Mechanism Of Action

In the absence of pharmacological manipulation, the reuptake of 5-HT into the presynaptic nerve terminal typically leads to its inactivation. Fluoxetine, through blockade of the reuptake process, acutely enhances serotonergic neurotransmission by permitting 5-HT to act for an extended period of time at synaptic binding sites. A net result is an acute increase in synaptic 5-HT. One difference separating SSRIs from direct-acting agonists is that SSRIs are dependent on neuronal release of 5 HT for their action—that is, SSRIs can be considered augmenters of basal physiological signals, but they are not direct stimulators of postsynaptic receptor function and they are dependent on presynaptic neuronal integrity. These pharmacodynamic features might explain SSRI nonresponse. If the release of 5-HT from presynaptic neuronal storage sites is substantially compromised, and in turn, if net synaptic 5-HT concentration is negligible, a clinically meaningful response to an SSRI would not be expected.

Serotonin receptors also include a family of presynaptic autoreceptors that suppress the further release of 5-HT, thus limiting the degree of postsynaptic receptor stimulation that can be achieved. de Montigny et al. (1989) investigated the mechanism of action of several SSRIs and suggested that the enhanced efficacy of serotonergic synaptic transmission is not the result of increased postsynaptic sensitivity. Rather, longer-term SSRI treatment induced a desensitization of somatodendritic and terminal 5-HT autoreceptors. This desensitization would permit 5-HT neurons to reestablish a normal rate of firing, despite sustained reuptake blockade. These neurons could then release a greater amount of 5-HT (per impulse) into the synaptic cleft. This modification reportedly occurs over a time course that is compatible with the antidepressant response.

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