Fluoxetine depresses glutamate exocytosis in the rat cerebrocortical nerve terminals (synaptosomes) via inhibition of P/Q‐type Ca²⁺ channels

Abstract

Fluoxetine, an antidepressant that is used clinically in the treatment of mood disorders, is a selective serotonin reuptake inhibitor. In the present study we investigated the effects of fluoxetine on 4-aminopyridine (4AP)-evoked glutamate release in cerebrocortical nerve terminals (synaptosomes). Fluoxetine suppressed the release of glutamate evoked by 4AP in a concentration-dependent manner. This effect was associated with a reduction in the depolarization-evoked increase in cytosolic free calcium levels in the absence of significant effect on the synaptosomal membrane potential. In addition, both ionomycin- and sucrose-evoked glutamate releases were not affected by fluoxetine, indicating that fluoxetine-mediated inhibition of glutamate release is not a direct effect on the exocytotic machinery. Furthermore, the inhibitory action of fluoxetine was completely abolished in synaptosomes pretreated with P/Q type Ca(2+) channel blocker omega-agatoxin IVA (omega-AgTX IVA) or protein kinase C (PKC) stimulator 4beta-phorbol 12, 13-dibutyrate (PDBu). These results suggest that, in cerebrocortical nerve terminals, fluoxetine inhibits glutamate release through the suppression of P/Q type Ca(2+) channel activity. The presynaptic action of fluoxetine is mediated by a PKC-sensitive signaling pathway. Synapse 48:170-177, 2003.

Chronic Antidepressants Reduce Depolarization-Evoked Glutamate Release and Protein Interactions Favoring Formation of SNARE Complex in Hippocampus

“…As reported above, in vitro application of fluoxetine reduces 4-AP-evoked release of glutamate from cerebrocortical synaptosomes, reportedly by inhibiting P/Q-type calcium channels (Wang et al, 2003). The fact that none of the drugs used here, including fluoxetine, exerted any acute effect on glutamate release suggests that this mechanism is not involved.…”

“…In the first (Wang et al, 2003), the effect of in vitro application of fluoxetine was studied (see below). In the second, two different drugs (imipramine and phenelzine) were found to reduce depolarization-evoked glutamate overflow from slices of prefrontal cortex after both acute and chronic treatment (Michael-Titus et al, 2000).…”

“…Indeed, in the last few years, numerous lines of evidence accumulated in favor of a role for glutamate in psychiatric pathophysiology, including the following: (1) higher glutamate plasma levels in patients with mood disorders (Altamura et al, 1993); (2) abnormal elevation of glutamate neurotransmission and glutamate levels in cortical/ limbic brain areas of depressed patients (Drevets, 2000(Drevets, , 2004Sanacora et al, 2004); (3) atrophy of apical dendrites in CA3 hippocampal neurons induced by chronic stress, a major factor in pathogenesis of mood disorders (Watanabe et al, 1992); (4) increased amplitude and reduced decay kinetics of NMDA current induced by chronic stress (Kole et al, 2002); (5) impaired longterm potentiation (LTP) and facilitated long-term depression induced by stress (Kim et al, 1996). Conversely, antidepressant treatments were also shown to affect glutamate neurotransmission: (1) antidepressants downregulate NMDA receptor subunits and dampen NMDA function (Skolnick, 1999); (2) antidepressants overcome the effects of stress on LTP (Shakesby et al, 2002); (3) fluoxetine, an antidepressant that selectively inhibits serotonin reuptake, reduces 4-aminopyridine (4-AP)-evoked glutamate release from cerebrocortical synaptosomes on acute exposure in vitro (Wang et al, 2003). As a consequence, now several compounds are under development for the treatment of mood disorders (depression, bipolar disorder, anxiety) that modulate glutamate receptors or neurotransmission at various levels (Holden, 2003).…”

Basic presynaptic functions in hippocampal neurons are not affected by acute or chronic lithium treatment

“…In support of this idea it has been demonstrated earlier that high concentrations of fluoxetine (5 mM), another antidepressant, inhibits glutamate exocytosis from nerve terminals (Wang, Su et al 2003). In addition, functional cellular imaging shows that antipsychotics such as chlorpromazine and clozapine, inhibit exocytosis (Tischbirek, Wenzel et al 2012), thus highlighting the importance of potential presynaptic pathologies in psychiatric diseases.…”

Gene Expression Profiling Reveals Complex Changes in the Olfactory Bulbectomy Model of Depression After Chronic Treatment With Antidepressants

“…Two different drugs (imipramine and phenelzine) were found to reduce depolarization-evoked glutamate overflow from slices of prefrontal cortex after both acute and chronic treatment (64). Acute exposure to fluoxetine reduces depolarization-evoked glutamate release from cerebrocortical synaptosomes in vitro via inhibition of P / Q-type Ca 2+ channels (65). Chronic antidepressant treatment suppresses depolarization-evoked release of glutamate from hippocampal synaptosomes, by reducing syntaxin-1/ CaM kinase II interaction, activity that promotes neurotransmitter release.…”