Behavioral effects of short-term administration of lithium and valproic acid in rats

Lithium and valproic acid are mood-stabilizing agents that are often used to manage the episodes of mania and depression that characterize bipolar disorder. These agents develop clinical efficacy with chronic treatment, but the neurobiological actions that contribute to their therapeutic effects remain unclear. The present work was designed to study and compare various behavioral effects of short-term administration of lithium chloride (LiCl) and valproic acid (VPA) in rats. Specifically, we examined the effects of acute and sub-acute injections of these agents on locomotor activity, behavior in the forced swim test (FST), and intracranial self-stimulation (ICSS) thresholds. Locomotor activity studies were used to identify the range of doses with gross behavioral effects in rats. At doses below those that suppressed activity (total distance traveled, in cm) in 1-h test sessions, LiCl had prodepressant-like effects: it increased immobility in the FST, an effect opposite to that typically seen with standard antidepressants, and it increased ICSS thresholds, an effect similar to that typically seen during withdrawal from drugs of abuse. In contrast, VPA had no effects in the FST or on ICSS thresholds. This work identifies potentially important characteristics that distinguish the drugs at doses below those that produce non-specific behavioral effects, and thus serves as a basis for designing and interpreting studies of long-term treatment.