Chronic Lithium Chloride Administration to Unanesthetized Rats Attenuates Brain Dopamine D2-Like Receptor-Initiated Signaling Via Arachidonic Acid

Abstract

We studied the effect of lithium chloride on dopaminergic neurotransmission via D 2 -like receptors coupled to phospholipase A 2 (PLA 2 ). In unanesthetized rats injected i.v. with radiolabeled arachidonic acid (AA, 20:4 n-6), regional PLA 2 activation was imaged by measuring regional incorporation coefficients k* of AA (brain radioactivity divided by integrated plasma radioactivity) using quantitative autoradiography, following administration of the D 2 -like receptor agonist, quinpirole. In rats fed a control diet, quinpirole at 1 mg/kg i.v. increased k* for AA significantly in 17 regions with high densities of D 2 -like receptors, of 61 regions examined. Increases in k* were found in the prefrontal cortex, frontal cortex, accumbens nucleus, caudate-putamen, substantia nigra, and ventral tegmental area. Quinpirole, 0.25 mg/kg i.v. enhanced k* significantly only in the caudate-putamen. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, neither 0.25 mg/kg nor 1 mg/kg quinpirole increased k* significantly in any region. Orofacial movements following quinpirole were modified but not abolished by LiCl feeding. The results suggest that downregulation by lithium of D 2 -like receptor signaling involving PLA 2 and AA may contribute to lithium's therapeutic efficacy in bipolar disorder.

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).…”

“…Both D 2 -like and NMDA receptors can be coupled to cPLA 2 , via a G-protein or by allowing Ca 2 + into the cell (Dennis, 1994;Nilsson et al, 1998;Vial and Piomelli, 1995;Weichel et al, 1999). Similarly, giving the D 2 -like receptor agonist quinpirole to unanesthetized rats increased k* for AA in many of the brain regions activated by 2.5 mg/ kg D-amphetamine, and the increases could be prevented by prior administration of the D 2 -like receptor antagonist, butaclamol (Basselin et al, 2005b;Bhattacharjee et al, 2005b;Hayakawa et al, 2001).…”

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

“…In this regard, chronic lithium increased the level of DARPP-32 in the rat frontal cortex (Guitart and Nestler, 1992), which may explain its ability to activate the ERK-signaling cascade (Einat et al, 2003). In view of the interplay between D 2 -like receptors and NMDARs, it is not surprising that chronic LiCl suppresses increments in k* for AA in unanesthetized rats given quinpirole (Basselin et al, 2005a), an agonist of D 2 -like receptors coupled to PLA 2 via a G-protein (Bhattacharjee et al, 2005;Hayakawa et al, 2001;Huo and Healy, 1991;Vial and Piomelli, 1995). This suppression agrees with evidence that drugs that interfere with dopaminergic neurotransmission can be effective in BD (Bunney and Garland-Bunney, 1987;Bymaster and Felder, 2002;Fisher et al, 1991;Peet and Peters, 1995;Post et al, 1980;Sultzer and Cummings, 1989).…”

“…However, no method exists, as far as we know, to image the Ca 2 + signal or its downstream effects in the brain in vivo. In this paper, we present such a method, which extends our published method of imaging brain PLA 2 activation in unanesthetized rats given drugs that act at receptors coupled a G-protein to PLA 2 (Basselin et al, 2005a(Basselin et al, , b, 2003Bhattacharjee et al, 2005;DeGeorge et al, 1991;Qu et al, 2003)Fcholinergic muscarinic M 1,3,5 , dopaminergic D 2 -like and serotonergic 5-HT 2A/2C receptors (Axelrod, 1995;Bayon et al, 1997;Felder et al, 1990;Vial and Piomelli, 1995).…”

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

“…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.…”