title: Methamphetamine affects cell proliferation in the medial prefrontal cortex: a new niche for toxicity.
abstract: Methamphetamine addicts demonstrate impaired frontal cortical-dependent cognitive function that could result from methamphetamine-induced maladaptive plasticity in the prefrontal cortex. Reduced adult gliogenesis observed in a rodent model of compulsive methamphetamine self-administration could contribute to the maladaptive plasticity in the medial prefrontal cortex (mPFC) as excessive methamphetamine intake is associated with loss of gliogenesis. The present study explored the vulnerability of mPFC progenitors to the duration of various sessions of methamphetamine self-administration in limited and extended access schedule of reinforcement. Proliferation of progenitors via Ki-67 labeling and apoptosis via activated caspase-3 labeling were studied in rats that intravenously self-administered methamphetamine in a limited access (1h/day: short access (ShA)) or extended access (6h/day: long access (LgA)) paradigm over 4, 13, 22 or 42 sessions, and in rats that experienced 22 sessions and were withdrawn from self-administration for a period of 4weeks. Four sessions of LgA methamphetamine enhanced proliferation and apoptosis and forty-two sessions of ShA and LgA methamphetamine reduced proliferation without effecting apoptosis. Withdrawal from twenty-two sessions of methamphetamine enhanced proliferation in LgA animals. Our findings demonstrate that proliferation of mPFC progenitors is vulnerable to psychostimulant exposure and withdrawal with distinct underlying mechanisms relating to methamphetamine toxicity. The susceptibility of mPFC progenitors to even modest doses of methamphetamine could account for the pronounced neuroadaptation in the mPFC linked to methamphetamine abuse.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Airee
authors.initials: A
authors.lastname: Kim
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: cmandyam@scripps.edu.
authors.forename: Chitra D
authors.initials: CD
authors.lastname: Mandyam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004334:Drug Administration Schedule; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000166:cytology* / Q000187:drug effects*; D051381:Rats; D012646:Self Administration; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D008694:Methamphetamine
keywords: AC3; Apoptosis; Ki-67; Medial prefrontal cortex; Proliferation; Self-administration