Glutamate: A Neurotransmitter in Mammalian Brain

Fonnum, Frode

doi:10.1111/j.1471-4159.1984.tb09689.x

Cited by 1,900 publications

(792 citation statements)

References 146 publications

(123 reference statements)

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“…Furthermore, the ability of MK-801, given alone or prior to NMDA, to significantly reduce k* for AA by 16-49%, suggests that NMDA-initiated PLA 2 activation contributes substantially to the baseline release of AA in control brain. This interpretation is consistent with evidence that glutamatergic receptors constitute about 75% of the synapses in the mammalian cortex, and that many of these synapses include NMDARs (Braitenberg and Schüz, 1998;Fonnum, 1984;Raichle and Gusnard, 2002).…”

Section: Discussionsupporting

confidence: 90%

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: Discussionsupporting

confidence: 90%

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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“…This is consistent with a low abundance of DA synapses compared with a high (70%) abundance of glutamatergic synapses in rat brain (Fonnum, 1984;Raichle and Gusnard, 2002). Thus, baseline values of k* for AA in rat brain are decreased 20% to 50% following administration of MK-801, which blocks Ca 2 + -mediated activation of cPLA 2 via the ionotropic NMDA receptor (Basselin et al, 2005a;Dumuis et al, 1988;Weichel et al, 1999).…”

Section: Discussionsupporting

confidence: 78%

D-Amphetamine Stimulates D₂Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

Bhattacharjee

Chang

White

et al. 2006

J Cereb Blood Flow Metab

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In rat brain, dopaminergic D 2 -like but not D 1 -like receptors can be coupled to phospholipase A 2 (PLA 2 ) activation, to release the second messenger, arachidonic acid (AA, 20:4n-6), from membrane phospholipids. In this study, we hypothesized that D-amphetamine, a dopamine-releasing agent, could initiate such AA signaling. The incorporation coefficient, k* (brain radioactivity/integrated plasma radioactivity) for AA, a marker of the signal, was determined in 62 brain regions of unanesthetized rats that were administered i.p. saline, D-amphetamine (2.5 or 0.5 mg/kg i.p.), or the D 2 -like receptor antagonist raclopride (6 mg/kg, i.v.) before saline or 2.5 mg/kg D-amphetamine. After injecting [1-14 C]AA intravenously, k* was measured by quantitative autoradiography. Compared to saline-treated controls, D-amphetamine 2.5 mg/kg i.p. increased k* significantly in 27 brain areas rich in D 2 -like receptors. Significant increases were evident in neocortical, extrapyramidal, and limbic regions. Pretreatment with raclopride blocked the increments, but raclopride alone did not alter baseline values of k*. In independent experiments, D-amphetamine 0.5 mg/kg i.p. increased k* significantly in only seven regions, including the nucleus accumbens and layer IV neocortical regions. These results indicate that D-amphetamine can indirectly activate brain PLA 2 in the unanesthetized rat, and that activation is initiated entirely at D 2 -like receptors. D-Amphetamine's lowdose effects are consistent with other evidence that the nucleus accumbens, considered a reward center, is particularly sensitive to the drug.

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“…MPP + is taken up intraneuronally by a mitochondrial carrier and inhibits complex I of the mitochondrial respiratory chain (Nicklas et al 1985). EAAs such as L-glutamate or L-aspartate are transmitters in the mammalian central nervous system (Fonnum 1984) and have been claimed to be involved in neurodegenerative disorders including Parkinson's disease (Olney 1989). This assumption is based on the observation that L-glutamate itself (Olney 1969) and compounds activating major glutamate receptor subtypes such as N-methyl-D-aspartate (NMDA, kainate, quisqualate (QUIS) or a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) have neurotoxic properties and can produce excitotoxic lesions reminiscent of human neurodegenerative disorders.…”

Section: Introductionmentioning

confidence: 99%

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Lange

Löschmann²,

Sofić

et al. 1993

Naunyn-Schmiedeberg's Arch Pharmacol

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Glutamate: A Neurotransmitter in Mammalian Brain

Cited by 1,900 publications

References 146 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

D-Amphetamine Stimulates D₂Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

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Glutamate: A Neurotransmitter in Mammalian Brain

Cited by 1,900 publications

References 146 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

D-Amphetamine Stimulates D2Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

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D-Amphetamine Stimulates D₂Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats