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

Nicole K. Horst, Bianca Jupp, Angela C. Roberts, Trevor W. Robbins

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)564-571
Number of pages8
Issue number3
Publication statusPublished - 1 Feb 2019
Externally publishedYes

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