For a better understanding of the neurobiology of premature and delayed ejaculation and its treatments, it is a prerequisite to have some basic knowledge of what is happening in serotonergic neurons in the central nervous system (1,2).
Serotonergic neurons originate in the raphe nuclei and adjacent reticular formation in the brainstem. There is a clear dichotomy in the serotonergic (5-hydroxytryptamine, 5-HT) system neuronal cell groups (1). A rostral part with cell-bodies in the midbrain and rostral pons projecting to the forebrain and a caudal part with cell-bodies predominantly in the medulla oblongata with projections to the spinal cord. In the forebrain and spinal cord, the serotoner-gic neurons contact other serotonergic neurons. The location of connection is the synaps, in which the neurotransmitter serotonin provides information from one neuron to another. After its fabrication in the cell-body, serotonin runs through the serotonergic neuron to the presynaptic membrane, through which it is released into the synaps. In the synaps, serotonin proceeds to receptors at the opposite neuron (postsynaptic receptors) and after it has contacted these receptors serotonin runs back to the presynaptic membrane. Through the activity of serotonin transporters (5-HTT) in the presynaptic membrane, serotonin is brought back into the presynaptic neuron. The process of serotonin release and its action on postsynaptic receptors is called serotonergic neurotransmission.
There is normally a sort of equilibrium in the serotonergic neurotransmission system due to remarkable mechanisms. If too much serotonin is released from the presynaptic neuron into the synaps, the so-called 5-HT1B autoreceptors, located in the presynaptic membrane, become activated. Their activation results in a diminished release of serotonin in the synaps. Consequently, the equilibrium is restored. This feedback mechanism of the cell, where the released 5-HT inhibits its own release, is a frequently occurring principle in neurotransmitter regulation and can allow the system with the possibility to prevent overstimulation of postsynaptic receptors (1).
However, serotonergic neurotransmission becomes seriously disturbed by the action of serotonergic antidepressants. Selective serotonin reuptake inhibitors (SSRIs) block the 5-HT transporters, both in the presynaptic membrane and around the cell-body. As a consequence, serotonin concentration increases outside the cell-body and in the synapses. Owing to the increased serotonin levels, 5-HT1A autoreceptors at the surface of the cell-body and 5-HT1B auto-receptors in the presynaptic membrane become activated. The activation of both the somatodendritic 5-HT1A autoreceptors and the presynaptic 5-HT1B auto-receptors results in an inhibition of 5-HT release into the synaptic cleft. Consequently, serotonin concentration in the synaps diminishes but remains slightly increased due to blockage of the 5-HT transporters leading to some stimulation of all postsynaptic 5-HT receptors. After some days, the 5-HT1A and 5-HT1B autoreceptors become desensitized resulting in a diminished inhibitory action of these receptors to 5-HT release. Consequently, serotonin again becomes released into the synaps. However, due to the SSRI-induced continuous blockade of the 5-HT transporters, serotonin cannot get back into the presynaptic neuron, and as a consequence serotonin levels in the synaps become higher. This increased serotoneric neurotransmission exerts a stronger effect on all post-synaptic receptors. It is the action of those postsynaptic receptors that determines the clinical effects of the SSRIs.
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