5-HT2C Receptor - Function

Function

The 5-HT_2C receptor is one of the many binding sites for serotonin. Activation of this receptor by serotonin inhibits dopamine and norepinephrine release in certain areas of the brain.

5-HT_2C receptors significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT_2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others.

Research indicates that some suicide victims have an abnormally high number of 5-HT_2C receptors in the prefrontal cortex. There is some mixed evidence that agomelatine, a 5-HT_2C antagonist, is an effective antidepressant. Antagonism of 5-HT_2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. Conversely, many SSRIs (but not fluoxetine, which is a 5-HT2C antagonist) indirectly stimulate 5-HT_2C activity by increasing levels of serotonin in the synapse although the delayed mood elevation that's usually typical of SSRIs is usually paralleled by the downregulation of the 5-HT2C receptors. Many atypical antipsychotics block 5-HT_2C receptors, but their clinical use is limited by multiple undesirable actions on various neurotransmitters and receptors. Fluoxetine acts as a direct 5-HT_2C antagonist in addition to inhibiting serotonin reuptake, however, the clinical significance of this action is variable.

An overactivity of 5-HT_2C receptors may contribute to depressive and anxiety symptoms in a certain population of patients. Activation of 5-HT_2C by serotonin is responsible for many of the negative side effects of SSRI and SNRI medications, such as sertraline, paroxetine, venlafaxine, and others. Some of the initial anxiety caused by SSRIs is due to excessive signalling at 5-HT_2C. Over a period of 1–2 weeks, the receptor begins to downregulate, along with the downregulation of 5-HT_2A, 5-HT1_A, and other serotonin receptors. This downregulation parallels the onset of the clinical benefits of SSRIs. 5-HT_2C receptors exhibit constitutive activity in vivo, and may retain the ability to influence neurotransmission in the absence of ligand occupancy. Thus, 5-HT_2C receptors do not require binding by a ligand (serotonin) in order to exhibit influence on neurotransmission. Inverse agonists may be required to fully extinguish 5-HT_2C constitutive activity, and may prove useful in the treatment of 5-HT_2C-mediated conditions in the absence of typical serotonin activity.

5-HT_2C receptors mediate the release and increase of extracellular dopamine in response to many drugs, including caffeine, nicotine, amphetamine, morphine, cocaine, and others. 5-HT_2C antagonism increases dopamine release in response to reinforcing drugs, and many dopaminergic stimuli. Feeding, social interaction, and sexual activity all release dopamine subject to inhibition by 5-HT_2C. Increased 5-HT_2C expression reduces dopamine release in both the presence and absence of stimuli.

Many GPCRs downregulate in response to agonists for the receptor, and upregulate in response to antagonists. The 5-HT_2A and 5-HT_2C receptors appear to downregulate in response to both antagonists and agonists. Chronic treatment with antipsychotic drugs, which possess 5-HT₂ antagonist activity, results in downregulation of both 5-HT_2A and 5-HT_2C, as does chronic treatment with SSRIs and other 5-HT agonists. However, chronic SSRI treatment may increase 5-HT_2C expression, specifically in the choroid plexus.

Conditions that increase cytokine levels in the human body may have potential to raise 5-HT_2C gene expression in the brain. This could possibly comprise a link between viral infections and associated depression. Cytokine therapy has been shown to increase 5-HT_2C gene expression, resulting in increased activity of 5-HT_2C receptors in the brain.