The Mysterious Serotonin 5-HT5A Receptors and their Function as Mediators of an "Unidentified Current" : Effects on Behavior and Sleep Patterns Explored

The Native Serotonin5-HT5A Receptor

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 Electrophysiological Characterization in Rodent Cortex and 5-HT1A-Mediated Compensatory Plasticity in the Knock-Out Mouse
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Nathalie M. Goodfellow,1 Craig D. C. Bailey,1 and Evelyn K. Lambe1,2
1
Department of Physiology and Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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~BEFORE ANYTHING ELSE, YES, HUMANS HAVE THIS RECEPTOR~

The 5-HT5A receptor is the least understood serotonin (5-HT) receptor. Here, we electrophysiologically identify and characterize a native5-HT5A receptor current in acute ex vivo brain slices of adult rodent prefrontal cortex.
In the presence of antagonists for the previouslycharacterized 5-HT1A and 5-HT2 receptors, a proportion of layer V pyramidal neurons continue to show 5-HT-elicited outward currentsin both rats and mice.

These 5-HT currents are suppressed by the selective 5-HT5A antagonist, SB-699551, and are not observed in 5-HT5A receptor knock-out mice. Further characterization reveals that the 5-HT5A current is activated by submicromolar concentrations of 5-HT,is inwardly rectifying with a reversal potential near the equilibrium potential for K (potassium) ions, and is suppressed by blockers of Kir3 channels.

Finally, we observe that genetic deletion of the inhibitory 5-HT5A receptor results in an unexpected, large increase in the inhibitory 5-HT1A receptor currents. The presence of functional prefrontal 5-HT5A receptors in normal rodents along with compensatory plasticity in5-HT5A receptor knock-out mice testifies to the significance of this receptor in the healthy prefrontal cortex.

Of all receptors I have researched, this one is indeed, mysterious! 

The interesting thing about this receptor , is not only is it a compensatory autoreceptor, it's unidentified currents seem to have both excitory and inhibitory effects. Mice lacking the 5-HT5A receptor, as in genetic deletion or knock out, did not display an anxiety-phenotype, nor did they respond to auditory startle. (!) (!)
In addition, the extracellular levels of serotonin were higher, indicating that 5-HT5A's are definitely autoreceptors regulating serotonin release.

The lack of startle in 5-HT5A knockout mice, and lack of anxiety is probably due to less inhibition and more overall serotonin release on the more localized areas where other inhibitory receptors are present(!), because either less 5-HT5A activation, as with blockade, or genetic deletion/knockout pushes more serotonin ESPECIALLY on the 5-HT1A receptor in order to compensate for the increases in serotonin, thus, by the 5-HT1A receptor, which also inhibits serotonin, the brain upregulates the activity of it to protect against excessive serotonin from 5-HT5A autoreceptor blockade, in the process of doing this however, the secondary effects of 5-HT1A activation, such as adenylyl cyclase inhibition become especially pronounced, leading to depressed nervous system responses.

This is also consistent with 5-HT1A agonists decreasing anxiety and some stress responses.

 because either less 5-HT5A activation, as with blockade, or genetic deletion/knockout pushes more serotonin ESPECIALLY on the 5-HT1A receptor 

5-HT5A may be involved as well in the startle response induced by serotonin. This has been my experience as well, that using a partial agonist to this receptor, such as valerian extract, had greatly stopped stimulants from causing me to be jumpy.Therefore, it must be that the cross noradrenergic-serotonergic activation of 5-HT5A is one mechanism in which stimulants may increase nervousness.

So , therefore, it can be said that 5-HT5A antagonism leads to indirect agonism of 5-HT1A---Receptors.



This receptor, the serotonin 5-HT5A is unique in that it's inhibitory , calming effects come from the REDUCTION OF CYCLIC AMP(!), whereas the startle and anxiety provoking effects come from it's inhibition of serotonin activity on other more inhibitory receptors.



We can conclude then that 5-HT5A receptors in the SPN and other areas can do the following when activated.

• Reduce serotonin release as an autoreceptor, and downregulate 5-HT1A's to compensate for the reduction of serotonin. 5-HT5A and 5-HT1A are inter-reactive receptors, and act on a behavioral parallel , eyeing each other down for signaling, when one receptor is activated, the other autoreceptor decreases etc.
• They are negatively coupled to adenylyl cyclase, so activating them reduces cyclic AMP!
• They increase behavioral excitation in response to loud noises, probably by acting locally to reduce serotonin activity where it would normally reduce these responses, or by reducing cAMP in discernment areas of the temporal lobe and vestibular neuronal networks.

THUS, A PLAUSIBLE MECHANISM, OF HOW TO REDUCE OR DOWNREGULATE 5-HT1A RECEPTORS, WOULD BE THE ACTIVATION OF 5-HT5A serotonin receptors.

ALSO IN REGARDS TO VALERIAN, THE FOLLOWING.

CITATION

https://www.mja.com.au/journal/2004/181/7/effectiveness-complementary-and-self-help-treatments-anxiety-disorders

Makes sense that the specific effects of VALERINIC ACID / VALERIAN EXTRACT in terms of partial agonism of 5-HT5A would be.

• Antagonize the autoreceptor part, raising serotonin, while agonizing the receptors in the SPN to reduce cyclic AMP.
• Modulating other autoreceptors as a direct interactive or downstream effect of modulating 5-HT5A activity.