[7] 5-HT2C receptors are located mainly in the choroid plexus,[8] and in rats is also found in many other brain regions in high concentrations, including parts of the hippocampus, anterior olfactory nucleus, substantia nigra, several brainstem nuclei, amygdala, subthalamic nucleus and lateral habenula.

[11] 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others.

[13][14] It has been called a norepinephrine-dopamine disinhibitor because antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex.

Fluoxetine acts as a direct 5-HT2C antagonist in addition to inhibiting serotonin reuptake, however, the clinical significance of this action is variable.

Activation of 5-HT2C by serotonin is responsible for many of the negative side effects of SSRI and SNRI medications, such as sertraline, paroxetine, venlafaxine, and others.

5-HT2C receptors exhibit constitutive activity in vivo, and may retain the ability to influence neurotransmission in the absence of ligand occupancy.

[20] 5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs,[21][22] including caffeine, nicotine, amphetamine, morphine, cocaine, and others.

Conditions that increase cytokine levels in the human body may have potential to raise 5-HT2C gene expression in the brain.

Prolonged activation and disturbances of the HPA axis contribute to depressive and anxiety symptoms seen in many psychopathological conditions.

Stimulation of 5-HT2C receptors leads to increase of corticotropin releasing hormone (CRH) and vasopressin mRNA in the paraventricular nucleus and proopiomelanocortin in the anterior pituitary lobe.

In rats, restraint stress (which can produce depressive symptoms if being chronic) induces secretion of prolactin, ACTH, vasopressin and oxytocin which is partially mediated via 5-HT2C receptor.

Combination of the hormones decrease the receptor concentration in the ventral hippocampus in rats and could thus affect mood.

Significant correlations are suggested, specifically in relation to psychiatric disorders such as depression, OCD, and anxiety-related conditions.

Editing occurs in 5 different closely located sites within exon 5, which corresponds to the second intracellular loop of the final protein.

[39] The predominant isoform in rat brain is VNV which differs from the most common type found in humans.

[43] 5HT2CR is different due to possessing an imperfect inverted repeat at the end of exon 5 and the beginning of intron 5 allowing formation of an RNA duplex producing the dsRNA required by ADARs for editing.

Second, the editing pattern controls the amount of the 5-HT2CR mRNA that leads to the expression of full-length protein through the modulation of alternative splice site selection 76,77.

Unedited pre-mRNAs tend to be spliced at the GU1 site, resulting in the truncated, non-functional protein if translated 76,77.

Thus, when editing is inefficient, increased splicing at GU1 may act as a control mechanism to decrease biosynthesis of the 5-HT2CR-INI and thereby limit serotonin response.

Third, RNA editing controls the ultimate physiological output of constitutively active receptors by affecting the cell surface expression of the 5-HT2CR.

Editing regulates the amount of 5HT2CR mRNA which leads to translation of the full length protein selection of alternative splice sites.

This is thought to be a regulatory mechanism to decrease the amount of unedited isoform INI to limit serotonin response when editing is inefficient.

[41][44] Dysregulation Serotonin family of receptors are often linked to pathology of several human mental conditions such as Schizophrenia, anxiety, Bipolar disorder and major depression.

[51] There have been several experimental investigations into the effects of alternative editing patterns of the 5HT2CR and these conditions with a wide variability in results especially those relating to schizophrenia.

[53] In rat models this increase is also observed and can be reversed with fluoxetine with some suggestion that E site editing maybe linked to major depression.

[54][55] This article incorporates text from the United States National Library of Medicine, which is in the public domain.