Abstract
Behavioral flexibility, which allows organisms to adapt their actions in response to environmental changes, is impaired in a number of neuropsychiatric conditions, including obsessive-compulsive disorder and addiction. Studies in human subjects and monkeys have reported correlations between individual differences in dopamine D2-type receptor (D2R) levels in the caudate nucleus and performance in a discrimination reversal task, in which established contingent relationships between abstract stimuli and rewards (or punishments) are reversed. Global genetic deletion of the D2R in mice disrupts reversal performance, indicating a likely causal role for this receptor in supporting flexible behaviors. To directly examine the specific role of caudate D2-type receptors in reversal performance, the D2/3/4R agonist quinpirole was infused via chronic indwelling cannulae into the medial caudate of male and female marmoset monkeys performing a touchscreen-based serial discrimination reversal task. Given prior evidence for dose-dependent effects of quinpirole and other dopaminergic drugs, a full dose-response curve was established. Individually, marmosets displayed marked differences in behavioral sensitivity to specific doses of intra-caudate quinpirole. Collectively, they exhibited a behaviorally specific bi-phasic deficit in reversal learning, being consistently impaired at both relatively low and high doses of quinpirole. However, intermediate doses of intra-caudate quinpirole produced significant improvement in reversal performance. These data support previous human and monkey neuroimaging studies by providing causal evidence of a U-shaped function describing how dopamine modulates cognitive flexibility in the primate striatum.
Highlights
The ability to adapt one’s actions following changes in the relationship between a stimulus in the environment and its associated outcome is a central component of cognitive flexibility
Post hoc general linear hypothesis tests on the model of reversal phase dose effects revealed that low doses of quinpirole increased (p = 0.0027) while mid-range doses decreased (p < 0.030) the error difference score as compared to saline, as well as a significant difference between low-range and mid-range doses (p < 1.4 × 10−7). These results provide evidence in support of the first two arms of the tri-phasic effects of intracaudate quinpirole on reversal performance (Fig. 3c)
The main findings from this study were that the D2-like agonist quinpirole infused into the medial caudate nucleus of marmoset monkeys over a very wide dose range (0.003–10.0 μg/0.5 μl) produced tri-phasic behavioral effects, on visual reversal learning performance in a computerized touchscreen paradigm: low dose impairments, mid-range dose improvements in the majority of animals, and high dose disruptions
Summary
The ability to adapt one’s actions following changes in the relationship between a stimulus in the environment and its associated outcome is a central component of cognitive flexibility Dysfunction in this domain is evident in conditions like obsessive-compulsive disorder (OCD) and addiction [1], wherein habit-like, compulsive behavior supersedes normal goal-directed behavior [2]. Such behavior can be modelled experimentally using a reversal task, wherein a previously learned stimulus-outcome association is reversed, and subjects must desist responding toward the formerly rewarded stimulus to redirect their responses toward a stimulus with no recent association with reward. Anatomical and functional differences have been identified in this region in OCD patients [11, 12] and stimulant abusers [13]
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