Monoamine levels within the orbitofrontal cortex and putamen interact to predict reversal learning performance

Abstract

Background: The compulsive and inflexible behaviors that are present in many psychiatric disorders, particularly behavioral addictions and obsessive-compulsive disorder, may be due to neurochemical dysfunction within the circuitry that enables goal-directed behaviors. Experimental removal of serotonin or dopamine within the orbitofrontal cortex or dorsal striatum, respectively, impairs flexible responding in a reversal learning test, suggesting that these neurochemical systems exert important modulatory influences on goal-directed behaviors. Nevertheless, the behavioral impairments present in psychiatric disorders are likely due to subtle neurochemical differences, and it remains unknown whether naturally occurring variation in neurochemical levels associate with individual differences in flexible, reward-directed behaviors.

Methods: The current study assessed the ability of 24 individual juvenile monkeys to acquire, retain, and reverse discrimination problems and examined whether monoamine levels in the orbitofrontal cortex, caudate nucleus, and putamen could explain variance in behavior.

Results: The interaction between dopamine levels in the putamen and serotonin levels in the orbitofrontal cortex explained 61% of the variance in a measure of behavioral flexibility but not measures of associative learning or memory. The interaction mirrored that of a hyperbolic function, with reversal learning performance being poorest in either monkeys with relatively low levels of orbitofrontal serotonin and putamen dopamine or in monkeys with relatively high levels of orbitofrontal serotonin and putamen dopamine levels.

Conclusions: These results support the hypothesis that subcortical and cortical neuromodulatory systems interact to guide aspects of goal-directed behavior, providing insight into the neurochemical dysfunction that may underlie the inflexible and compulsive behaviors present in psychiatric disorders.

Conflict of interest statement

Financial disclosure

The authors have no biomedical financial interests or potential conflicts of interest to disclose.

Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

A depiction of the brain regions collected for quantification of monoamine levels. The shaded area in Figure 1A (predominately Brodmann’s area 47) represents the area of the orbitofrontal cortex extracted (Bregma 13.50mm; Interaural 35.40mm). Tissue punches from the caudate nucleus and putamen (represented by the grey circles) were collected from tissue slices similar to that presented in Figure 1B (Bregma 2.70mm; Interaural 24.60mm). Figures were obtained from the Rhesus Monkey Brain in stereotaxic coordinates (37).

Figure 2

A three-dimensional plot of the relationship between standardized levels of dopamine in the putamen, standardized levels of serotonin in the orbitofrontal cortex and standardized behavioral performance measures in the acquisition (Figure 2A), retention (Figure 2B) and reversal (Figure 2C) phase. Values for individual monkeys are presented in closed circles. The transparent plane overlaid on the individual data points represents how the interaction between levels of dopamine in the putamen and serotonin in the orbitofrontal cortex predicts the number of trials required to reach criterion in each of the phases of the task. Relatively high trials to reach criterion is indicative of poorer performance in each stage.

Figure 3

A three-dimensional plot of the relationship between prefrontal and striatal neurochemical levels on reversal learning performance. Values for individual monkeys are presented in close circles. The transparent plane overlaid on the individual data points represents how the interaction between levels of monoamines predict the number of trials required to reach criterion in the reversal phase. Figure 3A presents the relationship between standardized levels of serotonin in the putamen, dopamine in the orbitofrontal cortex and reversal learning performance. Figure 3B presents the relationship between standardized levels of dopamine in the caudate nucleus, serotonin in the orbitofrontal cortex and reversal learning performance. Relatively high trials to reach criterion is indicative of poorer performance in each stage.