title: 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.
authors.affiliation: Laboratory of Neuropharmacology, EA3544, University of Paris X1, 92290 Chatenay-Malabry, Cedex, France. bruno.guiard@u-psud.fr.
authors.forename: Gaël
authors.initials: G
authors.lastname: Quesseveur
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
mesh_terms: D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015306:Biogenic Monoamines / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009414:Nerve Growth Factors / Q000378:metabolism; D017982:Receptors, Biogenic Amine / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D009414:Nerve Growth Factors; D017982:Receptors, Biogenic Amine; D017981:Receptors, Neurotransmitter