Serotonin System



Serotonin binds most populations of 5-HT receptors with low nanomolar affinity.

Semiselective agentsˇagents with selectivity for only two or three populations of 5-HT receptors.

Table 1: classes of agents that bind at 5-HT receptors.

Small structural changes can influence affinity, selectivity, and agonist vs. antagonist character

Example: R(+)-isomer 8-OH DPAT = 5-HT1A agonist vs. S(-)-enantiomer = partial agonist. Also add a (5-fluoro) group = antagonist.

5-HT1A Receptors

Highest densities are in the hippocampus, septum, amygdala, and cortical limbic areas.

Negatively coupled to an adenylate cyclase second messenger system.

G protein-coupled receptor consists of seven transmembrane (TM) helices connected by intra- and extracellular loops

-       Specific example of a 5-HT2A receptor model

Similarity to adrenergic receptors bind a number of adrenergic agents

Medical Significance

Main therapeutic potential = treatment of anxiety and depression.

5-HT1A receptors may be involved in impulsivity and alcoholism and in the different phases of sleep

Buspirone = effective in the treatment of mixed anxious-depressive patients

5-HT1 receptors may be involved in obsessive-compulsive disorders, sexual behavior, appetite control, thermoregulation, and cardiovascular function

New Studies 5-HT1A/5-HT2 antagonist S 21357 is being examined as a panic-modulating agent

5-HT1A agonist/5-HT2 antagonist FG5865 suppresses alcohol intake by rats

Mixed 5-HT1A agonists/5-HT2 antagonists are being evaluated as antipsychotic agents

5-HT1B Receptors

Presynaptically control the release of 5-HT

Postsynaptically the highest density substantia nigra, globus pallidus, and dorsal subiculum

Negatively coupled to adenylate cyclase.

Ligands- To date, no 5-HT1B-selective ligands have been identified.

Medical Significance Rodent 5-HT1B receptors play a role in thermoregulation, respiration, appetite control, sexual behavior, aggression, and anxiety

Recent studies support a role for 5-HT1B receptors in the regulation of sleep, sensorimotor inhibition, and to some extent, locomotor activity.

5-HT1D Receptors

Widely distributed throughout the central nervous system

G protein-linked, both 5-HT1Da & 5-HT1Db

Coupled to inhibition of adenylate cyclase.

Medical Significance Remains largely unknown

Speculation that these receptors might be involved in anxiety, depression, and other neuropsychiatric disorders

Localization of 5-HT1D receptors in human brain is thought to be consistent with potential involvement in Huntington's disease

5-HT1Da receptors seem to be primarily involved in neurogenic inflammation

5-HT1Db receptors may be more involved in vasoconstriction.  

5-HT1E Receptors

Receptors display low affinity for most serotonergic agents.

Negatively coupled to adenylate cyclase.

5-HT1F Receptors

5-HT1F receptors in uterus and mesentery suggesting possible role in vascular contraction

Distribution in the brain is limited

Medical significance - is unknown at this time.

5-HT1P Receptors - 5-HT1P receptors are found in the gut

5-HT1S Receptors

5-HT1S sites = high affinity for 5-HT and tryptamine

Predominant 5-HT1 receptor population in spinal cord

5-HT1S receptors may be involved with modulation of pain input to the spinal cord

5-HT2 Receptors

Specific example of a 5-HT2A receptor model: here

5-HT2A Receptors

Highest density is in the neocortex.

Antagonist= ketanserin.

Two states: High-affinity state and a low-affinity state, normal conditions equilibrium is heavily in favor of the low-affinity state

Receptors coupled to phosphoinositol hydrolysis

Medical Significance

Clinical actions involve combination of 5-HT2A and 5-HT2C receptors

5-HT2A receptors play a role in appetite control, thermoregulation and sleep.

Involved in cardiovascular function and muscle contraction.

Various antipsychotic agents and antidepressants bind with high affinity at 5-HT2A receptors.

Chronic administration of 5-HT2A antagonists (Antidepressants) results in a paradoxical down-regulation of 5-HT2A receptors: treatment of depression.

Several 5-HT2A antagonist are potential antipsychotic agents

Additionally, many 5-HT2A antagonists bind at dopamine receptors.

Antagonist= ritanserin, produced an antianxiety effect in humans

5-HT2A receptors may be involved in the actions of the classical hallucinogens : phenylalkylamine hallucinogens (e.g., DOB, DOI) are 5-HT2-selective

5-HT2B Receptors

Specific role of 5-HT2B receptors is unknown

A number of DOI-related hallucinogens have been shown to bind at 5-HT2B receptors

5-HT2C Receptors

Receptors coupled to phosphoinositol hydrolysis

No specific 5-HT2C-selective agents

Evidence of a role for 5-HT2C receptors in eating disorders and epilepsy has been obtained using mice lacking these receptors. Mice that lacked the carboxy-terminal half of the protein, showed an increase in body mass and had spontaneous seizures that had features in common with some forms of human epilepsy.

5-HT2 Subpopulation Selectivity -No agents display absolute specificity for one subpopulation of 5-HT2 receptors

5-HT3 Receptors

Unique family of 5-HT receptors: nonselective Na+/K+ ion channel receptors

Located in periphery and central nervous system(postrema, entorhinal cortex, frontal cortex, and hippocampus) (158).

Similar in structure to nicotinic acetylcholine receptors, another ion channel

Ligands- MDL 72222 was the first selective 5-HT3 antagonist.

Medical Significance

5-HT3 antagonists = treatment of chemotherapy-induced or radiation-induced nausea and vomiting, ineffective against motion sickness and apomorphine-induced emesis.

May be effective in the treatment of migraine or the pain associated with migraine.

Preclinical studies suggest that 5-HT3 antagonists may enhance memory and be of benefit in the treatment of anxiety, depression, pain, and dementia.

5-HT3 receptors can control dopamine release and may also be involved acetylcholine release and control of the GABAergic system

Dopamine itself acts as a 5-HT3 partial agonist

5-HT3 antagonists may suppress the behavioral consequences of withdrawing chronic treatment with drugs of abuse, including alcohol, nicotine, cocaine, and amphetamine.

Most attractive features of 5-HT3 antagonists is general lack of undesirable side effects

5-HT4 Receptors

5-HT4 receptors have a broad tissue distribution

Positively coupled to adenylate cyclase

5-HT4 receptors stimulate adenylate cyclase, >receptors inhibit K+ channels in collicular neurons > cAMP production > activation of cAMP-dependent protein kinase A.

Peripherally, 5-HT4 receptors facilitate acetylcholine release in guinea pig ileum and may play a role in peristalsis.

Ligands - similar affinities for 5-HT3 and 5-HT4 receptors

Medical Significance

Studied for peripheral effects (e.g., irritable bowel syndrome, gastroesophageal reflux) and for central effects.

5-HT4 agonists may restore deficits in cognitive function

5-HT4 antagonists useful in the treatment of dopamine-related disorders.

5-HT4 receptors may be involved in memory and learning, and they are markedly decreased in patients with Alzheimer's disease .

Use of highly potent and selective 5-HT4 agonists might result in cardiovascular side effects.

A high density of 5-HT4 receptors in the nucleus accumbens has led to speculate that these receptors may be involved in the reward system and may influence self-administration behavior.

GR113808 reduces alcohol intake in rats, and it ethanol-induced reinforcing properties in rats may involve 5-HT4 receptors (105).

5-HT5 Receptors

Failure to demonstrate G-protein coupling, represent a distinct family of receptors

May utilize a novel (perhaps an ion channel) second messenger system.

Primary site of expression is non-neuronal

Pharmacological function of 5-HT5 receptors is unknown

Disruption of 5-HT neuron-glial interactions may be involved in the development Alzheimer's disease, Down's syndrome, and some drug-induced developmental deficits of the CNS.

5-HT6 Receptors

First cloned 5-HT receptor

Coupled to activation of adenylate cyclase.

Highest levels expressed in the caudate nucleus.

Medical Significance

High affinity of various antipsychotics and antidepressants,-possible connection to certain psychiatric disorders.

May be useful in the treatment of anxiety and memory deficits.

5-HT7 Receptors

Expressed mainly in the CNS

Low level of expression in the periphery

Positively coupled to adenylate cyclase.

Clinical Implications

5-HT7 receptors might be involved in mood and learning, also neuroendocrine and vegetative behaviors.

Role in certain psychiatric disorders.- 5-HT7 receptors reported to be down-regulated after chronic administration of fluoxetine (Prozac).

Implicated in serotonergic regulation of circadian rhythm

5-HT7-selective agents might be effective in the treatment of jet lag or sleep disorders of a circadian nature.

5-HT produces both contraction and relaxation of coronary artery from various species:-Agents active at 5-HT7 receptors might thus be effective in the treatment of coronary heart disease.


Anxiety, depression, schizophrenia, migraine, and drug abuse are at the top of the list for research in 5-HT receptor treatment.

5-HT receptors may also play important roles in appetite control, aggression, sexual behavior, and cardiovascular disorders.


1. Human Polyomavirus (JVC)- The human polyomavirus, JCV, causes the fatal demyelinating disease progressive multifocal leukoencephalopathy

Findings: the serotonergic receptor 5HT2AR could act as the cellular receptor for JCV on human glial cells Serotonin receptor antagonists may thus be useful in the treatment of progressive multifocal leukoencephalopathy.

2. Serotonin and Bulimia - A sign of susceptibility to the eating disorder bulimia: an abnormality in the way the brain processes the neurotransmitter serotonin.

Findings: Disturbance of 5HT2A binding is consistent with mood problems and the impulsive (undercontrolled) and obsessive (overcontrolled) behavior seen in people with bulimia.

3. Ecstasy and Serotonin: Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy"), a selective serotonin neurotoxin.