Fluoxetine, not donepezil, reverses anhedonia, cognitive dysfunctions and hippocampal proteome changes during repeated social defeat exposure

Role of NMDA and AMPA glutamatergic receptors in the effects of social defeat on the rewarding properties of MDMA in mice

“…defeat had elevated reward thresholds in the intracranial self-stimulation paradigm (Boutros et al, 2018;Gottschalk et al, 2018) and mice defeated for four consecutive days showed reduced sucrose preference (Yashiro & Seki, 2017). In previous works from our laboratory, we attempted to uncover the behavioural mechanisms underlying the impairment in the acquisition of MDMA CPP induced by social defeat, using the same strain of mice and schedule of social defeat as in the present study.…”

“…In particular, the optogenetic stimulation of glutamatergic neurons in the PFC, which increases glutamate release in the striatum, prevented the consequences of social defeat (Covington et al ., ), while chronic social defeat decreased glutamate levels in the ventral striatum (Bagot et al ., ). Similarly, the decrease in GluN1, GluA1, and GluA2 observed in the hippocampus agree with the reduction in glutamate neurotransmission observed in this brain area after chronic social defeat (Gottschalk et al ., ).…”

“…With respect to AMPA receptors, the decreased expression of GluA1 and GluA2 that we observed in the hippocampus and striatum (only GluA1) was in agreement with a recent study that reported that mice exposed to social defeat stress for four consecutive days had markedly decreased membrane expression of GluA1 and GluA2 in the PFC and of GluA1 in the ventral midbrain (Yashiro & Seki, ). Similarly, mice exposed to chronic social defeat for 5 or 10 days showed decreased membrane expression of GluA1 and GluA2 in the hippocampus (Li et al ., ) and a reduction of the Gria 2 gene (which encodes the expression of GluA2) in this brain area (Gottschalk et al ., ).…”

“…Taken together, these results suggest that the deficit in cognitive and reward processes can underlie the short‐term impairing effects of social defeat on the acquisition of MDMA CPP. In support of this idea, the reductions in the membrane expression of AMPA receptors subunits induced by social defeat has been associated with anhedonia: lower sucrose preference in defeated mice (Yashiro & Seki, ; Li et al ., ) and impaired reward processing in the intracranial self‐stimulation paradigm in rats (Gottschalk et al ., ). From our point of view, the decrease in GluA1 and/or GluA2 induced by intermittent social defeat in the present study could be related with the impaired acquisition of MDMA CPP observed in defeated mice.…”

“…If this were the case, the stressed animals could need a greater quantity of the drug to feel rewarding effects. In support of this hypothesis, it has been demonstrated that social defeat exposure induces anhedonia; for example, rats that underwent chronic social defeat had elevated reward thresholds in the intracranial self‐stimulation paradigm (Boutros et al ., ; Gottschalk et al ., ) and mice defeated for four consecutive days showed reduced sucrose preference (Yashiro & Seki, ). In previous works from our laboratory, we attempted to uncover the behavioural mechanisms underlying the impairment in the acquisition of MDMA CPP induced by social defeat, using the same strain of mice and schedule of social defeat as in the present study.…”