Effects of acute and chronic lamotrigine treatment on basal and stimulated extracellular amino acids in the hippocampus of freely moving rats

Ahmad, Shagufta; Fowler, Leslie J.; Whitton, Peter S.

doi:10.1016/j.brainres.2004.09.016

Cited by 39 publications

(27 citation statements)

References 34 publications

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“…Similarly, lamotrigine was more potent at inhibiting glutamate release evoked by veratridine (IC 50 ∼31 μM; Waldmeier et al 1995) but was unable to inhibit release from cortical synaptosomes evoked by depolarization with potassium chloride (Lingamaneni and Hemmings 1999). In a recent in vivo study, Ahmad et al (2004a) reported that lamotrigine, at therapeutically relevant concentrations, could inhibit an increase in extracellular glutamate induced by veratridine applied via a microdialysis probe to the hippocampus. The inhibitory effect of lamotrigine increased with chronic dosing (21 days), although this could be explained by increases in plasma and brain concentrations of the drug over the first few days of dosing.…”

Section: Glutamate Releasementioning

confidence: 94%

The potential role of lamotrigine in schizophrenia

2005

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The efficacy of lamotrigine is most likely explained within the framework of a glutamate neuron dysregulation hypothesis, and may arise primarily through the drugs ability to influence glutamate transmission and neural activity in the cortex. The drug is likely to act through inhibition of voltage-gated sodium channels, though other molecular interactions cannot be ruled out. Lamotrigine may add to or synergise with some atypical antipsychotic drugs acting on glutamate transmission; alternatively, they may act independently on glutamate and dopamine systems to bring about a combined therapeutic effect. We propose new strategies for the treatment of schizophrenia using a combination of anti-dopaminergic and anti-glutamatergic drugs.

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Section: Glutamate Releasementioning

confidence: 94%

The potential role of lamotrigine in schizophrenia

2005

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“…Both riluzole and lamotrigine reduce glutamate release through mechanisms that inactivate voltage-dependent sodium channels (Ahmad et al, 2004;Lees and Leach, 1993;Benoit and Escande, 1991;Hebert et al, 1994), and recent clinical studies of both pharmaceuticals (Zarate et al, 2005;Calabrese et al, 1999) suggest that this regulation of the glutamatergic system is critical in treating bipolar depression. In accordance with the increasing need for providing therapeutics with novel mechanisms (Sanacora et al, 2008), lamotrigine has been more frequently considered as the first-line medication for the depressed phase of BD (reviewed by Fountoulakis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

Yoon

Lyoo

Haws

et al. 2009

Neuropsychopharmacol

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Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine's efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1-4; p ¼ 0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p ¼ 0.004, 0.004, and 0.02, respectively). Cytidinerelated glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p ¼ 0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine's efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.

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“…This assumption was called into question by the demonstrationFin a double-blind, placebo-controlled studyFthat lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) was effective in acute bipolar depression (Calabrese et al, 1999); indeed, lamotrigine is now increasingly accepted as a very effective agent for the depressed phase of bipolar disorder, but its use is limited by its side-effect profile. Lamotrigine is a comparatively novel antiepileptic agent used primarily in the treatment of generalized and partial seizures (Bazil, 2002;Kwan and Brodie, 2001); its mechanism of action is considered to be a reduction in glutamate release following inhibition of Na + channels and consequent neurotransmitter glutamate exocytosis (Ahmad et al, 2004;Lees and Leach, 1993). Riluzole (2-amino-6-trifluoromethoxybenzothiazole), an inhibitor of sodium channel and thus glutamate release, is approved by the US Food and Drug Administration for the treatment of amyotrophic lateral sclerosis (Bensimon et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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

Suzuki

Wei

et al. 2006

Neuropsychopharmacol

194

153

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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.

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Effects of acute and chronic lamotrigine treatment on basal and stimulated extracellular amino acids in the hippocampus of freely moving rats

Cited by 39 publications

References 34 publications

The potential role of lamotrigine in schizophrenia

The potential role of lamotrigine in schizophrenia

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

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

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