Why do SRIs help in serotonergic neurotransmission?

Question

Serotonin reuptake inhibitors (SRIs) block the action of the serotonin transporter (SERT) which, according to Wikipedia, leads to an increase in serotonergic neurotransmission.

Now this book summarizes serotonergic neurotransmission as follows:

[The neurotransmitter] binds to specific receptors on the postsynaptic cell, thereby generating a postsynaptic electrical signal [...]. The transmitter must then be removed rapidly to enable the postsynaptic cell to engage in another cycle of neurotransmitter release, binding, and signal generation. [Neurotransmitters are removed by] reuptake into nerve terminals [...].

So my question is the following: If, as stated in the quote, the transmitter must be removed rapidly, shouldn't an increased amount / binding potential of SERT actually be a good thing because if there are more transporters, the process of removing the neurotransmitter is much faster? And consequently, why would blocking the SERTs help in serotonergic neurotransmission? Is it because the neurotransmitter must remain in the synaptic cleft for a certain amount of time? Is it because the reuptake takes place before the neurotransmitter could bind to the receptors of the postsynaptic cell? Or ist there yet another reason?

Answer 1

Excellent question.

Different neurotransmitters operate at different temporal scales (and even the same transmitter can operate at different temporal scales). Examples of the fastest-acting neurotransmitters are glutamate, GABA, and acetylcholine (with the caveat that they can also act more slowly). These neurotransmitters (usually) open ion channels in the postsynaptic cell, and are cleared rapidly after release, which allows for a temporally precise code, with each release event individually important.

Other neurotransmitters are also considered neuromodulators, such as dopamine, serotonin, epinephrine/norepinephrine, and others. While the basic machinery for release is the same, these neuromodulators aren't cleared as fast, bind to g-protein coupled receptors, and their concentrations can build in the synaptic space between neurons when the presynaptic cell fires multiple action potentials in sequence. For these neurotransmitters/neuromodulators, the amount of neurotransmitter sitting around outside the cell acts as a time average of release in the recent past.

SRIs/SSRIs/similar drugs slow down the reuptake process, such that the concentration of serotonin reaches higher levels with the same presynaptic activity.

Although reuptake can also be important to "restock" the presynaptic cell with neurotransmitter for release, there is typically enough precursor around that reuptake is not the only limiting step.

Your suggested reasoning that is closest to the truth is both: "...because the neurotransmitter must remain in the synaptic cleft for a certain amount of time? Is it because the reuptake takes place before the neurotransmitter could bind to the receptors of the postsynaptic cell?" but it isn't that the transmitter "must remain" longer or that reuptake takes place "before" it can bind: it is that if the neurotransmitter remains longer it has a larger integrated effect on the postsynaptic cell.

Lastly, "good thing" is relative - of course increasing SERT activity would help with faster transmission, but faster transmission might not be important/necessary/fit the function of the circuit where serotonergic signalling is involved.