The Anticonvulsants Lamotrigine, Riluzole, and Valproate Differentially Regulate AMPA Receptor Membrane Localization: Relationship to Clinical Effects in Mood Disorders

Abstract

A growing body of data suggests that the glutamatergic system may be involved in the pathophysiology and treatment of severe mood disorders. Chronic treatment with the antimanic agents, lithium and valproate, resulted in reduced synaptic expression of the AMPA(-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunit GluR1 in the hippocampus, while treatment with an antidepressant (imipramine) enhanced the synaptic expression of GluR1. The anticonvulsants, lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) and riluzole (2-amino-6-trifluoromethoxybenzothiazole), have been demonstrated to have efficacy in the depressive phase of bipolar disorder. We therefore sought to determine the role of these anticonvulsants, compared to that of the predominantly antimanic anticonvulsant valproate, on AMPA receptor localization. We found that the agents with a predominantly antidepressant profile, namely lamotrigine and riluzole, significantly enhanced the surface expression of GluR1 and GluR2 in a time-and dose-dependent manner in cultured hippocampal neurons. By contrast, the predominantly antimanic agent, valproate, significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine-and riluzole-treated neurons, supporting the surface receptor changes. Phosphorylation of GluR1 at the PKA (cAMP-dependent protein kinase) site (S845) was enhanced in both lamotrigine-and riluzoletreated hippocampal neurons, but reduced in valproate-treated neurons. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, also increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment. Our findings suggest that regulation of GluR1/2 surface levels and function may be responsible for the different clinical profile of anticonvulsants (antimanic or antidepressant), and may suggest avenues for the development of novel therapeutics for these illnesses.

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

“…Biochemically diverse effects of lithium on the glutamateric system have been identified by a number of groups (Antonelli et al, 2000;Dixon and Hokin, 1998;Dixon et al, 1994;Du et al, 2004;Du et al, 2006;Gray et al, 2003;Hokin et al, 1996;Marcus et al, 1986). Specifically, these effects include evidence suggesting a decrease in glutamate reuptake, decrease in glutamate release, and/or modulation of receptor levels.…”

“…Modulation of the AMPA receptor subclass of glutamate receptors has been linked to the mechanism of action of antidepressant medications as well as a target for future medications (Alt et al, 2006;Du et al, 2006;Li et al, 2001;Li et al, 2003;Martinez-Turrillas et al, 2002;Svenningsson et al, 2002). It has recently been reported by us that the antidepressantlike effects of ketamine in the FST, as well as the NMDA antagonist MK801 and NR2B antagonist, Ro25-6981, are prevented by preadministration of NBQX (Maeng et al, 2007).…”

“…A substantial body of data suggests that the AMPA receptor subclass of glutamate receptors may be particularly interesting targets for the treatment of mood disorders (Alt et al, 2006;Li et al, 2001;Li et al, 2003;Martinez-Turrillas et al, 2002; Svenningsson et al, 2002). Lithium has been reported to have diverse effects on AMPA receptors including modulation of receptor levels in rats (Du et al, 2004;Du et al, 2006;Gray et al, 2003) and, at high concentrations or when replacing extracellular sodium with lithium, direct effects on AMPA-mediated currents in model systems such as Xenopus oocytes or larval lamprey spinal cord neurones (Karkanias and Papke, 1999a, b;Nanou and El Manira, 2007). Glutamate is the most prevalent excitatory neurotransmitter in the mammalian brain.…”

Antidepressant-like Effects of the Gastrodia elata Bl Extract in Mice

“…Modulation of the AMPA receptor subclass of glutamate receptors has been linked to the mechanism of action of antidepressant medications as well as a target for future medications 11,[59][60][61][62][63][64] . ti-psychotic effect of GE on schizophrenia in a recent study 50) , imply that GE acts possibly on glutamate system.…”

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

“…Riluzole increases the surface expression of the AMPAR subunits glutamate receptor 1 (GluR1) and GluR2, and reversibly attenuates AMPAR-mediated synaptic currents in cultured cells [100,101] . Fluoxetine regulates the phosphorylation state of AMPARs [102] .…”