Lithium and valproate attenuate dextroamphetamine-induced changes in brain activation

Abstract

Previous studies have suggested that both lithium and valproate may decrease phosphoinositol second messenger system (PI-cycle) activity. There is also evidence that dextroamphetamine may increase PI cycle activity. It was previously demonstrated that dextroamphetamine administration in volunteers causes a region and task dependent decrease in brain activation in healthy volunteers. The current study assessed the effect of 14 days pretreatment with lithium and valproate on these dextroamphetamine-induced changes in regional brain activity in healthy volunteers. This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n = 12), 900 mg lithium (n = 9) or placebo (n = 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after administration of dextroamphetamine (25 mg). Changes in the number of activated pixels and changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after dextroamphetamine administration were then determined. In keeping with previous findings dextroamphetamine administration decreased regional brain activation in all three tasks. Pretreatment with lithium attenuated changes in the word generation paradigm and the spatial attention task, while pretreatment with valproate attenuated the changes in the working memory task. These results suggest that both lithium and valproate can significantly attenuate dextroamphetamine-induced changes in brain activity in a task dependent and region specific manner. This is the first human evidence to suggest that both lithium and valproate may have a similar effect on regional brain activation, conceivably via similar effects on PI-cycle activity.