Lithium stimulates glutamate "release" and inositol 1,4,5-trisphosphate accumulation via activation of the N-methyl-D-aspartate receptor in monkey and mouse cerebral cortex slices.

Abstract

Beginning at therapeutic concentrations (1-1.5 mM), the anti-manic-depressive drug lithium stimulated the release of glutamate, a major excitatory neurotransmitter in the brain, in monkey cerebral cortex slices in a time-and concentration-dependent manner, and this was associated with increased inositol 1,4,5-trisphosphate [Ins(1,4,5) monkey (2, 3). In the case of guinea pig and rabbit, inositol 1,3,4,5-tetrakisphosphate was also increased. These effects are in contrast to cholinergically stimulated cerebral cortex slices of rat and mouse, where lithium decreased accumulation ofIns(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate (2, 4, 5). The explanation for the species differences lies in the fact that rat and mouse cerebral cortex slices are uniquely deficient in inositol (2, 6, 7), and when the incubation medium was supplemented with inositol, cerebral cortex slices of these two species also showed lithium-stimulated increases in Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate (2).In the case of rhesus monkey, neither inositol nor an agonist was required to demonstrate lithium-stimulated accumulation of Ins(1,4,5)P3 (3). This suggested that an endogenous neurotransmitter was involved in the lithium effect. We show here that, beginning at therapeutic concentrations, lithium stimulated the release of glutamate in rhesus monkey and mouse cerebral cortex slices, and this in turn increased accumulation of Ins(1,4,5)P3 via activation of the N-methyl-D-aspartate (NMDA) receptor.

Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

“…Biochemically diverse effects of lithium on the glutamateric system have been identified by a number of groups (Antonelli et al, 2000;Dixon and Hokin, 1998;Dixon et al, 1994;Du et al, 2004;Du et al, 2006;Gray et al, 2003;Hokin et al, 1996;Marcus et al, 1986). Specifically, these effects include evidence suggesting a decrease in glutamate reuptake, decrease in glutamate release, and/or modulation of receptor levels.…”

“…Among the many biochemical effects of lithium, evidence has suggested actions on the glutamateric system (Antonelli et al, 2000;Dixon and Hokin, 1998;Dixon et al, 1994;Du et al, 2004;Hokin et al, 1996;Marcus et al, 1986). A substantial body of data suggests that the AMPA receptor subclass of glutamate receptors may be particularly interesting targets for the treatment of mood disorders (Alt et al, 2006;Li et al, 2001;Li et al, 2003;Martinez-Turrillas et al, 2002; Svenningsson et al, 2002).…”

“…Lithium, in particular, has been implicated in modulating the glutamatergic system and AMPA receptors (Antonelli et al, 2000;Dixon and Hokin, 1998;Dixon et al, 1994;Du et al, 2004;Hokin et al, 1996;Marcus et al, 1986). Given the clinical profile of lithium, we hypothesized that regulation of AMPA receptor activation may be implicated in the antidepressant-like effects of lithium in the FST and TST.…”

“…Thus, lithium has a clinical profile as an antidepressant medication, but understanding the therapeutic mechanism of lithium action has been a major challenge for psychiatric neuroscience, and lack of knowledge regarding how lithium exerts its therapeutic effects has likely hindered the development of novel antidepressant medications. To narrow the effects of lithium that are most likely related to the therapeutic actions of the drug, we have begun studying the neurobiology underlying the effects of lithium in established behavioral models.Among the many biochemical effects of lithium, evidence has suggested actions on the glutamateric system (Antonelli et al, 2000;Dixon and Hokin, 1998;Dixon et al, 1994;Du et al, 2004;Hokin et al, 1996;Marcus et al, 1986). A substantial body of data suggests that the AMPA receptor subclass of glutamate receptors may be particularly interesting targets for the treatment of mood disorders (Alt et al, 2006;Li et al, 2001;Li et al, 2003;Martinez-Turrillas et al, 2002; Svenningsson et al, 2002).…”

Molecular Cloning of a Novel Isoform of Diphosphoinositol Polyphosphate Phosphohydrolase: A Potential Target of Lithium Therapy

“…Electrophysiolgical studies in Drosophila have provided evidence of aberrant synaptic transmission in response to lithium exposure, which is attributable to a marked increase in the probability of synaptic vesicle release (Acharya et al 1998). In line with the latter observation, lithium has been shown to increase the release of serotonin (Wang and Friedman 1988) and glutamate (Dixon et al 1994) in brain cerebral cortical slices. These results, taken together, suggest that lithium modulation of synaptic function may be mediated partly by its influences on diphosphoinositol polyphosphate metabolism and/or turnover.…”