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Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine.
Eur J Pharmacol. 1990 Nov 20; 191(1):1-10.EJ

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+Show Affiliations

Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

1982656

Citation

Johnson, M P., et al. "Behavioral, Biochemical and Neurotoxicological Actions of the Alpha-ethyl Homologue of P-chloroamphetamine." European Journal of Pharmacology, vol. 191, no. 1, 1990, pp. 1-10.
Johnson MP, Huang XM, Oberlender R, et al. Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine. Eur J Pharmacol. 1990;191(1):1-10.
Johnson, M. P., Huang, X. M., Oberlender, R., Nash, J. F., & Nichols, D. E. (1990). Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine. European Journal of Pharmacology, 191(1), 1-10.
Johnson MP, et al. Behavioral, Biochemical and Neurotoxicological Actions of the Alpha-ethyl Homologue of P-chloroamphetamine. Eur J Pharmacol. 1990 Nov 20;191(1):1-10. PubMed PMID: 1982656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine. AU - Johnson,M P, AU - Huang,X M, AU - Oberlender,R, AU - Nash,J F, AU - Nichols,D E, PY - 1990/11/20/pubmed PY - 1990/11/20/medline PY - 1990/11/20/entrez SP - 1 EP - 10 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 191 IS - 1 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/1982656/Behavioral_biochemical_and_neurotoxicological_actions_of_the_alpha_ethyl_homologue_of_p_chloroamphetamine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0014-2999(90)94090-K DB - PRIME DP - Unbound Medicine ER -