Effect of co-administration of subchronic lithium pretreatment and acute MAO inhibitors on extracellular monoamine levels and the expression of contextual conditioned fear in rats.

We investigated the effects of clorgyline [a selective MAO (monoamine oxidase inhibitor)-A inhibitor] and lazabemide (a selective MAO-B inhibitor) on extracellular serotonin, dopamine and noradrenaline concentrations in the medial prefrontal cortex after 1-week treatment with subchronic 0.2% or 0.05% Li2CO3 (p.o.) and the effects on expression of contextual conditioned fear, previously reported to be reduced by facilitation of serotonin neurotransmission. As compared to normal diet controls, the subchronic 0.2% Li2CO3 group showed significantly higher levels of extracellular serotonin, but not noradrenaline. No changes were observed in the 0.05% Li2CO3 group. Acute clorgyline (10 mg/kg) treatments combined with subchronic 0.2% Li2CO3 treatments showed significant increases in extracellular serotonin concentrations, but not in dopamine or noradrenaline, as compared with clorgyline treatment alone. There was an additive effect with combined treatment of subchronic 0.2% Li2CO3 and acute clorgyline on the reduction of conditioned freezing, an index of conditioned fear, and this was not observed with subchronic 0.05% Li2CO3. These behavioral data indicate the functional significance of increased extracellular serotonin concentrations due to combined use of a MAO-A inhibitor with subchronic lithium. Effects of lazabemide (10 mg/kg) on extracellular monoamine concentrations and conditioned fear were slight or negligible, and were not affected by subchronic lithium treatment. The present study suggests that lithium augmentation of the antidepressant effect of MAO inhibitors is mediated by additional increases in the extracellular serotonin concentrations induced by MAO-A inhibition and suggests that the anxiolytic action of MAO inhibitors may be enhanced by lithium.