Effects of a 5-HT4 receptor antagonist in the caudate nucleus on the performance of macaques in a delayed reward task

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT₄ receptor (5-HT₄R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT₄R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT₄R in the dCDh. We then examined the effects of a specific 5-HT₄R antagonist infused into the dCDh. Blockade of 5-HT₄R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT₄R blockade because saline controls showed no such effect. The results demonstrate that 5-HT₄Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT₄R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms.