M S Quinton1, B K Yamamoto. 1. Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
Abstract
RATIONALE: 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. MATERIALS AND 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.
RATIONALE: 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. MATERIALS AND 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.
Authors: T V Gurvits; M E Shenton; H Hokama; H Ohta; N B Lasko; M W Gilbertson; S P Orr; R Kikinis; F A Jolesz; R W McCarley; R K Pitman Journal: Biol Psychiatry Date: 1996-12-01 Impact factor: 13.382
Authors: Mark S Gold; Firas H Kobeissy; Kevin K W Wang; Lisa J Merlo; Adriaan W Bruijnzeel; Irina N Krasnova; Jean Lud Cadet Journal: Biol Psychiatry Date: 2009-04-05 Impact factor: 13.382