The underlying premise of Professor Okamoto’s hypothesis is that behavioural choices seem to be based on comparison of values which combine reward size and delay (small delay and small reward gives a small ‘value’ reward; big delay for big reward gives a big ‘value’ reward.)  Reward discounting is a theoretical concept of the ‘value’ of a reward after delay. Normal discounting results in a large reward whereas steep discounting results in a small, immediate reward.

Discounting serotonin means increased impulsivity

If 5-HT controls reward discounting in humans, a higher level of 5-HT -- ie levels found in healthy subjects -- means a higher setting of the discount factor. Such levels promote waiting for the delayed reward. However, lower levels of 5-HT ie levels found in depressive patients, are associated with a lower setting of the discount factor and so with more impulsive behaviour.

Dorsal striatum and prefrontal cortex activity indicative of reward patience

Human fMRI studies have shown that there is differential involvement of cortico-basal ganglia loops in the prediction of immediate and delayed rewards. In particular, the dorsal striatum and prefrontal cortex show consistent activity for delayed rewards. Combined behavioural and fMRI studies were undertaken to determine the role of 5HT in waiting for future rewards in depression.

In the first study, on each of three successive days, healthy male volunteers were given drinks containing no tryptophan (depleted), balanced amount of tryptophan (control) or excess tryptophan (loaded) and, after 1 hour, underwent fMRI scanning. In depleted conditions, volunteers preferred more immediate rewards and steeper discounting was also noted – they were more impatient.  Blood oxygenation level dependent (BOLD) signals in the striatum correlated with the discount factor. Serotonin appears to differentially regulate small and large discount factors in the ventral and dorsal striatum. Thus, the parallel loops in reward discounting might be differentially modulated in the striatum under different serotonin levels.

Greater discounting factors = greater hopelessness in MDD

In a modified version of the first study, study volunteers had either MDD, remitted MDD or were healthy controls. Those with MDD showed significantly larger discounting rates compared to controls. Discount factors correlated with the severity of hopelessness in the MDD group. However, the remitted MDD group did not differ from the healthy subjects.   Furthermore, the dorsal cortico-basal ganglia loops related to delayed rewards appear to be malfunctioning in depressive patients as activation in the dorsal striatum is attenuated during waiting for delayed rewards.

In a third study, a 5-HT1A receptor agonist was applied locally in the dorsal raphe nucleus (DRN) in rats to see if there was any causal relationship between serotonergic activity and waiting behaviour for delayed reward.

Suppression of 5-HT neural activity impairs patience

The 5-HT1A receptor agonist treatment suppressed 5-HT neural activity via autoreceptors. Rats performed a sequential food-water navigation task under two reward conditions: short or long delay. Suppression of 5-HT neural activity in the DRN by a 5-HT1A receptor agonist increased premature exit from reward sites before the delivery of delayed rewards, which indicated impaired patience. Thus, DRN activation is necessary for waiting for long delayed rewards in animals.

These findings support the hypothesis that 5-HT promotes waiting for longer delayed rewards, and might explain not only impulsivity but also other aspects of depressive behavior.