Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons

Amphetamine analogs have emerged as popular recreational drugs of abuse. Th e number of reports of these substances producing severe acute toxicity and death is increasing, In 'Ecstasy'-associated deaths, focal necrosis in the liver and individual myocytic necrosis has been reported. Furthermore, ser otonergic and dopaminergic neuronal cell damage has been observed in experi mental amphetamine intoxication in laboratory animals, Here we demonstrate that subchronic exposure to D-amphetamine, methamphetamine, methylenedioxya mphetamine, and methylenedioxymethamphetamine ('Ecstasy') results in signif icant neurotoxicity in rat neocortical neurons in vitro, This neuronal cell death is accompanied by endonucleosomal DNA cleavage and differential expr ession of anti- and proapoptotic bcl-x(L/S) splice variants. In addition, w e observed pronounced induction of cell stress-associated transcription fac tor c-jun and translation initiation inhibitor p97 after amphetamine treatm ent. These data support that the neurotoxic effects of different amphetamin es are extended to rat neocortical neurons and that apoptotic pathways are involved in amphetamine-induced neurotoxicity.