Original Investigation

Psychopharmacology

, Volume 220, Issue 3, pp 495-508

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

  • Kevin Sean MurnaneAffiliated withDivision of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Yerkes Imaging Center Email author 
  • , Shane Alan PerrineAffiliated withDepartment of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine
  • , Brendan James FintonAffiliated withDivision of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Yerkes Imaging CenterDepartment of Medical and Clinical Psychology, Uniformed Services University
  • , Matthew Peter GallowayAffiliated withDepartment of Psychiatry and Behavioral Neurosciences, Wayne State University School of MedicineDepartment of Anesthesiology, Wayne State University School of Medicine
  • , Leonard Lee HowellAffiliated withDivision of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Yerkes Imaging CenterDepartment of Psychiatry and Behavioral Sciences, Emory University
  • , William Edward FantegrossiAffiliated withDepartment of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences

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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 parachloroamphetamine (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

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.

Keywords

Drug abuse Amphetamine Neurotoxicity Monoamine Mouse Dopamine Learning and memory Behavior Methamphetamine HPLC