Restraint stress and other neuroprotective manipulations increase brain concentration of d-3,4-methylenedioxymethamphetamine (D-MDMA) in C57BL/6J mouse.
Toxicologist 2001 Mar; 60(1):344
Temperature lowering manipulations, including restraint stress as well as co-administration of temperature lowering agents have proven protective against the dopaminergic neurotoxicity induced by repeated doses of d-MDMA. It is reasonable to expect that such neuroprotective effects may arise from an alteration in the amount of toxic compound that is able to reach the target site, in this case the striatum of mouse brain. Therefore, we determined brain concentrations of unchanged drug at two hours after completion of drug administration (d-MDMA 15 mg/kg. s.c. given every 2 hours for a total of 4 doses) using an HPLC assay with fluorimetric detection of d-MDMA. Restraint stress increased by 3 fold the amount of d-MDMA that reached striatum. Similarly, co-administration of ethanol 3 gm/kg (s.c. given 30 minutes before the first and third doses of d-MDMA) increased by 5 fold the striatal concentration of d-MDMA. Both these manipulations are associated with neuroprotection. The results imply that protection of the neurotoxic effecs of d-MDMA is due to altered pharmacokinetics. The results suggest that dopaminergic neurotoxicity induced by d-MDMA is a result of drug metabolism which yields a product that is toxic to nigrostriatal neurons of mouse. Both restraint stress and ethanol co-administration may be neuroprotective by inhibition of the production of a toxic metabolite of d-MDMA. An equally neuroprotective manipulation, co-administration of MK-801 1mg/kg s.c. 30 minutes before the first and third dose of d-MDMA, reduced body temperature but only doubled the concentration of d-MDMA in striatum. All these manipulations lower body temperature but alter distribution to disimilar extents. Overall these data suggest that there may be multiple mechanisms of neuroprotection against d-MDMA- induced dopaminergic neurotoxicity in mouse.
Stress; Temperature-control; Ethanols; Neurotoxic-effects; Neurotoxicity; Body-temperature
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California