NEUROTOXICITY PROFILES OF SUBSTITUTED AMPHETAMINES IN THE C57BL 6J MOUSE/

Dopaminergic (DA) and serotonergic (5-HT) projections to striatum and cortex have been implicated as the primary targets of substituted amph etamine (AMP)-induced neurotoxicity, largely on the basis of the prope nsity of these compounds to cause protracted decrements in DA and 5-HT rather than on the basis of AMP-induced alterations of indices linked to neural damage. Moreover, most studies of AMP-induced neurotoxicity , regardless of the endpoints assessed, have been conducted using a ra t model; relatively little attention has been focused on the effects o f these compounds in the mouse. Here, we evaluated the potential neuro toxic effects of d-methamphetamine (dMETH), d-methylenedioxyamphetamin e (d-MDA), d-methylenedioxymethamphetamine (d-MDMA) and d-fenfluramine (d-FEN) in the C57BL6/J mouse. Astrogliosis, assessed by quantificati on of glial fibrillary acidic protein (GFAP), was taken as the main in dex of AMP-induced neural damage. A silver degeneration stain also was used to obtain direct evidence of AMP-induced neuronal damage. Assays of tyrosine hydroxylase (TH), DA and 5-HT were used to assess effects on DA and 5-HT systems. Mice received d-METH (10 mg/kg), d-MDA (20 mg /kg), d-MDMA (20 mg/kg) or d-FEN (25 mg/kg) every 2 hr for a total of four s.c. injections. d-METH, d-MDA and d-MDMA caused a large (300%) i ncrease in striatal GFAP that resolved by 3 weeks and a 50 to 75% decr ease in TH and DA that did not resolve. d-METH, d-MDA and d-MDMA also caused fiber and terminal degeneration in striatum as revealed by silv er staining. d-FEN did not affect any parameters in striatum. d-METH, d-MDA and d-MDMA also increased GFAP in cortex, effects that were asso ciated with small (10-25%) and transient decrements in cortical 5-HT. d-FEN caused prolonged (weeks) decrements (20%) in cortical 5-HT but d id not affect cortical GFAP. The effects of d-METH, d-MDA and d-MDMA w ere stereoselective and were blocked by pretreatment with MK-801. Core temperature was slightly elevated by d-METH, d-MDA and d-MDMA but was dramatically lowered by d-FEN. The data suggest that d-METH, d-MDA an d d-MDMA, but not d-FEN, produce damage to neural elements of mouse st riatum and cortex.