title: Co-administration of betulinic acid and methamphetamine causes toxicity to dopaminergic and serotonergic nerve terminals in the striatum of late adolescent rats.
abstract: Psychostimulant methamphetamine (METH) is toxic to striatal dopaminergic and serotonergic nerve terminals in adult, but not in the adolescent, brain. Betulinic acid (BA) and its derivatives are promising anti-HIV agents with some toxic properties. Many METH users, particularly young men, are HIV-positive; therefore, they might be treated with BA or its derivative for HIV infection. It is not known whether BA, or any of its derivatives, are neurotoxic in combination with METH in the adolescent brain. The present study investigated the effects of BA and binge METH in the striatum of late adolescent rats. BA or METH alone did not decrease the levels of dopaminergic or serotonergic markers in the striatum whereas BA and METH together decreased these markers in a BA dose-dependent manner. BA+METH also caused decreases in the levels of mitochondrial complex I in the same manner; BA alone only slightly decreased the levels of this enzyme in striatal synaptosomes. BA or METH alone increased cytochrome c. METH alone decreased parkin, increased complex II and striatal BA levels. These results suggest that METH in combination with BA can be neurotoxic to striatal dopaminergic and serotonergic nerve terminals in the late adolescent brain via mitochondrial dysfunction and parkin deficit. We report a synergistic neurotoxicity of betulinic acid (BA) and methamphetamine (METH) to monoaminergic terminals in the striatum of male late adolescent rats. BA contribution to the neurotoxicity is decreasing mitochondrial complex I whereas METH contribution is decreasing parkin and increasing brain concentration of BA. We propose that clinical use of BA in young male METH users can be neurotoxic.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.
authors.forename: Bryan
authors.initials: B
authors.lastname: Killinger
authors.forename: Mrudang
authors.initials: M
authors.lastname: Shah
authors.forename: Anna
authors.initials: A
authors.lastname: Moszczynska
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002918:Chymotrypsin / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D042963:Electron Transport Complex II / Q000187:drug effects / Q000378:metabolism; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology*; D009411:Nerve Endings / Q000187:drug effects*; D053978:Pentacyclic Triterpenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D059326:Serotonergic Neurons / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000473:pathology; D014315:Triterpenes / Q000633:toxicity*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000094062:Betulinic Acid
chemical_list: D019380:Anti-HIV Agents; D015259:Dopamine Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D008694:Methamphetamine; D045304:Cytochromes c; D042963:Electron Transport Complex II; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D002918:Chymotrypsin; D053148:Caspase 3; D042967:Electron Transport Complex I; D000094062:Betulinic Acid
keywords: betulinic acid; methamphetamine; mitochondria; neurotoxicity; striatum