title: R-modafinil attenuates nicotine-taking and nicotine-seeking behavior in alcohol-preferring rats.
abstract: (±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long-Evans rats. As Long-Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long-Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans.
authors.affiliation: Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Bi
authors.affiliation: Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Hong-Ju
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Jun-Tao
authors.initials: JT
authors.lastname: Gao
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Oluyomi M
authors.initials: OM
authors.lastname: Okunola-Bakare
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Slack
authors.affiliation: Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
authors.affiliation: Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.affiliation: Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000284:Administration, Oral; D000438:Alcohols / Q000008:administration & dosage*; D000818:Animals; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans; D012055:Reinforcement Schedule; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy*; D064690:Wakefulness-Promoting Agents / Q000627:therapeutic use*
chemical_list: D000438:Alcohols; D001559:Benzhydryl Compounds; D018722:Nicotinic Agonists; D064690:Wakefulness-Promoting Agents; D009538:Nicotine; D000077408:Modafinil