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

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 44; no. 3; pp. 564 - 571
• Main Authors: Horst, Nicole K., Jupp, Bianca, Roberts, Angela C., Robbins, Trevor W.
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.02.2019; Springer International Publishing
• Subjects: Addictions; Animals; Behavior, Animal - drug effects; Callithrix; Caudate nucleus; Caudate Nucleus - drug effects; Cognitive ability; Discrimination Learning - drug effects; Dopamine; Dopamine Agonists - administration & dosage; Dopamine Agonists - pharmacology; Dopamine D2 receptors; Dose-Response Relationship, Drug; Drug addiction; Environmental changes; Female; Flexibility; Male; Mental disorders; Neostriatum; Neuroimaging; Obsessive compulsive disorder; Quinpirole; Quinpirole - administration & dosage; Quinpirole - pharmacology; Receptors, Dopamine D2 - physiology; Reversal learning; Reversal Learning - drug effects; Serial Learning - drug effects
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-018-0272-9

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.