D2 receptors and cognitive flexibility in marmosets: tri-phasic dose-response effects of intra-striatal quinpirole on serial reversal performance.

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Jupp, Bianca 
Roberts, Angela C 
Robbins, Trevor W 

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.

Animals, Behavior, Animal, Callithrix, Caudate Nucleus, Discrimination Learning, Dopamine Agonists, Dose-Response Relationship, Drug, Female, Male, Quinpirole, Receptors, Dopamine D2, Reversal Learning, Serial Learning
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Springer Science and Business Media LLC
Wellcome Trust (104631/Z/14/Z)
Medical Research Council (MR/J012084/1)
Medical Research Council (G1000183)
Medical Research Council (G0001354)
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