Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder

Serotonin, one of the first neurotransmitters to be identified, is an evolutionarily old molecule that is highly conserved across the animal kingdom, and widely used throughout the brain. Despite this, ascribing a specific set of functions to brain serotonin and its receptors has been difficult and controversial. The 2A subtype of serotonin receptors (5-HT2A receptor) is the major excitatory serotonin receptor in the brain and has been linked to the effects of drugs that produce profound sensory and cognitive changes. Numerous studies have shown that this receptor is upregulated by a broad variety of stressors, and have related 5-HT2A receptor function to associative learning. This review proposes that stress, particularly stress related to danger and existential threats, increases the expression and function of 5-HT2A receptors. It is argued that this is a neurobiological adaptation to promote learning and avoidance of danger in the future. Upregulation of 5-HT2A receptors during stressful events forms associations that tune the brain to environmental cues that signal danger. It is speculated that life-threatening situations may activate this system and contribute to the symptoms associated with post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine, which activates 5-HT2A receptors, has been successful in the treatment of PTSD and has recently achieved status as a breakthrough therapy. An argument is presented that 3,4-methylenedioxymethamphetamine may paradoxically act through these same 5-HT2A receptors to ameliorate the symptoms of PTSD. The central thematic contention is that a key role of serotonin may be to function as a stress detection and response system.