Extended methamphetamine self-administration in rats results in a selective reduction of dopamine transporter levels in the prefrontal cortex and dorsal striatum not accompanied by marked monoaminergic depletion

SCHWENDT M; ROCHA A; SEE R; PACCHIONI AM; MCGINTY JF; KALIVAS PW

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Año: 2009 vol. 331 p. 555 - 562

0022-3565

Chronic abuse of methamphetamine leads to cognitive dysfunction and high rates of relapse, paralleled by significant changes of brain dopamine and serotonin neurotransmission. Previously we found that rats with extended access to methamphetamine self-administration displayed enhanced methamphetamine-primed reinstatement of drug-seeking and cognitive deficits relative to limited-access animals. The present study investigated whether extended access to methamphetamine self-administration produced abnormalities in dopamine and serotonin systems in rat forebrain. Rats self-administered methamphetamine (0.02 mg/ i.v. infusion) during daily 1-h sessions for 7-10 days, followed by either short- (1 h) or long-access (6 h) selfadministration for 12-14 days. Lever responding was extinguished for two weeks prior to either reinstatement testing or rapid decapitation and tissue dissection. Tissue levels of monoamine transporters and markers of methamphetamine-induced toxicity were analyzed in severalforebrain areas. Long-access methamphetamine self-administration resulted in escalation of daily drug intake (~ 7 mg/kg/day) and enhanced drug-primed reinstatement when compared to the short access group. Furthermore, long-, but not short-access to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex and dorsal striatum. In contrast, only minor alterations in the tissue levels of dopamine or its metabolites were found, and no changes in markers specific for dopamine terminals or glial cell activation were detected. Our findings suggest that persistent methamphetamine-seeking is associated with region-selective changes in DAT levels without accompanying monoaminergic neurotoxicity. Greater understanding of the neuroadaptations underlying persistent methamphetamine-seeking and cognitive deficits could yield targets suitable for future therapeutic interventions.