How do SSRIs work?

Question

I've found a reasonable explanation on Wikipedia...

SSRIs are believed to increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor.

But I'm confused about one thing. The whole point of reuptake is that after serotonin (or any other neurotransmitter) binds to the postsynaptic receptors, it has to vacate the receptor so that other signals can be conveyed. If SSRIs inhibit the reuptake of serotonin, it remains in the synaptic cleft... but then what happens?

Do the serotonin molecules bind to the receptors multiple times, since they keep on ending up in the synaptic cleft? If so, when would this end, and how would it affect the signal across two neurons?

Answer 1

The serotonin that remains in the cleft continues to bind to receptors again and again, increasing the total membrane potential change in the postsynaptic neuron.

Think of this process as lowering the threshold for generating an action potential in the postsynaptic neuron. The serotonin that remains in the cleft has already changed potential of the postsynaptic neuron somewhat. Now, when a new release of neurotransmitter comes along, it has a greater chance of raising the membrane potential to the point that an action potential is generated.

While the effect of an SSRI on neurotransmitter levels can occur relatively quickly, most patients will not see an effect on their mood for several weeks. It is thought that the antidepressant action of these drugs may be an effect of a longer term downregulation of serotonin receptors. See Eison and Mullins (1996) for greater detail.

• Eison AS, Mullins UL (1996). "Regulation of central 5-HT2A receptors: a review of in vivo studies". Behavioural Brain Research 73 (1–2): 177–81.

Answer 2

When serotonin (5HT) uptake is inhibited, 5HT diffuses away from the synaptic cleft. It is believed that eventually 5HT disperses in the extracellular space and reaches the dendritic regions.

The delayed action (say, 2 weeks) can be explained by 5HT's action on 5HT₁A receptors in the dendritic region. After continuous activation of 5HT₁A receptors, they start to downregulate, which in turn changes the firing pattern of the serotonergic neuron into a more fluttering mode over time. This mode of firing tends to release a lot more 5HT (Lucas et al., 2007). Downregulation takes time, explaining the few weeks delayed onset.

<sub>Reference
- Duman, Neuron 2007;55: 679-81</sub>