title: Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle.
abstract: BACKGROUND
  Previous studies have shown that female rats exhibit enhanced cocaine-seeking across several phases of the addiction cycle when compared to males. Drug-seeking in females is also estrous cycle dependent and inversely associated with plasma progesterone. Although sex and estrous cycle-dependent differences have been reported in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues, it is not yet known what role the estrous cycle may have on stress-induced reinstatement, either alone or in combination with drug-paired cues.
  
  
  OBJECTIVE
  Here, we examined male and female rats for reinstatement of extinguished cocaine-seeking produced by cocaine-paired cues or the stress-activating drug, yohimbine.
  
  
  METHODS
  Male and female Sprague-Dawley rats self-administered intravenous cocaine (0.5 mg/kg/infusion) paired with a light + tone stimulus for 10-14 days. Lever responding was then allowed to extinguish, with subsequent reinstatement testing occurring 30 min following an injection of yohimbine (1.25 or 2.5 mg/kg, intraperitoneal) or vehicle either in the presence or absence of the conditioned stimulus.
  
  
  RESULTS
  While males and females showed similar cue- and yohimbine-induced reinstatement (3-4 times over "No Cue"-vehicle responding), combining these stimuli resulted in a robust enhancement in cocaine-seeking in both groups, with a greater increase in females (10-12 vs. 14-15 times over "No Cue"-vehicle responding for the males and females, respectively). When examined as a function of the estrous cycle, females in proestrus demonstrated higher levels of responding during yohimbine + cues reinstatement.
  
  
  CONCLUSIONS
  This cycle-dependent enhanced sensitivity to stress enhancement of cocaine-paired cues may generalize to greater relapse susceptibility under stressful conditions.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA. feltens@musc.edu
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Feltenstein
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Henderson
authors.forename: Ronald E
authors.initials: RE
authors.lastname: See
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019970:Cocaine-Related Disorders / Q000097:blood / Q000503:physiopathology* / Q000523:psychology; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D030762:Estrous Cycle / Q000097:blood / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D011374:Progesterone / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D012727:Sex Characteristics; D015016:Yohimbine / Q000494:pharmacology*
chemical_list: D015016:Yohimbine; D011374:Progesterone