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Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine
journal contribution
posted on 2019-06-05, 00:00 authored by Xavier López-Gil, Laura Jiménez-Sánchez, Leticia Campa, Elena Castro, Clara Frago, Albert AdellDepression
is a chronic and debilitating illness that interferes
severely with many human behaviors, and is the leading cause of disability
in the world. There is data suggesting that deficits in serotonin
neurotransmission can contribute to the development of depression.
Indeed, >90% of prescribed antidepressant drugs act by increasing
serotonergic transmission at the synapse. However, this increase is
offset by a negative feedback operating at the level of the cell body
of the serotonin neurons in the raphe nuclei. In the present work,
we demonstrate: first, the intracortical infusion
of ketamine induced an antidepressant-like effect in the forced swim
test, comparable to that produced by systemic ketamine; second, systemic and intracortical ketamine increased serotonin and noradrenaline
efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; third, systemic and intracortical administration of ketamine
increased the efflux of glutamate in the prefrontal cortex and dorsal
raphe nucleus; fourth, systemic ketamine did not
alter the functionality of 5-HT1A receptors in the dorsal
raphe nucleus. Taken together, these findings suggest that the antidepressant-like
effects of ketamine are caused by the stimulation of the prefrontal
projection to the dorsal raphe nucleus and locus coeruleus caused
by an elevated glutamate in the medial prefrontal cortex, which would
stimulate release of serotonin and noradrenaline in the same area.
The impact of both monoamines in the antidepressant response to ketamine
seems to have different time frames.