Abstract
Single and multiple high-dose administrations of methamphetamine (METH) differentially decrease dopamine (DA) transporter (DAT) function, as assessed by measuring [3H]DA uptake into rat striatal synaptosomes prepared 1 h after treatment. Prevention of METH-induced hyperthermia attenuated the decrease in DAT activity induced by multiple injections of the stimulant. Likewise, this decrease was attenuated by previous depletion of striatal DA levels using α-methyl-p-tyrosine (αMT) or pretreatment with the D1 and D2 antagonists SCH-23390 and eticlopride, respectively. However, METH-induced hyperthermia was also blocked by αMT and eticlopride. Reinstatement of hyperthermia to αMT- or eticlopride-pretreated rats partially restored the METH-induced decrease in DAT activity. In contrast, neither prevention of METH-induced hyperthermia depletion of DA, nor DA antagonists altered the decrease in DAT function induced by a single administration of METH. Pretreatment with the antioxidantN-t-butyl-α-phenylnitrone prevented part of the decrease in DAT function associated with multiple, but not a single, METH injections. Although not tested directly, additional data presented here suggest that the reduction in DAT activity induced by a single METH administration constitutes a part of the total reduction observed immediately after multiple administrations. Taken together, the results indicate that DA, hyperthermia, and oxygen radicals contribute to a component of the rapid decrease in DAT function induced by multiple injections of METH but do not appear to be associated with the reduction induced by a single administration of the stimulant.
Footnotes
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Send reprint requests to: Annette E. Fleckenstein, Ph.D., University of Utah, Department of Pharmacology and Toxicology, 30 S. 2000 E., Rm. 201, Salt Lake City, UT 84112. E-mail:fleckenstein{at}hsc.utah.edu
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↵1 This study was supported by U.S. Public Health Service Grants DA05859, DA11389, and DA00869.
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↵2 This work was presented in part at the 29th Annual Meeting of the Society for Neuroscience; 1999 Oct 23–28; Miami Beach, FL.
- Abbreviations:
- METH
- methamphetamine
- DA
- dopamine
- DAT
- dopamine transporter
- PBN
- N-t-butyl-α-phenylnitrone
- pCPA
- para-chlorophenylalanine
- NMDA
- N-methyl-d-aspartate
- αMT
- α-methyl-para-tyrosine
- 5HT
- 5-hydroxytryptamine
- Received May 26, 2000.
- Accepted August 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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