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Comparative Study
, 220 (3), 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

Affiliations
Comparative Study

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 Murnane et al. Psychopharmacology (Berl).

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.

Figures

Figure 1
Figure 1
An illustration of the approximate anatomical localization of regions removed for neurochemical analysis overlaid on coronal sections reproduced from Paxinos and Franklin (2001). A. Coronal section at 1.54 mm anterior to Bregma showing the localization of the frontal cortex (light gray circle) and anterior striatum (dark gray circle). B. Coronal section at 0.02 mm anterior to Bregma showing the localization of the cingulate (light gray circle) and posterior striatum (dark gray circle). C. Coronal section at 2.06 mm posterior to Bregma showing the localization of the hippocampus (light gray circle) and amygdala (dark gray circle).
Figure 2
Figure 2
Effects of MDMA (closed squares), METH (closed circles), and PCA (closed triangles) in comparison to saline (open squares) on passive avoidance behavior. All points represent the mean ± SEM. Abscissae: Unit dose of each dosing regimen expressed as milligrams of drug / kilogram of body weight and plotted on a linear scale. Ordinates: Initial step-through latency (left) or the absolute change in step-though latency from the training session to the test session (right) expressed in seconds and plotted on a linear scale. An * indicates a significant difference (p < 0.05) from saline treatment assessed via a one-way repeated measures analysis of variance with post-hoc analysis carried out using Dunnett's test.
Figure 3
Figure 3
Peak absolute change in body weight (left) or rectal temperature (right) measured over the six hour dosing regimen at the maximum unit dosage used for each drug, regardless of the time point at which the peak change occurred. Abscissae: Drug treatment and the unit dose of the dosing regimen for that treatment. Ordinates: Peak absolute change in body weight (left) or rectal temperature (right) measured in grams or degrees Celsius, respectively, and plotted on a linear scale. Values are normalized to the baseline value for each subject. An * indicates a significant difference (p < 0.05) from saline treatment.
Figure 4
Figure 4
Correlation between the absolute change in step-through latency from the training session to the test session in the passive avoidance assay and tissue concentration of dopamine in the anterior striatum (left) or 5-HIAA in the cingulate (right) for MDMA (black closed squares), METH (gray closed circles), PCA (light gray closed triangles), and saline (open squares) treated subjects. Each data point represents values from a single subject. Best fit regression lines are overlaid for all subjects (black solid line) and subjects treated with a dosing regimen of PCA (gray dashed line) or METH (gray dotted line). Abscissae: The absolute change in step-though latency from the training session to the test session expressed in seconds and plotted on a linear scale. Ordinates: Tissue concentration of dopamine (left) or 5-HIAA (right) expressed as nanograms neurochemical / milligram tissue weight (ng/mg) and plotted on a linear scale.

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