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bioRxiv · 10.1101/2023.02.23.529630

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

Hori, Y.·Mimura, K.·Nagai, Y.·Kumata, K.·Zhang, M.-R.·Suhara, T.·Higuchi, M.·Minamimoto, T.
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Abstract

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.

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Hori, Y., Mimura, K., Nagai, Y., Kumata, K., Zhang, M.-R., Suhara, T., Higuchi, M., Minamimoto, T.. 2023-02-23. Reduced serotonergic transmission alters sensitivity to cost and reward via 5-HT1A and 5-HT1B receptors in monkeys. https://doi.org/10.1101/2023.02.23.529630

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