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

Abstract

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.

Chronic Carbamazepine Administration Attenuates Dopamine D2-like Receptor-Initiated Signaling via Arachidonic Acid in Rat Brain

“…The baseline values of k* for AA in vehicle-treated rats, which ranged from 2.65 to 20.9 × 10 −4 ml/s/g brain, are similar to previously reported values [5,6,8,10,15]. Quinpirole significantly increased k* in 35 regions, many of which belong to dopaminergic circuits containing D 2 receptors (e.g.…”

“…In addition to attenuating D 2 -like receptor-mediated AA signaling, chronic lithium, CBZ and valproic acid [6][7][8] each attenuates AA signaling mediated by glutamatergic N-methyl-Daspartate (NMDA) receptors in unanesthetized rats [6,8]. As D 2 -like and NMDA receptors are often functionally coupled and co-localized on the same neurons in brain [52,54], these data suggest that mood stabilizers that are effective against mania suppress AA signaling coupled to both D 2 -like and NMDA receptors.…”

“…The signaling process can be imaged in unanesthetized rats by injecting intravenously [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]AA and measuring tracer AA uptake into brain using quantitative autoradiography. Regional brain AA incorporation coefficients k* (brain radioactivity/integrated plasma radioactivity) are calculated and, if multiplied by unlabeled unesterified plasma AA concentrations, are converted to regional incorporation rates J in that represent regional brain AA consumption.…”

Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

“…Male CDF-344 rats (weighing 200-215 g, Charles River Laboratories; Wilmington, MA, USA) were randomly assigned to a control group (n = 10) that received vehicle (0.9% saline) once daily for 21 days, and to an NMDA group (n = 10) that received 25 mg/kg NMDA (Sigma Chemical Co., St Louis, MO, USA) once daily for 21 days. The NMDA dose was based on our earlier studies with NMDA in rats [4,14,32]. Three hours after the last saline or NMDA injection, a rat was anesthetized with CO 2 and then decapitated.…”

“…Excitotoxicity has been implicated in the pathophysiology of various human brain disorders, including Alzheimer disease [9,10], Parkinson disease [11], Huntington disease [12], schizophrenia [13], and bipolar disorder [14][15][16]. Studies have demonstrated increased concentrations of glutamate and reduced levels of NMDA receptor (NR) subunits in the brain of some of these patients.…”