Abstract
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 (∼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.
- Meth, methamphetamine
- DAT, dopamine transporter(s)
- SERT, serotonin transporter(s)
- dSTR, dorsal striatum
- NAc, nucleus accumbens
- PFC, prefrontal cortex
- HPLC, high-performance liquid chromatography
- DOPAC, 3,4-dihydroxyphenylacetic acid
- HVA, homovanillic acid
- GFAP, glial fibrillary acidic protein
- Iba, ionized calcium-binding adaptor molecule
- ANOVA, analysis of variance
- vPFC, ventral prefrontal cortex.
Footnotes
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This work was supported in part by the Translational Research in Addiction Center at Medical University of South Carolina; the National Institutes of Health National Institute on Drug Abuse [Grant P20-DA022658]; and the National Institutes of Health National Center for Research Resources [Grant CO6-RR015455] (Extramural Research Facilities Program).
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This work has been presented previously at the 38th Annual Meeting of the Society for Neuroscience, in 2008 Abstract Viewer/Itinerary Planner; 2008 Nov 15–19; Washington, DC. Rocha A, Pacchioni A, and Kalivas PW (2008) Role of the dorsal and ventral prefrontal cortex in cue- and drug-induced reinstatement following extended access to methamphetamine. Program number 358.13; and Schwendt M, Rogers JL, McGinty JF, and See RE (2008) Extended-access to methamphetamine self-administration produces region-specific changes in dopamine transporter signaling assembly in rat forebrain. Program number 358.13.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.155770
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ABBREVIATIONS:
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M.S. and A.R. contributed equally to this work.
- Received May 4, 2009.
- Accepted July 30, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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