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Repeated exposure results in the loss of the neuroprotective properties of restraint-induced hypothermia in the substituted amphetamine model of striatal dopaminergic neurotoxicity.

Johnson-EA; O'Callaghan-JP; Miller-DB
Toxicologist 1999 Mar; 48(1-S):290
Substituted amphetamines (SA) are well characterized striatal dopaminergic (DA) neurotoxicants in mouse and restraint stress throughout the period of dosing prevents this neurotoxicity. The mechanism of this neuroprotection is unclear but appears linked to the ability of restraint to reduce SA-induced hyperthermia. We investigated whether with repeated exposure restraint remains neuro-protective. Female C57BL6J mice received 4 s.c. inj (0.2 mls every 2 hrs) of saline (SAL) or d-methylenedioxymethamphetamine (MDMA) at a dosage of 0 or 20 mg/kg, respectively on the 0, 1 (acute restraint) or 5th (repeated restraint) day of restraint (8 hrs duration in plastic 50 ml centrifuge tubes) and rectal temperatures were monitored. On day 1-4 mice in the repeated restraint condition received SAL. Striatal tissue was collected at 72 hrs and levels of DA, its metabolites, tyrosine hydroxylase (TH) and GFAP (an astrocyte-localized protein known to increase in response to neural injury) were used to evaluate neurotoxicity. In concert with our previous findings MDMA induced hyperthermia and caused striatal dopaminergic neurotoxicity as indicated by significant depletions of DA and TH as well as elevations in GFAP; acute restraint blocked this hyperthermia and was neuroprotective. In repeatedly restrained mice significant core temperature reductions were observed on each of the first 4 days of restraint but not during MDMA administration on the final day. Neuroprotection was not observed in repeatedly restrained mice. These data suggest that hypothermia induced by restraint is a critical factor in the neuroprotective effects of this stressor. The molecular and cellular changes associated with acute and chronic restraint stress will be the focus of future work.
Toxins; Toxicology; Toxic-materials; Laboratory-animals; Animal-studies; Neurotoxins; Neurotoxic-effects; Statistical-analysis; Analytical-chemistry; Analytical-methods; Chemical-analysis; Hyperthermia; Dose-response; Exposure-assessment; Risk-analysis; Methyl-compounds
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The Toxicologist. Society of Toxicology 38th Annual Meeting, March 14-18, 1999, New Orleans, Louisiana