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.
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 to 10 days, followed by either short- (1-h) or long-access (6-h) self-administration for 12 to 14 days. Lever responding was extinguished for 2 weeks before either reinstatement testing or rapid decapitation and tissue dissection. Tissue levels of monoamine transporters and markers of methamphetamine-induced toxicity were analyzed in several forebrain areas. Long-access methamphetamine self-administration resulted in escalation of daily drug intake ( approximately 7 mg/kg/day) and enhanced drug-primed reinstatement compared with 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.
Schwendt
Marek
M
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. schwendt@musc.edu
Rocha
Angelica
A
See
Ronald E
RE
Pacchioni
Alejandra M
AM
McGinty
Jacqueline F
JF
Kalivas
Peter W
PW
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005108:Extinction, Psychological; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D012008:Recurrence; D012646:Self Administration; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D004298:Dopamine