Reduced serotonergic transmission alters sensitivity to cost and reward via 5-HT1A and 5-HT1B receptors in monkeys

Deficiency of the serotonin (5-HT) system is considered one of the core biological pathologies of depression and other psychiatric disorders whose key symptom is decreased motivation. Yet, the exact role of 5-HT in motivation remains controversial and elusive. Here, we pharmacologically manipulated the 5-HT system and quantified effects on motivation in terms of incentives and costs for goal-directed action in monkeys. Reversible inhibition of 5-HT synthesis increased refusal responses and reaction times in goal-directed task performance, indicating decreased motivation that could be separated into value-dependent and -independent components. To identify the receptor subtypes involved in these components, we systemically administered antagonists specific for four major 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4. Positron emission tomography visualized the unique distribution of each subtype in limbic brain regions and determined the systemic antagonist dose that achieved approximately 30% occupancy. We found that blockade of 5-HT1A, but not other receptor subtypes, increased sensitivity to future workload and time-delay to reward, and decreased motivation in a value-independent manner. Moreover, blocking only 5-HT1B receptors reduced the impact of incentive value on motivation. These results suggest that two distinct processes, mediated by 5-HT1A and 5-HT1B receptors, lead to reduced motivation in 5-HT system deficiency.