Antidepressant and anxiolytic effects of activating 5HT2A receptors in the anterior cingulate cortex and the theoretical mechanisms underlying them - A scoping review of available literature.

Activating 5HT2A receptors in the anterior cingulate cortex (ACC) with psychedelic drugs reduces anxious preoccupation, obsessional thoughts, and anhedonia while promoting cognitive flexibility and long-lasting mood improvements. This occurs through enhanced AMPA receptor signaling that alters the AMPA-to-NMDA activity ratio, dismantling established neuronal connections and aiding new ones, which benefits fear extinction and reversal learning. Psychedelics also strengthen connectivity from the dorsal ACC and Salience Network to the Default Mode Network and Central Executive Network, improving attentional shifting and anti-anhedonic effects, while reducing the Default Mode Network's inhibitory influence over the Central Executive Network to decrease overevaluation of internal states. Downstream effects include reduced amygdala reactivity to threats and enhanced mesolimbic dopamine, improving anxiety and natural reward experience.

Study at a glance

Abstract

Psychedelic drugs that activate the 5HT2A receptor have long been the target of extensive clinical research, particularly in models of psychiatric illness. The aim of this literature review was to investigate the therapeutic effects of 5HT2A receptor activation in the anterior cingulate cortex (ACC) and the respective mechanisms that underlie them. Based on the available research, I suggest that 5HT2A receptors in the ACC exert profound changes in excitatory neurotransmission and brain network connectivity in a way that reduces anxious preoccupation and obsessional thoughts, as well as promoting cognitive flexibility and long-lasting mood improvements in anhedonia. This is possibly due to a complex interplay with glutamate and gamma-butyric acid neurotransmission, particularly 5HT2A activation enhances α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signalling, thus altering the ratio of AMPA to N-methyl-D-Aspartate (NMDA) activity in the ACC, which can dismantle previously established neuronal connections and aid the formation of new ones, an effect that may be beneficial for fear extinction and reversal learning. Psychedelics potentially change intra- and internetwork connectivity, strengthening connectivity from the dorsal ACC / Salience Network to the Default Mode Network (DMN) and Central Executive Network (CEN), which correlates with improvements in attentional shifting and anti-anhedonic effects. Additionally, they may decrease inhibitory influence of the DMN over the CEN which may reduce overevaluation of internal states and ameliorate cognitive deficits. Activation of ACC 5HT2A receptors also has important downstream effects on subcortical areas, including reducing amygdala reactivity to threatening stimuli and enhancing mesolimbic dopamine, respectively improving anxiety and the experience of natural rewards.