The effects of p-chloroamphetamine, methamphetamine and 3,4-methylenedioxymethamphetamine (ecstasy) on the gene expression of cytoskeletal proteins in the rat brain.
Repeated administration of beta-phenylalkylamines is known to produce neuronal changes in the central and peripheral nervous systems of mammals. It is suggested that various components of the cytoskeleton undergo profound alterations after amphetamine use and misuse, contributing to behavioral changes and neurotoxicity. Here we studied the expression of microtubule-associated protein 2 (MAP2) and beta-actin after repeated intraperitoneal applications with equimolar doses of p-chloroamphetamine (PCA), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) in the brain of male Wistar rats. Effective (molecular) pharmacological doses (ED) were derived and used for the calculation of (molecular) pharmacological indices (PI). Besides clear but different dose-response curves on the toxicity of the drugs, in situ hybridization and Western blot analysis revealed that repeated administration of these compounds resulted in different substance- and dose-dependent changes in MAP2 gene expression, e.g. in the frontoparietal somatosensoric cortex. In contrast, the expression of beta-actin was not influenced by any of the compounds at the dose levels tested. Lethal doses were determined with 2.1 (PCA), >5.1 (METH) and 8.4 mg/kg/day (MDMA). Linear and non-linear repeat-dose lethality was observed for MDMA and PCA, respectively, whereas METH was non-lethal in the dose range used. Values for ED(MAP2) were 0.3, 0.52 and >16.8 mg/kg/day, and therefore those for PI(MAP2) were 20, 4, and 0.5 for METH, PCA and MDMA, respectively. Although the results on mortality did not reflect changes in MAP2 gene expression, they suggest a remarkable difference for those amphetamines without substituents or with a halogen atom at the paraposition of the benzene ring, such as METH or PCA, when compared with MDMA-like substances.
Putzke
Jörg
J
Institute of Medical Neurobiology, OvG-University, Germany. joerg.putzke@parexel.com
Spina
Mariarosa G
MG
Büchler
Jochen
J
Kovar
Karl-Artur
KA
Wolf
Gerald
G
Smalla
Karl-Heinz
KH
D000199:Actins / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D001931:Brain Mapping; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D010133:p-Chloroamphetamine / Q000633:toxicity*
D000199:Actins; D000697:Central Nervous System Stimulants; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D008694:Methamphetamine; D010133:p-Chloroamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine