Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder

Scarr, Elizabeth; Pavey, Geoffrey; Sundram, Suresh; Mackinnon, Andrew; Dean, Brian

doi:10.1034/j.1399-5618.2003.00024.x

Cited by 116 publications

(73 citation statements)

References 26 publications

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“…Reduced NMDAR signaling as contributing to lithium's efficacy is consistent with evidence of disturbed NMDAR subunit expression in the BD brain. NR1 and NR2 genes are reported to confer susceptibility to BD (Itokawa et al, 2003;Mundo et al, 2003), and NMDAR density is decreased in the post-mortem BD hippocampus (Scarr et al, 2003). In other studies, NR2D mRNA was higher in the post-mortem BD striatum (Meador-Woodruff et al, 2001), NR1 mRNA was decreased in the BD dentate gyrus and CA3 of the hippocampus (Law and Deakin, 2001), and NR3A mRNA was decreased in the BD prefrontal cortex (Mueller and Meador-Woodruff, 2004).…”

Section: Discussionmentioning

confidence: 87%

“…One suggestion has been that it acts in part by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate (NMDA) receptors (NMDARs) (Bauer et al, 2003;Farber et al, 2002;Krystal et al, 2002;Stewart and Reid, 2002;Zarate et al, 2003). Supporting this is evidence of disturbed markers of NMDA functioning in the BD brain (Itokawa et al, 2003;Mundo et al, 2003;Scarr et al, 2003), and data that drugs effective against BD, such as lamotrigine, carbamazepine and valproic acid, have direct or indirect NMDA antagonist properties (Farber et al, 2002;Hough et al, 1996;Kubota et al, 1994;McIntyre et al, 2004;Zeise et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

Basselin

Chang

Bell

et al. 2005

Neuropsychopharmacol

106

132

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It has been proposed that lithium is effective in bipolar disorder (BD) by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate receptors (NMDARs). To test this hypothesis and to see if the neurotransmission could involve the NMDARmediated activation of phospholipase A 2 (PLA 2 ), to release arachidonic acid (AA) from membrane phospholipid, we administered subconvulsant doses of NMDA to unanesthetized rats fed a chronic control or LiCl diet. We used quantitative autoradiography following the intravenous injection of radiolabeled AA to measure regional brain incorporation coefficients k* for AA, which reflect receptormediated activation of PLA 2 . In control diet rats, NMDA (25 and 50 mg/kg i.p.) compared with i.p. saline increased k* significantly in 49 and 67 regions, respectively, of the 83 brain regions examined. The regions affected were those with reported NMDARs, including the neocortex, hippocampus, caudate-putamen, thalamus, substantia nigra, and nucleus accumbens. The increases could be blocked by pretreatment with the specific noncompetitive NMDA antagonist MK-801 ((5R,10S)-( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate) (0.3 mg/kg i.p.), as well by a 6-week LiCl diet sufficient to produce plasma and brain lithium concentrations known to be effective in BD. MK-801 alone reduced baseline values for k* in many brain regions. The results show that it is possible to image NMDA signaling via PLA 2 activation and AA release in vivo, and that chronic lithium blocks this signaling, consistent with its suggested mechanism of action in BD.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

Basselin

Chang

Bell

et al. 2005

Neuropsychopharmacol

106

132

View full text Add to dashboard Cite

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“…26,27 Moreover, a decrease in the NMDA agonistic MK-801 binding in bipolar patients was observed. 28 The glutamate system in depression: quinolinic acid as a depressiogenic NMDA receptor agonist Investigating the glutamatergic neurotransmission and activation of the NMDA receptors, neurochemists often forget to include the potential endogenous NMDA agonist quinolinic acid into their considerations.…”

Section: Glutamate In Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…As discussed previously (Scarr et al, 2003), all binding studies were of the single-point saturation design, where all available receptor sites are occupied by radioligand because the binding of each radioligand was measured at a concentration at least three times that of the K D of the ligand for the receptor of interest (Hoffman et al, 1997;Nishikawa et al, 1983;Piggott et al, 1992;Sills et al, 1991).…”

Section: In Situ Radioligand Bindingmentioning

confidence: 99%

Cortical Glutamatergic Markers in Schizophrenia

Scarr

Beneyto

Meador‐Woodruff

et al. 2005

Neuropsychopharmacol

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Post-mortem studies have yet to produce consistent findings on cortical glutamatergic markers in schizophrenia; therefore, it is not possible to fully understand the role of abnormal glutamatergic function in the pathology of the disorder. To better understand the changes in cortical glutamatergic markers in schizophrenia, we measured the binding of radioligands to the ionotropic glutamate H]CGP39653 binding did not differ between the diagnostic cohorts. Levels of mRNA for the GluR5 subunit were decreased overall (po0.05), with no changes in levels of mRNA for GluR6, GluR7, KA1, or KA2 in tissue from subjects with schizophrenia. These data indicate that the decreased number of kainate receptors in the dorsolateral prefrontal cortex in schizophrenia may result, in part, from reduced expression of the GluR5 receptor subunits.

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Decreased hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder

Cited by 116 publications

References 26 publications

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Cortical Glutamatergic Markers in Schizophrenia

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