NMDA receptors activate the arachidonic acid cascade system in striatal neurons

Abstract

Receptors for excitatory amino-acid transmitters on nerve cells fall into two main categories associated with non-selective cationic channels, the NMDA (N-methyl-D-aspartate) and non-NMDA (kainate and quisqualate) receptors. Special properties of NMDA receptors such as their voltage-dependent blockade by Mg2+ (refs 3, 4) and their permeability to Na+, K+ as well as to Ca2+ (refs 5, 6), have led to the suggestion that these receptors are important in plasticity during development and learning. They have been implicated in long-term potentiation (LTP), a model for the study of the cellular mechanisms of learning. We report here that glutamate and NMDA, acting at typical NMDA receptors, stimulate the release of arachidonic acid (as well as 11- and 12-hydroxyeicosatetraenoic acids from striatal neurons probably by stimulation of a Ca2+-dependent phospholipase A2. Kainate and quisqualate, as well as K+-induced depolarization were ineffective. Our results provide direct evidence in favour of the hypothesis, that arachidonic acid derivatives, produced by activation of the postsynaptic cell, could be messengers that cross the synaptic cleft to modify the presynaptic functions known to be altered during LTP. In addition, we suggest that NMDA receptors are the postsynaptic receptors which trigger the synthesis of these putative transynaptic messengers.

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

“…On the other hand, the ability of chronic LiCl to potentiate k* responses in rats to the muscarinic M 1,3,5 receptor agonist, arecoline (Basselin et al, 2003), is consistent with reports that cholinomimetics can be therapeutic as well (Bunney and Garland-Bunney, 1987;Bymaster and Felder, 2002). These published data, and the data of this study, suggest that lithium acts in BD by rectifying several neurotransmitter-signaling imbalances through downregulating NMDAR and D 2 -like receptor signaling and upregulating M 1,3,5 receptor signaling involving PLA 2 and the AA cascade (Bunney and Garland-Bunney, 1987;Bymaster and Felder, 2002;Dumuis et al, 1988;Rapoport and Bosetti, 2002;Shimizu and Wolfe, 1990).…”

“…NMDAprovoked EPLA 2 activation has been demonstrated in rat hippocampal slices, where it could be blocked by a specific cPLA 2 inhibitor and was accompanied by the formation of lyso-phosphatidylcholine and glycerophosphocholine, consistent with activation of the AA-selective cPLA 2 (Dennis, 1994;Weichel et al, 1999). Other studies also reported that Ca 2 + -mediated activation of PLA 2 in neurons released AA following NMDA (Dumuis et al, 1988;Lazarewicz et al, 1990;Pellerin and Wolfe, 1991;Tapia-Arancibia et al, 1992). Although both cPLA 2 and sPLA 2 were activated in some of those studies (Kim et al, 1995), it is likely that mainly cPLA 2 was activated in ours, as cPLA 2 is sensitive to the low Ca 2 + concentrations, 300 nM to 1 mM (Clark et al, 1995;Ismailov et al, 2004) that occur during normal neuronal activation.…”

“…Finally, interference in the normal NMDAR-initiated PLA 2 -mediated release of AA by lithium may disturb long-term potentiation in the hippocampus, considered the basis of learning and memory (Dumuis et al, 1988;Nishizaki et al, 1999;Otmakhov et al, 2004;Schmitt et al, 2005;Williams et al, 1989). This may be relevant to reports that lithium treatment inhibited learning, memory, and speed of information processing in BD patients and to some extent in control subjects (Honig et al, 1999;Pachet and Wisniewski, 2003;Stip et al, 2000).…”

“…Exposure of neurons from different brain regions to NMDA is reported to activate PLA 2 through the Ca 2 + mechanism, to release the second messenger, arachidonic acid (AA, 20 : 4 n-6), from membrane phospholipid (Dumuis et al, 1988;Kim et al, 1995;Kolko et al, 1999Kolko et al, , 2003Lazarewicz et al, 1990;Pellerin and Wolfe, 1991;Sanfeliu et al, 1990;Tapia-Arancibia et al, 1992;Tencé et al, 1994;Weichel et al, 1999). The AA release could be blocked by the nonspecific PLA 2 inhibitor, mepracrine, or in the rat hippocampus by bilobalide, a constituent of Ginkgo biloba, and by a specific inhibitor of cPLA 2 (cytosolic PLA 2 ) (see below) (Sanfeliu et al, 1990;Tapia-Arancibia et al, 1992;Tencé et al, 1994;Weichel et al, 1999).…”

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

“…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).…”