Effects of repeated cocaine on the release and clearance of dopamine within the rat medial prefrontal cortex.

Previous data suggest that cocaine-induced dopamine (DA) transmission within the medial prefrontal cortex (mPFC) undergoes time-dependent changes during withdrawal from repeated cocaine administration. The current studies assessed two potential mechanisms that may underlie this neuroadaptation. One set of experiments examined alterations in DA clearance in the mPFC of rats that had been pretreated with four administrations of cocaine (15 mg/kg, i.p.; once per day for 4 days) and were withdrawn 1, 7, or 30 days. No significant changes in mPFC DA uptake into crude mPFC synaptosomes or in mPFC DA transporter levels were observed at any of the time points examined. Uptake assay and Western blotting sensitivity was confirmed with prefrontal 6-hydroxydopamine lesions, which significantly reduced [3H]DA uptake and DA transporter immunoreactivity in mPFC synaptosomes. To evaluate temporal changes in DA release resulting from repeated cocaine, additional experiments utilized in vivo microdialysis to locally infuse KCl (10, 30, or 100 mM) into the mPFC over the same withdrawal time course used in the uptake studies. After 1-7 days of withdrawal, KCl-stimulated DA release was significantly reduced in the mPFC of cocaine-pretreated animals. However, after 30 days of withdrawal the evoked release of DA in the mPFC of saline- and cocaine-pretreated animals was similar. These data suggest that previously reported modulation of cocaine-induced mPFC DA transmission occurring upon withdrawal from repeated cocaine might arise from transient changes in DA releasability rather than clearance. The relevance of these findings is discussed in relation to mPFC involvement in psychostimulant sensitization.