The Monoaminergic Tripartite Synapse: A Putative Target for Currently Available Antidepressant Drugs

Abstract

Antidepressant drugs such as the serotonin (5-HT)/norepinephrine (NE) and dopamine (DA) reuptake inhibitors activate monoaminergic neurotransmission in various brain regions, such as the amygdala, the frontal cortex or the hippocampus. Although this property is well established, the post-synaptic mechanisms by which these pharmacological agents exert therapeutic activity in major depressive disorders (MDD) is not fully understood. Recent clinical and preclinical studies have indicated that the density and reactivity of glia and more particularly of astrocytes are reduced in MDD patients. These data along with the fact that astrocytes express monoaminergic transporters and receptors make these cells putative targets for antidepressant treatments. Accordingly, in vitro evidence has demonstrated that the application of various classes of antidepressant drugs on rodent primary astrocyte cultures elicits a wide spectrum of responses, from the rise in cytosolic calcium concentrations, as a marker of cellular activity, to the release of glucose metabolites, gliotransmitters and neurotrophic factors. Remarkably, antidepressant drugs also attenuate the release of inflammatory molecules from reactive astrocytes or microglia, suggesting that part of the beneficial effects in depressed patients or animal models of depression might result from the ability of antidepressants to regulate the synthesis and release of psychoactive substances acting on both pre- and post-synaptic neurons. Among the many long-term targets of antidepressant drugs, brainderived neurotrophic factor (BDNF) has been well studied because of the positive influence on adult hippocampal neurogenesis, synaptogenesis and the local serotonergic tone. This review will illustrate how the concept of the tripartite synapse, which is classically associated with different forms of plasticity involving glutamate, could be expanded to the monoaminergic systems to regulate antidepressant drug responses. The recent in vivo data supporting that hippocampal astrocytes act in concert with neurons to release BDNF under pharmacological conditions and thereby regulate different facets of anxiolytic-/antidepressant-like activities through neurogenesis-dependent and independent mechanisms will be emphasized.

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Some of standard or herbal monoaminergic medicines already show a profile of multi-target drugs acting via modulation of multiple proteins/systems rather than single targets (Di Matteo et al, 2000; Quesseveur et al, 2013), a phenomenon known as polypharmacology (Hopkins, 2008). …”

“…Monoamine receptors, (Azmitia et al, 1996), such as 5-HT 2A/2B/2C receptors are expressed on astrocytes (Hirst et al, 1998; Sanden et al, 2000; Hwang et al, 2008), but also 5-HT 4 , 5-HT 5 , and 5-HT 7 receptors (Quesseveur et al, 2013), α-ARs (Bekar et al, 2008) and β 2 -ARs (Mantyh et al, 1995), and all the DA receptors (Miyazaki et al, 2004) are detected. The SERT, NAT, DAT, and the catabolic isoenzymes responsible for the degradation of monoamines (i.e., MAO-A and MAO-B; COMT) were clearly identified in this cell type (see Quesseveur et al, 2013 for a recent review and references within). These observations emphasize the fact that astrocytes can regulate the extracellular monoamine levels by modulating the expression and function of MAO-A, MAO-B, and COMT and at the same time are regulated by feedback by monoamines via the glial monoamine receptors.…”

Monoaminergic Control of Cellular Glucose Utilization by Glycogenolysis in Neocortex and Hippocampus

“…Moreover, due to the lamellar nature of their fine peripheral processes astrocytes have a much higher local surface-to-volume ratio compared with neurons, especially in humans [48, 49]. Since astrocytes express MA transporters as well as the metabolic machinery to catabolize MA neuromodulators, they can also regulate the extracellular concentration of MA levels [50]. It is likely that part of the above-mentioned “preparatory” mechanism exerted by brainstem nuclei on forebrain regions depends on astrocytic responses mediated by MA receptor signaling.…”

Hemichannels: new roles in astroglial function

“…These express a variety of receptors including monoaminergic transporters and receptors, leading to the possibility that antidepressants exert their effects at least in part through modifying astroglial function (Peng and Huang, 2012; Quesseveur et al, 2013a). In this sense, it's been demonstrated that application of antidepressants on rodent primary astrocyte cultures may elicit Ca 2+ waves, Ca 2+ oscillations, release of gliotransmitters, glucose metabolites, and neurotrophic factors (Hisaoka et al, 2011), whereas studies in post-mortem human brain tissue suggest that antidepressants may reverse major depression associated glial reductions in the amygdala (Bowley et al, 2002).…”