Chronic Fluoxetine Selectively Upregulates Dopamine D1-Like Receptors in the Hippocampus

Abstract

The dentate gyrus of the hippocampus has been implicated in mechanisms of action of selective serotonin reuptake inhibitors (SSRIs). We have recently demonstrated that the SSRI fluoxetine can reverse the state of maturation of the adult dentate granule cells and enhances serotonin 5-HT 4 receptor-mediated synaptic potentiation at the synapses formed by their mossy fiber axons. Here, we show that fluoxetine can induce long-lasting enhancement of dopaminergic modulation at the mossy fiber synapse. Synaptic responses arising from the mossy fiber-CA3 pyramidal cell synapse were recorded using acute mouse hippocampal slices. Dopamine potentiates mossy fiber synaptic transmission by activating D 1 -like receptors. Chronic fluoxetine treatment induced a prominent increase in the magnitude of dopamine-induced synaptic potentiation, and this effect was maintained at least up to 1 month after withdrawal of fluoxetine. Quantitative autoradiography revealed that binding of the D 1 -like receptor ligand [ 3 H]SCH23390 was selectively increased in the dentate gyrus and along the mossy fiber in fluoxetine-treated mice. However, binding of the 5-HT 4 receptor ligand [ 3 H]GR113808 was not significantly changed. These results suggest that chronic fluoxetine enhanced the dopaminergic modulation at least in part by upregulating expression of D 1 -like receptors, while the enhanced serotonergic modulation may be mediated by modifications of downstream signaling pathways. These enhanced monoaminergic modulations would greatly increase excitatory drive to the hippocampal circuit through the dentate gyrus. The highly localized upregulation of D 1 -like receptors further supports the importance of the dentate gyrus in the mechanism of action of SSRIs.

Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice

“…The prominent frequency facilitation, presynaptic short-term plasticity that is characteristic of mature MF synapses, was greatly decreased in mutants (Figure 3G). These changes are very similar to the changes observed in mice treated with FLX, which exhibit a “dematurated” DG [33,38]. Taken together, these results suggest that the granule cells in SNAP-25 KI mice have physiological properties that are characteristic of immature cells.…”

“…The iDG phenotype has been identified in alpha-isoform of calcium/calmodulin-dependent protein kinase II (αCaMKII) heterozygous knockout (HKO) mice [32,34-36], Schnurri-2 (Shn-2) KO mice [37], and chronic fluoxetine (FLX)-treated mice [33,38,39]. To elucidate the molecular mechanisms responsible for the iDG phenotype in SNAP-25 KI mice, DNA microarray analysis was performed using the hippocampi of mutant mice.…”

Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice

“…Antidepressants have been found to rescue AMPA dysfunction in chronically stressed animals (Kallarackal et al., 2013) and further increase AMPA phosphorylation and surface expression (Martinez-Turrillas et al., 2002, Svenningsson et al., 2002). Specifically, fluoxetine, a selective reuptake inhibitor, increases AMPA-induced currents in pyramidal cells via activation of D1 receptors in the prefrontal cortex (Bjorkholm et al., 2015) and reverses behavioral signs of depression by increasing them (Kobayashi et al., 2012). Future studies will be needed to delineate whether the alterations observed in hippocampal spine morphology may be restored within the CA1 via dopamine and glutamate-dependent antidepressant mechanisms.…”

The role of serotonin in adult hippocampal neurogenesis

“…Other recent studies reveal Flx's additional effect on DA receptors, and levels of neurotrophic signaling (Kobayashi et al, 2012, Lesemann et al, 2012. In accordance to the delayed effects of antidepressant action, a crucial involvement of cyclic AMP regulatory element-binding protein (CREB) (Palmer et al, 1997, Chen et al, 2001 and non-monoamine-based antidepressants have been suggested (Berton and Nestler, 2006).…”