The Effects of Antidepressant Treatment in Prenatally Stressed Rats Support the Glutamatergic Hypothesis of Stress-Related Disorders

Abstract

Abnormalities of synaptic transmission in the hippocampus represent an integral part of the altered programming triggered by early life stress, which enhances the vulnerability to stress-related disorders in the adult life. Rats exposed to prenatal restraint stress (PRS) develop enduring biochemical and behavioral changes characteristic of an anxious/depressive-like phenotype. Most neurochemical abnormalities in PRS rats are found in the ventral hippocampus, a region that encodes memories related to stress and emotions. We have recently demonstrated a causal link between the reduction of glutamate release in the ventral hippocampus and anxiety-like behavior in PRS rats. To confer pharmacological validity to the glutamatergic hypothesis of stress-related disorders, we examined whether chronic treatment with two antidepressants with different mechanisms of action could correct the defect in glutamate release and associated behavioral abnormalities in PRS rats. Adult unstressed or PRS rats were treated daily with either agomelatine (40 mg/kg, i.p.) or fluoxetine (5 mg/kg, i.p.) for 21 d. Both treatments reversed the reduction in depolarization-evoked glutamate release and in the expression of synaptic vesicle-associated proteins in the ventral hippocampus of PRS rats. Antidepressant treatment also corrected abnormalities in anxiety-/depression-like behavior and social memory performance in PRS rats. The effect on glutamate release was strongly correlated with the improvement of anxiety-like behavior and social memory. These data offer the pharmacological demonstration that glutamatergic hypofunction in the ventral hippocampus lies at the core of the pathological phenotype caused by early life stress and represents an attractive pharmacological target for novel therapeutic strategies.

Stress In Utero: Prenatal Programming of Brain Plasticity and Cognition

“…Since corticosterone is the main hormone released during stress, it was not surprising to find that corticosterone by itself reduced the ability to generate LTP in brain slices (61). Subsequent studies proposed that corticosterone affects glutamate receptor distribution and kinetics (62,63). Corticosterone and stress affect other neurotransmitter systems, including GABA, as well as the expression of several peptides and growth factors (64,65).…”

“…To disentangle the contribution of every neurotransmitter/hormone requires the individual pharmacological manipulation of each system. This is especially important since some of the proposed drugs for dealing with PS are actually aimed at monoamines (62).…”

Mouse psychosocial stress reduces motivation and cognitive function in operant reward tests: A model for reward pathology with effects of agomelatine

“…During its preclinical development, using repeated dosing, AGO was shown to be efficacious in several rat and mouse models relevant to depression domains (de Bodinat et al, 2010). These include reversal of decreased saccharin consumption induced by chronic mild stress (Papp et al, 2003), reversal of specific learned helplessness (Bertaina-Anglade et al, 2006), antagonism of increased anxiety and decreased grooming induced by repeated corticosterone administration (Rainer et al, 2012), and antagonism of increased anxiety, immobility in the forced swim test, and altered circadian rhythm of activity and sleep-wake pattern induced by prenatal restraint stress (Mairesse et al, 2013;Marrocco et al, 2014;Morley-Fletcher et al, 2011). In clinical trials, therapeutic efficacy of AGO is increased relative to placebo in moderate to severe depression (Kennedy et al, 2014).…”

Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats

“…Abnormalities in hippocampal synaptic transmission and plasticity lie at the core of the pathological phenotype induced by prenatal stress (Yaka et al, 2007;Mairesse et al, 2012;Marrocco et al, 2012Marrocco et al, , 2014. Prenatally restraint stressed (PRS) rats, i.e.…”