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

Abstract

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-HT 2A 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-HT 2A 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-HT 2A receptors. It is argued that this is a neurobiological adaptation to promote learning and avoidance of danger in the future. Upregulation of 5-HT 2A 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. 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 MDMA may paradoxically act though these same 5-HT2A receptors to ameliorate the symptoms of PTSD. The central thematic contention is that a central role of serotonin may be to function as a stress detection and response system.

Pivotal mental states

“…Somewhat consistent ideas have been expressed in the past ( Jaynes, 1976 ), and more recently in two separate reviews (e.g. Carhart-Harris and Nutt, 2017 ; Murnane, 2019 ), but are more fully developed here.…”

“…A relevant recent perspective on the evolutionary origin and potential treatment of PTSD ( Murnane, 2019 ) is largely consistent with an earlier perspective piece on 5-HT2AR-mediated ‘active coping’ and radical adaptation proposed by Carhart-Harris and Nutt (2017) , as well as animal work linking serotonergic functioning to faster learning rates ( Harvey, 2003 ; Iigaya et al, 2018 ), plasticity ( Iigaya et al, 2018 ) and adaptability ( Matias et al., 2017 ). It is also consistent with a growing literature base supporting the value of classic (5-HT2AR agonist) psychedelic therapy in the treatment of a broad range of psychiatric disorders ( Carhart-Harris and Goodwin, 2017 ; Nutt et al, 2020 ; Rucker et al, 2018 ).…”

“…al., 2000; Pitts et al., 2017 ; van Wel et al, 2012 ). These factors have led us ( Carhart-Harris and Nutt, 2017 ) and others ( Murnane, 2019 ) to speculate that the 5-HT2AR system is a stress response system that services adaptability.…”

“…Social isolation and defeat also reliably sensitize behavioural responses to 5-HT2AR agonists ( Benekareddy et al, 2010 ; Brotto et al, 1998 ; Gorzalka et al, 1998 ; Sakaue et al, 2002 ; Sood et al, 2018 ; Wright et al, 1991 ; see also Table 1 ). The role of stress and the 5-HT2AR system has been the focus of two recent review papers ( Carhart-Harris and Nutt, 2017 ; Murnane, 2019 ). Supplementing these findings, direct agonism of the 5-HT2AR via psychedelic drugs can sometimes induce psychological states exhibiting phenomena that mimic those seen in extreme stress states, for example, enhanced associative learning and a significant capacity for mediating psychological transformation ( Briere et al, 2015 ; Hefferon et al, 2009 ; Joëls et al, 2006 ), as can occur via traumatic encounters.…”

Mimosa tenuiflora (Willd.) Poir e Anadenanthera colubrina como alternativas no tratamento da adicção às drogas

“…Logo, observa-se o aparecimento do fenômeno da tolerância, mas não de adicção (Gresch et al;2005). A diminuição da densidade de receptores 5HT2A explica, em parte, seu efeito benéfico no tratamento de adictos já que fatores desencadeadores de recaídas como: aumento da ansiedade e resposta exagerada ao estresse, são observadas com o aumento de receptores 5HT2A fronto-límbicos (Guiard & Giovanni, 2015;Murnane, 2019;Underwood et al, 2018;Xu et al, 2016).…”