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

Abstract

Shukla, G.S.:GABAergic mechanism of interaction of lithium and valproate in discrete rat brain regions following their combined treatment and subsequent withdrawal. Drug Dev. Res. 11:209-218. 1987.Rats administered intraperitoneally with 1 mmol lithium carbonatelkglday, 300 mg valproic acidlkglday, and their combination for 12 days lithium treatment were found to increase the levels of r-aminobutyric acid (GABA) and its synthesizing enzymes, glutamic acid decarboxylase (GAD), in corpus striatum and midbrain regions. However, these elevated levels returned to normal after withdrawal of the treatment for 2 days. Valproic acid treatment alone increased GABA and GAD in the cerebral cortex and hippocampus regions. In addition, 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 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 regions. 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.

Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers

“…VPA increases GABA levels in various brain regions via inhibition of GABA catabolism and activation of GABA synthesis (Chapman et al . 1982; Shukla 1987), while Li + has effects on multiple neurotransmitters, increasing serotonin and dopamine (Waldmeier 1987). Given that both of these drugs with such different effects on CNS neurotransmitters have been shown to be effective in treating both phases of bipolar illness, mania as well as depression, the question arises as to what common mechanism might underlie their efficacy (Emilien et al .…”

Lithium and Valproate Combined Administration: Acute Behavioural Effects and Drug Plasma Levels

“…Hyponatraemia does not increase head-shaking behaviour in rats by itself, but increases the number of headshakes induced by valproic acid and lithium. Although producing a moderate degree of hyponatraemia, it has since long been demonstrated that the intraperitoneal glucose method also induces a change in cerebral ion distribution accompanied by a decrease in convulsant threshold (Swinyard et al 1946). However, increased sensitivity to drug effect does not entirely explain our observations, since hyponatraemic rats also show higher valproic acid and lithium plasma levels.…”

“…On the other hand, valproic acid-induced head-shakes may have a GABA mechanism of action (de Boer et al 1980) and lithium has been demonstrated to increase the activity of GABAergic systems in distinctive brain regions (Otero Losada & Rubio 1986). Furthermore, a significant synergistic effect of both drugs in elevating GABA and GAD levels in striatum and midbrain regions after subacute administration has been demonstrated (Shukla 1987). However, because excitation of GABAA receptors potentiates serotonin-induced head-shakes (Glennon et al 199 1) it cannot be ruled out that the mechanism involved in the potentiation of head-shakes is different from serotonin.…”