Abstract
Methamphetamine (METH) abuse is a serious public health issue. Of particular concern are findings that repeated high-dose administrations of METH cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. Previous studies have also revealed that METH treatment causes alterations in the dopamine transporter (DAT), including the formation of higher molecular mass DAT-associated complexes. The current study extends these findings by examining mechanisms underlying DAT complex formation. The association among DAT complex formation and other METH-induced phenomena, including alterations in vesicular monoamine transporter 2 (VMAT2) immunoreactivity, astrocytic activation [as assessed by increased glial fibrillary acidic protein (GFAP) immunoreactivity], and persistent dopaminergic deficits was also explored. Results revealed that METH-induced DAT complex formation and reductions in VMAT2 immunoreactivity precede increases in GFAP immunoreactivity. Furthermore, and as reported previously for DAT complexes, pretreatment with the D2 receptor antagonist eticlopride [S-(−)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride] attenuated the decrease in VMAT2 immunoreactivity as assessed 24 h after METH treatment. DAT complexes distinct from those present 24 h after METH treatment, decreases in VMAT2 immunoreactivity, and increased GFAP immunoreactivity were present 48 to 72 h after METH treatment. Pretreatment with eticlopride attenuated each of these phenomena. Finally, DAT complexes were present 7 days after METH treatment, a time point at which VMAT2 and DAT monomer immunoreactivity were also reduced. Eticlopride pretreatment attenuated each of these phenomena. These findings provide novel insight into not only receptor-mediated mechanisms underlying the effects of METH but also the interaction among factors that probably are associated with the persistent dopaminergic deficits caused by the stimulant.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA00869, DA04222, DA13367, DA11389, DA019447, DA00378] and a fellowship from the Pharmaceutical Research and Manufacturers of America Foundation (to G.C.H.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.166660.
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ABBREVIATIONS:
- METH
- methamphetamine
- DA
- dopamine
- DAT
- DA transporter
- eticlopride
- S-(−)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-hydroxy-2-methoxybenzamide hydrochloride
- GFAP
- glial fibrillary acidic protein
- SCH23390
- R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
- VMAT2
- vesicular monoamine transporter 2.
- Received April 3, 2010.
- Accepted July 8, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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