The effects of methamphetamine on serotonin transporter activity: role of dopamine and hyperthermia.
Multiple administrations of methamphetamine (METH) rapidly decreased serotonin (5HT) transporter (SERT) function in rat striatum and hippocampus. The purpose of this study was to identify the mechanisms/ factors contributing to this METH-induced decrease in SERT function. Multiple high-dose METH injections rapidly decreased 5HT uptake without altering binding of the 5HT transporter ligand paroxetine. Hyperthermia contributed to this deficit in transporter function in striatum and hippocampus, as prevention of METH-induced hyperthermia attenuated this decrease. A role for dopamine (DA) was suggested by findings that pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine, the D1 antagonist SCH-23390, or the D2 antagonist eticlopride attenuated the METH-induced decrease in striatal, but not hippocampal, SERT activity. These effects were independent of the ability of these DA-antagonizing drugs to prevent METH-induced hyperthermia. These results suggest that DA contributes to the decrease in SERT function caused by multiple METH injections in the striatum, but not hippocampus, and that hyperthermia facilitates these deficits in SERT function in both brain regions. In contrast, the response of SERT to a single administration of METH was DA and hyperthermia independent. These findings suggest that the mechanisms/ factors involved in decreasing SERT activity after a single administration of METH are distinct from that caused by multiple administrations.
Haughey
H M
HM
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA.
Fleckenstein
A E
AE
Metzger
R R
RR
Hanson
G R
GR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006979:Hyperthermia, Induced; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins; D017374:Paroxetine / Q000378:metabolism; D010627:Phenethylamines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D013574:Synaptosomes / Q000378:metabolism
D000975:Antioxidants; D002352:Carrier Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010627:Phenethylamines; D017447:Receptors, Dopamine D1; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D017374:Paroxetine; D008694:Methamphetamine; D004298:Dopamine