addiction compared with males. The orexin/hypocretin system recently has been implicated in drug addiction in male rats. Based on the known sex differences in cocaine addiction, in the current study we examined orexin-mediated cocaine seeking during self-administration, extinction, and reinstatement in age-matched male (initial weight 250–300 g) and female (initial weight 175–225 g) Sprague-Dawley rats by using the orexin-1 receptor (OX1R) antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea (SB-334867) (10–30 mg/kg). OX1R blockade had no effect on established cocaine self-administration, but attenuated cocaine seeking during extinction in both male and female rats. It is noteworthy that OX1R blockade potently attenuated cue-induced reinstatement in males but had no effect on females. SB-334867 also reduced cocaine seeking during pharmacological stress-induced (yohimbine, 2.5 mg/kg) and yohimbine + cue-induced reinstatement in both sexes. SB-334867 failed to affect reinstatement induced by cocaine (10 mg/kg) in either male or female rats, but selectively reduced cocaine + cue-induced reinstatement only in males. In separate experiments examining basal and cocaine-induced locomotion, SB-334867 attenuated locomotion in both male and female rats. Finally, assessment of plasma and brain levels of SB-334867 showed that estrus females had slightly higher plasma levels than diestrus females, but no overall sex differences or estrous cycle differences were observed in plasma or brain SB-334867 concentrations. These results show that OX1R signaling plays a role in mediating cocaine seeking, but differs between the sexes for cue-induced reinstatement.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants P50 DA16511, DA023915]; and the National Institutes of Health National Center for Research Resources [Grant C06 RR015455].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.187567.

  • ABBREVIATIONS:

    OX1R
    orexin-1 receptor
    OX2R
    orexin-2 receptor
    SB-334867
    1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea
    FR
    fixed ratio
    PR
    progressive ratio
    ANOVA
    analysis of variance.

  • Received August 31, 2011.
  • Accepted December 19, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleBehavioral Pharmacology

Orexin and Drug Seeking in Males and Females

Luyi Zhou, Shannon M. Ghee, Clifford Chan, Li Lin, Michael D. Cameron, Paul J. Kenny and Ronald E. See
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 801-809; DOI: https://doi.org/10.1124/jpet.111.187567

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Research ArticleBehavioral Pharmacology

Orexin and Drug Seeking in Males and Females

Luyi Zhou, Shannon M. Ghee, Clifford Chan, Li Lin, Michael D. Cameron, Paul J. Kenny and Ronald E. See
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 801-809; DOI: https://doi.org/10.1124/jpet.111.187567
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