Somatodendritic autoreceptors serotonin

Serotonin 5-HT1A Human cDNA Alzheimer s disease, anxiety, depression, schizophrenia, hypertension, inflammation, pain, migraine, spasticity ulcers, obesity glaucoma Somatodendritic autoreceptor in hippocampus and raphe nuclei, circadian rhythm, somatodendritic heteroreceptor at cholinergic terminals of myenteric plexus... 

Once the 5HT1A somatodendritic autoreceptors are desensitized, 5HT can no longer effectively inhibit its own release, and the serotonin neuron is therefore dis-inhibited. This results in a flurry of >HT release from axons due to an increase in neuronal impulse flow (Fig. 6—38). This is just another way of saying that the serotonin release is turned on at the axon terminals. The serotonin that now pours out of the various projections of serotonin pathways in the brain theoretically mediates the various therapeutic actions of the SSRls. 

FIGURE 8—11. Serotonin 1A partial agonists such as buspirone may reduce anxiety by actions both at presynaptic somatodendritic autoreceptors (left) and at postsynaptic receptors (right). Presynaptic actions are more likely related to anxiolytic actions, and postsynaptic actions are perhaps more likely linked to side effects such as nausea and dizziness. 

Hallucinogens have rather complex interactions at neurotransmitter systems, but one of the most prominent is a common action as agonists at serotonin 2A (5HT2A) receptor sites (Fig. 13—10). Hallucinogens certainly have additional effects at other 5HT receptors (especially 3HT1A somatodendritic autoreceptors) and also at other neurotransmitter systems, especially norepinephrine and dopamine, but the relative importance of these other actions are less well known. Also, MDMA appears to be a powerful releaser of serotonin and it and several drugs structurally related to it... 

Romero L, Artigas F. Preferential potentiation of the effects of serotonin uptake inhibitors by 5-HT1A receptor antagonists in the dorsal raphe pathway role of somatodendritic autoreceptors. JNeurochem 1997 68 2593-2603. 

Local application of 8-OH-DPAT in the raph4 nuclei reduces the firing rate of serotonergic neurons by acting on the somatodendritic autoreceptor. This in turn leads to a reduction of the serotonergic neurotransmission, i.e. less serotonin is released in the synaptic cleft. It is not known which of the postsynaptic receptors is critically involved in the mediation of LLR. As far as we know, no local application studies have been performed in the major projection areas of the serotonin system. 

Figure 7. A serotonergic synapse including a depiction of the acute tryptophan depletion method discussed in the text. All large neutral amino acids (SLNAAs) share a common blood-brain barrier transporter. The serotonergic precursor, tryptophan, essentially competes with the other LNAAs for transport. Thus tryptophan is uniquely susceptible to acute dietary manipulation. Numerous serotonergic receptor types exist, including presynaptic S-HTm and (somatodendritic) 5-HTia autoreceptors and postsynaptic 5-HTia, 5-HTid, 5-HT2a 5-HT2c 5-HT3 and 5-HT4 receptors. Additional modulation of serotonin activity can occur via the action of selective serotonin re-uptake inhibitors (SSRls) including fluoxetine, fluvoxamine, and citalopram.

The delay in onset of anxiolytic and antipanic effects of serotonin reuptake inhibitors and related compounds is still an issue of much speculation. It appears paradoxical that serotonin reuptake inhibitors block serotonin uptake immediately, whereas it takes weeks before their therapeutic effects become apparent. Recently, the idea was advanced that the tentative enhanced serotonin neurotransmission caused by short-term administration of serotonin reuptake inhibitors is offset by negative feedback in the raphe nuclei (Artigas 1993 Blier and de Montigny 1994). The increased level of serotonin in the somatodendritic area, resulting from serotonin uptake inhibition, reduces serotonin neuronal firing through activation of the 5-HTj, autoreceptors. Alterations in the feedback regulation upon repeated administration may... 

Over time, the increased 5HT at the somatodendritic 5HT1A autoreceptors causes them to down-regulate and become desensitized (Fig. 6—37). When the increase in serotonin is recognized by these presynaptic 5HT1A receptors, this information is sent to the cell nucleus of the serotonin neuron. The genome s reaction to this information is to issue instructions that cause these same receptors to become de-... 

FIGURE 6-37. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 3. The consequence of serotonin increasing in the somatodentritic area of the serotonin neuron, as depicted in the Figure 6-36, is to cause the somatodendritic serotonin 1A autoreceptors to desensitize or down-regulate (red circle). 

FIGURE 6-39. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 5. Finally, once the SSRIs have blocked the reuptake pump (Fig. 6-36), increased somatodendritic serotonin (Fig. 6-36), desensitized somatodendritic serotonin 1A autoreceptors (Fig. 6—37), turned on neuronal impulse flow (Fig. 6-38), and increased release of serotonin from axon terminals (Fig. 6— 38), the final step shown here may be the desensitization of postsynaptic serotonin receptors. This has also been shown in previous figures demonstrating the actions of monoamine oxidase (MAO) inhibitors (Fig. 6-4) and the actions of tricyclic antidepressants (Fig. 6—6). This desensitization may mediate the reduction of side effects of SSRIs as tolerance develops. 

If serotonin is very low or depleted from serotonergic neurons in depression, there would not be much of it released for an SSRI to block its reuptake (Fig. 7—31). Thus, there would theoretically be inadequate desensitization of somatodendritic 5HT1A autoreceptors. Unlike the SSRIs, which are all dependent for their actions on the endogenous release of serotonin, buspirone is not dependent on serotonin levels because it has direct actions on 5HT1A receptors (Fig. 7—32). Thus, buspirone may be able to kick start the desensitization process directly. Initially,... 

Partial agonist actions at presynaptic somatodendritic serotonin autoreceptors may theoretically enhance serotonergic activity and contribute to antidepressant actions... 

Therapy for 2 or more weeks is required for the uiitidepres-.sant effect. Somatodendritic. SHTia autoreceptor dcscndii-zation with chronic exposure to high levels of. S-HT is the accepted explanation for the delayed effect for this and othit serotonin reupiakc inhibitors. 

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