GABAergic mechanism of interaction of lithium and valproate in discrete rat brain regions following their combind treatment and subsequent withdrawal

Abstract

AbstractRats administered intraperitoneally with 1 mmol lithium carbonate/kg/day, 300 mg valproic acid/kg/day, and their combination for 12 days lithium treatment were found to increase the levels of γ‐aminobutyric acid (GABA) and its synthesizing enzymes, glutamic acid decarboxylase (GAD), in corpus striatum and midbrain regions. However, these elevated treatment alone increased GABA and GAD in the cerebral cortex and hippocampus regions. in adition, an increased cerebellar GABA concentration was observed. The combined treatment of lithium and valproic acid enhanced GABA and GAD levels in all brain regions, except for GABA and GAD in the pons‐medulla. A statistically significant synergistic effect of the two drugs was noticed in elevating GABA and GAD levels in the corpus striatum, cerebral cortex, and midbrain region. Furthermore, the elevated levels remained stable even 2 days after cessation of the combined therapy. The observed stable and synergistic increase in the regional GABA and GAD suggested a possible role of facilitated GABAergic transmission in the mechanism of therapeutic action of lithium and valproic acid combination in the treatment of mania.