title: Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine.
abstract: The present set of experiments was designed to examine the effects of extension of the alpha-methyl of p-chloroamphetamine (PCA) to an alpha-ethyl. Therefore, the alpha-ethyl homologue of PCA, 1-(4-chlorophenyl)-2-aminobutane (CAB), was compared to PCA in a number of pharmacological assays. CAB was 2-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and 5-fold less potent at inhibiting uptake of [3H]dopamine ([3H]DA). In drug discrimination assays, CAB was approximately 3-fold less potent than PCA in animals trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or its alpha-ethyl homologue, S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-(+)-MBDB), from saline. Monitoring with in vivo microdialysis, 10 mg/kg of PCA caused a large increase in extracellular DA and a significant decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. In contrast, 11 mg/kg CAB caused no increase and 22 mg/kg CAB caused only a slight increase in extracellular DA. Both doses of CAB caused a decrease in extracellular DOPAC. The potential 5-HT neurotoxicity of CAB was examined by measuring monoamine and metabolite levels and [3H]paroxetine binding at one week following acute doses. A 10 mg/kg dose of PCA caused an 80% decrease in cortical and hippocampal serotonergic markers, while an equimolar dose of CAB decreased only hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels. However, 22 mg/kg of CAB produced a 20-40% decrease in all serotonergic markers. Thus, extension of the alpha-alkyl significantly decreases the dopaminergic effects of PCA. The similar decrease in relative 5-HT neurotoxicity and the decreased ability to alter dopaminergic systems in vivo and in vitro supports the involvement of DA in the neurotoxicity of PCA.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
authors.forename: M P
authors.initials: MP
authors.lastname: Johnson
authors.forename: X M
authors.initials: XM
authors.lastname: Huang
authors.forename: R
authors.initials: R
authors.lastname: Oberlender
authors.forename: J F
authors.initials: JF
authors.lastname: Nash
authors.forename: D E
authors.initials: DE
authors.lastname: Nichols
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009420:Nervous System / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D010133:p-Chloroamphetamine / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: C068405:1-(4-chlorophenyl)-2-aminobutane; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D010133:p-Chloroamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine