Stress, Coping and the Bipartite Serotonin Neurotransmission Hypothesis:
Implications for Neuropsychopharmacology in Brain Injury Medicine and Beyond.
Goldberg G 1,2
1 Hunter Holmes McGuire Veterans Administration Medical Center, Richmond Virginia, United States
2 Medical College of Virginia / Virginia Commonwealth University Healthcare System, Richmond Virginia, United States

A novel bipartite functional model of serotonin neurotransmission has recently been proposed in which two major serotonin receptor subtypes--5-HT1AR and 5-HT2AR, respectively--are involved in a complementary manner in the processes involved in ‘flexible coping’ with allostatic load.(1) While the 5-HT1AR receptor subsystem is proposed to be involved in 'passive coping' understood as habituation to adverse circumstances, the 5-HT2AR subsystem is proposed to be involved in 'active coping' understood as the active process of addressing a source of stress. This active process involves 'enhanced plasticity' associated with a ‘capacity for change’ in relation to the projected impact of the source of stress. While the typically dominant ‘default’ response to stress may be the habituation/accommodation mediated through the 5-HT1AR receptor subsystem, 5-HT2AR mediated plasticity supporting 'creative re-structuring' may become an increasingly dire imperative as the level of adversity and perceived existential threat rises to a critical point at which a decompensating ‘catastrophic reaction’ due to overwhelming existential uncertainty may be precipitated resulting in incapacitating severe anxiety and/or depression.(2) This hypothesis will be reviewed and presented along with various implications for clinical strategies for neuropsychopharmacological facilitation of serotonin-mediated adaptive response to the allostatic load produced by acquired brain injury (ABI). This approach will be developed recognizing that the central nervous system (CNS) normally plays a primary role in coordinating the strategic dynamic management of existential uncertainty through allostasis (3,4) and the reduction of free energy in the system comprised of the injured person striving to function effectively in the context of various affordances offered through perceived environmental conditions.(5) The basic challenges in effective holistic ABI rehabilitation relate to the fact that it is injury to the CNS that itself produces complex allostatic load while simultaneously precipitating increased personal vulnerability to adversity through diminishment of the capacity of the primary organ system involved in conferring resilience through the intentional effective strategic coordination of allostasis.(6) The broader implications of this overall conceptual approach for Brain Injury Medicine will be examined in this paper.

1. Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors. Journal of Psychopharmacology 31:1091-1120, 2017

2. Goldstein K. Der Aufbau des Organismus. Einführung in die Biologie unter besonderer Berücksichtigung der Erfahrungen am kranken Menschen. Den Haag, Nijhoff, 1934

3. Peters A, McEwen BS, Friston K. Uncertainty and stress: Why it causes diseases and how it is mastered by the brain. Progress in Neurobiology 156:164-188, 2017

4. Peters A, McEwen BS. Stress habituation, body shape and cardiovascular mortality. Neuroscience and Biobehavioral Reviews 56:139-150, 2015

5. Friston K. The free-energy principle: a unified brain theory? Nature Reviews in Neuroscience 11:127-138, 2010

6. Karatsoreos IN, McEwen BS. Psychobiological allostasis: resistance, resilience and vulnerability. Trends in Cognitive Science 15:576-584, 2011

Stress, Coping and the Bipartite Serotonin Neurotransmission Hypothesis.  Implications for Neuropsychopharmacology in Brain Injury Medicine and Beyond.