5-HT2C receptor

The 5-HT_2C receptor is a subtype of the 5-HT2 receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, it is a G protein-coupled receptor (GPCR) that is coupled to G_q/G₁₁ and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located on the X chromosome. As males have one copy of the gene and females have one of the two copies of the gene repressed, polymorphisms at this receptor can affect the two sexes to differing extent.

At the cell surface the receptor exists as a homodimer. The crystal structure has been known since 2018.

5-HT_2C receptors are located mainly in the choroid plexus, 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. 5-HT_2C receptors are also found on epithelial cells lining the ventricles.

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 are claimed to 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. Agomelatine, which is a 5-HT_2C and 5-HT_2B antagonist as well as a MT₁ and MT₂ agonist, is an effective antidepressant. It has been found to act, through its 5-HT2C receptor antagonism, as a norepinephrine-dopamine disinhibitor because antagonism of 5-HT_2C results in an increase of dopamine and norepinephrine activity in the frontal cortex.

Conversely, many atypical antipsychotic and antidepressants act as 5-HT2C receptor antagonists,, like Loxapine, an antipsychotic structurally related to Clozapine and its metabolite Amoxapine, which is an antidepressant in its own right, act as 5-HT2C receptor antagonist. Fluoxetine acts as a direct 5-HT_2C antagonist in addition to inhibiting serotonin reuptake, however, the clinical significance of this action is variable. Several tetracyclic antidepressants, including mirtazapine and Mianserin, as well as certain Tricyclic antidepressant such as Amitriptyline and Clomipramine are potent 5-HT_2C antagonists; this action may contribute to their efficacy. 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 receptors. 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. In addition to the evidence for a role of 5-HT_2C receptor stimulation in depressive symptoms there also is evidence that activation of 5-HT_2C receptors may have beneficial effects upon certain aspects of depression, one group of researchers found that direct stimulation of 5-HT_2C receptors with a 5-HT_2C agonist reduced cognitive deficits in mice with a TPH2 loss-of-function mutation.

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 of 5-HT_2C. Increased 5-HT_2C expression reduces dopamine release in both the presence and absence of stimuli.