Effects of exposure to amphetamine derivatives on passive avoidance performance and the central levels of monoamines and their metabolites in mice: correlations between behavior and neurochemistry

• Authors: Kevin Murnane, Emory University; Shane Alan Perrine, Wayne State University; Brendan James Finton, Yerkes National Primate Research Center; Matthew Peter Galloway, Wayne State University; Leonard Howell, Emory University; William Edward Fantegrossi, Emory University
• Journal Title: Psychopharmacology
• Volume: Volume 220, Number 3
• Publisher: Springer Verlag (Germany) | 2012-04, Pages 495-508
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s00213-011-2504-0
• Subjects: Health Sciences, Pharmacology
• Keywords: Drug abuse; amphetamine; neurotoxicity; monoamine; mouse; dopamine; learning and memory; behavior; methamphetamine; HPLC

Abstract

Rationale Considerable evidence indicates that amphetamine derivatives can deplete brain monoaminergic neurotransmitters. However, the behavioral and cognitive consequences of neurochemical depletions induced by amphetamines are not well established. Objectives In this study, mice were exposed to dosing regimens of 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH), or para-chloroamphetamine (PCA) known to deplete the monoamine neurotransmitters dopamine and serotonin, and the effects of these dosing regimens on learning and memory were assessed. Methods In the same animals, we determined deficits in learning and memory via passive avoidance (PA) behavior and changes in tissue content of monoamine neurotransmitters and their primary metabolites in the striatum, frontal cortex, cingulate, hippocampus, and amygdala via ex vivo high pressure liquid chromatography. Results Consistent with previous studies, significant reductions in tissue content of dopamine and serotonin were readily apparent. In addition, exposure to METH and PCA impaired PA performance and resulted in significant depletions of dopamine, serotonin, and their metabolites in several brain regions. Multiple linear regression analysis revealed that the tissue concentration of dopamine in the anterior striatum was the strongest predictor of PA performance, with an additional significant contribution by the tissue concentration of the serotonin metabolite 5-hydroxyindoleacetic acid in the cingulate. In contrast to the effects of METH and PCA, exposure to MDMA did not deplete anterior striatal dopamine levels or cingulate levels of 5-hydroxyindoleacetic acid, and it did not impair PA performance. Conclusions These studies demonstrate that certain amphetamines impair PA performance in mice and that these impairments may be attributable to specific neurochemical depletions.