Differential effects of acute and short-term lithium administration on dialysate glutamate and GABA levels in the frontal cortex of the conscious rat

Abstract

In the present study, we employed in vivo microdialysis in the frontal cortex of the awake rat to investigate the effects of acute and short‐term (twice daily, 3 days) lithium chloride administration (1, 2, and 4 meq/kg, s.c.) on local dialysate glutamate and GABA levels. Acute lithium (1 meq/kg) failed to influence cortical glutamate levels while the higher (2 and 4 meq/kg) doses increased (+38 ± 6% of basal levels) and reduced (‐27 ± 4%) cortical glutamate levels, respectively. Cortical GABA levels were affected by acute lithium only at the highest 4 meq/kg dose (+62 ± 6%). Furthermore, these effects were prevented by tetrodotoxin (1 μM) and low‐calcium (0.2 mM) medium perfusion. Following short‐term administration, lithium increased (+58 ± 4%) cortical dialysate glutamate levels at the 1 meq/kg dose, was ineffective at 2 meq/kg, while the effect of the 4 meq/kg dose was similar to that observed after acute administration. Interestingly, intracortical perfusion with the GABAB receptor antagonist CGP 35348 (100 μM) reversed the acute lithium (4 meq/kg)‐induced decrease in glutamate levels. Taken together, these findings indicate a differential dose and duration dependent effect of lithium on cortical dialysate glutamate levels involving both a direct enhancement and an indirect inhibition that is mediated via an activation of local GABAB receptor. These findings may be relevant for the therapeutic effects of the drug. Synapse 38:355–362, 2000. © 2000 Wiley‐Liss, Inc.

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

“…This result is consistent with several studies showing lithium to induce an acute and subacute increase of GABA in the rat brain. [63][64][65] GABA receptor binding has also previously been found to be decreased in rat brain after chronic lithium treatment, indicating a downregulation of GABA receptors, potentially through overactivation of the system. 66 This is the first report of an increase in GABA levels after chronic lithium treatment.…”

Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol

“…71 Conversely, another recent study in rats found that lower doses of lithium led to increases in cortical glutamate concentration. 72 Notably, it is also an established clinical fact that lithium levels required for an acute antimanic response (that is, > 0.9 mmol l À1 ) exceed those required for relapse prevention.…”

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.…”