title: 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 riluzole-treated 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.
authors.affiliation: Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.forename: Katsuji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wei
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Rayah
authors.initials: R
authors.lastname: Blumenthal
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Cynthia
authors.initials: C
authors.lastname: Falke
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D019921:Biotinylation / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002462:Cell Membrane / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D018091:Receptors, AMPA