[Behavioral and neurochemical study on the mechanism of the anxiolytic effect of a selective serotonin reuptake inhibitor, a selective serotonin1A agonist and lithium carbonate].

The authors investigated the effects of citalopram [selective serotonin (5-HT) reuptake inhibitor; SSRI] and MKC-242 (a selective 5-HT1A agonist) following treatment with subchronic lithium (p.o., 1 week) on the expression of conditioned freezing, an index of anxiety, and on extracellular 5-HT concentrations in the medial prefrontal cortex (mPFC). In conditioned fear stress experiments, acute administration of citalopram (s.c.) reduced freezing significantly at a high dose (30 mg/kg), while showing no effect at lower doses (3 and 10 mg/kg). Acute administration of MKC-242 (s.c.; 0.1-10 mg/kg) dose-dependently reduced freezing. Subchronic lithium treatment (1 week; 0.05 or 0.2% lithium carbonate in diet; p.o.) showed no effect on freezing behavior. Acute treatment with both citalopram (3 and 30 mg/kg) and MKC-242 (1 mg/kg) after subchronic treatment with high, but not low, concentrations of lithium (1 week) reduced freezing markedly and significantly, as compared with either drug alone. In brain microdialysis experiments, acute treatment with citalopram showed significant increases in the extracellular 5-HT concentrations in a dose-dependent manner. Subchronic lithium group showed significantly higher basal levels of extracellular 5-HT, compared with normal diet controls. Acute citalopram (3 and 30 mg/kg) treatment with subchronic lithium treatment showed significant increases in the extracellular 5-HT concentrations, compared with citalopram treatment alone. Subchronic lithium did not cause decreases in extracellular 5-HT after presynaptic stimulation of 5-HT1A receptors by MKC-242. These results suggest that subchronic lithium treatment enhanced the anxiolytic-like effects of these serotonergic drugs by facilitating central 5-HT neurotransmission at clinically therapeutic plasma lithium levels. It is hypothesized that subchronic lithium treatment gives an additive effect to the treatment with citalopram (3 and 30 mg/kg) by increasing the extracellular 5-HT concentrations in the mPFC, and that subchronic lithium treatment enhances the anxiolytic effect of MKC-242 by increasing sensitivity of postsynaptic 5-HT1A receptors.