Neurotoxic effects of chronic restraint stress in the striatum of methamphetamine-exposed rats.
BACKGROUND
Stress is a common experience in drug abusers. Methamphetamine (METH) is an abused psychostimulant that damages dopamine and serotonin terminals through pro-oxidant mechanisms and glutamate-mediated excitotoxicity. Both METH and stress increase dopamine and glutamate release in the striatum. Since dopamine inhibits striatal glutamate release and METH depletes dopamine, stress-induced glutamate release may be disinhibited after METH exposure.


OBJECTIVE
We examined if repeated stress would worsen excitotoxic damage to the striatum after METH pretreatment.


METHODS
In vivo microdialysis was used to examine stress-induced striatal glutamate release in rats pre-exposed to METH (7.5 mg/kg x 4 injections) or saline. The effects on striatal DA, serotonin, DAT, SERT, and spectrin proteolysis produced by chronic restraint stress (CRS, 6 h/day for 21 days) in the presence or absence of corticosterone synthesis inhibition by metyrapone (50 mg/kg) beginning 7 days after METH were also examined.


RESULTS
Stress-induced glutamate release was augmented in rats pre-exposed to METH. CRS 7 days after METH enhanced METH-induced DAT depletions from 23 to 44% in the nonstressed versus stressed rats, respectively. Striatal SERT and serotonin tissue content were decreased by 51 and 36%, respectively, in rats exposed to both METH and CRS but was unchanged by either treatment alone. Spectrin proteolysis was increased by 53% in rats treated with both METH and CRS but was unaffected by either treatment alone. Metyrapone blocked the effects of CRS on METH-induced depletions of SERT but not DAT.


CONCLUSIONS
Exposure to chronic stress depleted striatal dopamine and serotonin terminal markers possibly through excitotoxic mechanisms in METH-treated rats.
Quinton
M S
MS
Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
Yamamoto
B K
BK
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D008797:Metyrapone / Q000494:pharmacology; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000139:chemically induced* / Q000209:etiology / Q000378:metabolism
D000963:Antimetabolites; D015259:Dopamine Agents; D012701:Serotonin; D018698:Glutamic Acid; D008694:Methamphetamine; D004298:Dopamine; D008797:Metyrapone