Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus

Abstract

Studies of visual discrimination reversal learning have revealed striking neurochemical dissociations at the level of the orbitofrontal cortex (OFC) with serotoninergic, but not dopaminergic, integrity being important for successful reversal learning. These findings have considerable implications for disorders such as obsessive compulsive disorder and schizophrenia, in which reversal learning is impaired, and which are primarily treated with drugs targeting the dopaminergic and serotoninergic systems. Dysfunction in such disorders however, is not limited to the OFC and extends subcortically to other structures implicated in reversal learning, such as the medial caudate nucleus. Therefore, because the roles of the serotonin and dopamine within the caudate nucleus are poorly understood, this study compared the effects of selective serotoninergic or selective dopaminergic depletions of the marmoset medial caudate nucleus on serial discrimination reversal learning. All monkeys were able to learn novel stimulus-reward associations but, unlike control monkeys and monkeys with selective serotoninergic medial caudate depletions, dopamine-depleted monkeys were markedly impaired in their ability to reverse this association. This impairment was not perseverative in nature. These findings are the opposite of those seen in the OFC and provide evidence for a neurochemical double dissociation between the OFC and medial caudate in the regulation of reversal learning. Although the specific contributions of these monoamines within the OFC-striatal circuit remain to be elucidated, these findings have profound implications for the development of drugs designed to remediate some of the cognitive processes underlying impaired reversal learning.

Figure 1.

A schematic diagram illustrating the sequence of visual discriminations presented during the study and their occurrence relative to surgery. For each discrimination, correct and incorrect exemplars are indicated by the + and −, respectively. Actual stimuli were multicolored.

Figure 2.

Postmortem depletions of DA in the medial head of the caudate as a function of time since surgery in DA-depleted monkeys. The gray region indicates the time period in which reversals (rev) 1, 2, and 3 were completed by the dopamine-depleted monkeys. The horizontal lines represent the maximum duration of each reversal (extending from the earliest starting point to the latest endpoint and thus reflecting the quickest and slowest learning monkeys, respectively), and the vertical marks on the lines represent the mean time points for the beginning and end of the reversal. Thus, the periods where the maximal behavioral impairment is seen correspond to high levels of medial caudate dopamine depletion. a, b, and c, Pilot lesions 10, 95, and 141 d postsurgery, respectively; d, termination of current behavioral study. Inset; Dopamine depletions in all striatal regions for monkeys a–c.

Figure 3.

Serial discrimination reversal performance. A, Total errors to criterion for each reversal (rev). Repeated-measures ANOVA revealed a main effect of group (p = 0.025) attributable to an increased number of errors in the dopamine-depleted group. B, Total errors, collapsed across reversals. *p < 0.05. C, Mean perseveration, chance, and learning errors, showing that the increase in errors shown by the dopamine-depleted monkeys was not due to a specific error type (error type × group interaction, F < 1).