Methamphetamine affects cell proliferation in the medial prefrontal cortex: A new niche for toxicity

• Meth reduces the number of glial progenitors in the medial prefrontal cortex (mPFC)
• Levels of mPFC progenitors and apoptosis were assessed over a time course of Meth
• Modest amount of Meth intake enhances glial progenitors and apoptosis in the mPFC

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 (1 h/day: short access (ShA)) or extended access (6 h/day: long access (LgA)) paradigm over 4, 13, 22 or 42 sessions, and in rats that experienced 22 sessions and were withdrawn from self-administration for a period of 4 weeks. 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.