Chloroquine alters the behavioral effects of lithium in rats

Several hypotheses have been suggested to explain the therapeutic mechanism of action of lithium, however, none of these was proven beyond doubt. Accumulating evidence suggests that attenuated autophagy may contribute to the pathophysiology of BD, and that lithium may mitigate these alterations by enhancing autophagy.

Objectives were to determine the effects of low-dose lithium treatment on protein levels of autophagy markers and to examine the effects of the autophagy inhibitor chloroquine on behavioral effects of lithium.

Rats were fed regular rodent chaw or lithium-containing food to produce low plasma lithium concentration, for 6 weeks. Chloroquine 3 mg/kg was given intraperitoneally. At baseline and during final days of treatment, rats were subjected to behavioral tests, including: open field test (OFT), sucrose consumption test, and elevated plus-maze test (EPMT). A preliminary experiment was performed to determine the effect of lithium and chloroquine on the autophagy associated protein p62 using Western blot analysis.

Lithium significantly increased sucrose consumption, suggestive of antidepressant-like effect. Chloroquine did not alter sucrose consumption. Lithium did not alter basic locomotor activity in the OFT, while chloroquine significantly increased total distance travelled and mean velocity, suggestive of a hyperactivity/manic-like behavior. In the EPMT, lithium led to a non-significant decrease in time spent in the open arm, suggestive of a pro-anxious-like effect. Chloroquine did not affect rats’ behavior in this test. Furthermore, unlike therapeutically-relevant lithium levels (0.6-1.2 meq/liter), low-dose lithium did not influence p62 levels while chloroquine, as expected, prominently increased them, indicative of autophagy arrest.