What are the 5-hydroxytryptamine (5HT) receptors responsible for?

5-Hydroxytryptamine (5-HT) Receptors: Functions and Clinical Significance

5-HT receptors are responsible for coordinating critical physiological functions including respiratory control, arousal, autonomic regulation, mood, appetite, cognition, and cardiovascular reflexes through diverse receptor subtypes distributed throughout the central nervous system and peripheral tissues. 1, 2

Core Physiological Functions by Receptor Subtype

5-HT1A Receptors: Central Control Hub

• 5-HT1A receptors function as the central control hub of the entire serotonergic system, operating through G-protein coupled mechanisms with slower signaling kinetics 1
• These receptors restore synaptic plasticity and improve depression-like behaviors in the hippocampus CA1 region 1
• Decreased 5-HT1A receptor binding in the brainstem occurs in up to 70% of SIDS cases, affecting the coordination of respiratory, arousal, and autonomic functions that are essential for survival 3, 1
• The brainstem serotonergic system containing 5-HT1A receptors regulates breathing patterns and responses to carbon dioxide, preventing normal protective responses to stressors during sleep when dysfunctional 3, 1

5-HT2C Receptors: Appetite and Weight Control

• 5-HT2C receptors are primarily responsible for appetite suppression and satiety enhancement through selective activation of anorexigenic POMC neurons in the hypothalamus 4
• This receptor also modulates mood, motor behavior, and endocrine secretion 4
• Selective 5-HT2C agonists produce clinically meaningful weight loss (5-6% body weight reduction) in obesity treatment, as demonstrated by FDA-approved lorcaserin 4
• At therapeutic doses, selective 5-HT2C agonists avoid activation of 5-HT2A receptors (which cause hallucinations) and 5-HT2B receptors (which cause cardiac valve insufficiency) 4

5-HT3 Receptors: Rapid Excitatory Responses

• 5-HT3 receptors are ligand-gated ion channels responsible for rapid excitatory neurotransmission 5
• 5-HT3 antagonists (ondansetron, granisetron, palonosetron) are first-line treatments for chemotherapy-induced nausea and vomiting, blocking these rapid excitatory responses 1

5-HT7 Receptors: Circadian and Mood Regulation

• 5-HT7 receptors control serotonin-induced phase shifting of the circadian rhythm, memory, and locomotor/exploratory activity 6
• These receptors are coupled to stimulatory Gs-protein, activating adenylyl cyclase and raising cAMP concentration 6
• 5-HT7 receptors show high relevance for treatment of major depressive disorders 6

Autonomic and Cardiovascular Functions

• Serotonin contributes to autonomic nervous system regulation, affecting blood pressure control, heart rate, and respiratory function 2
• The serotonin transporter (5-HTT) removes serotonin from the synaptic cleft, determining the magnitude and duration of serotonergic signaling across all receptor subtypes 2
• Prenatal exposure to tobacco smoke alters cardiovascular reflexes mediated by 5-HT receptors, causing greater-than-expected increases in blood pressure and heart rate in response to carbon dioxide or postural changes 3

Cognitive and Behavioral Functions

• Multiple 5-HT receptor subtypes (5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6, 5-HT7) play physiological, pathophysiological, and therapeutic roles in learning and memory 7
• 5-HT receptors regulate aggression, anxiety, cognition, learning, memory, mood, sleep, and thermoregulation 8, 9
• Dysregulation of serotonin in the ventrolateral prefrontal cortex and brainstem has been linked to impulsivity and emotional volatility 2

Gut-Brain Axis Communication

• 5-HT serves as a major neurotransmitter in the gut-brain axis, though peripheral and central serotonin systems are separated by the blood-brain barrier 4
• Altered serotonin metabolism involving 5-HT2C receptors has been observed in irritable bowel syndrome 4

Clinical Pitfalls and Caveats

The diversity of 5-HT receptor subtypes (14 distinct receptors across 7 families) explains why serotonergic medications produce wide-ranging side effects 2, 5. Excessive serotonergic activity can lead to autonomic hyperactivity manifesting as hypertension, tachycardia, and hyperthermia, with serotonin syndrome carrying an approximately 11% mortality rate 2. The high sequence similarity among 5-HT receptors makes designing subtype-selective drugs challenging, which is why many serotonergic medications affect multiple receptor subtypes simultaneously 8.