We have evidence from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (n = 3) that citalopram (5 mg/kg/d for 6 d) did not inhibit microglial activation as evidenced by Mac-1 immunocytochemical staining. However, another serotonin uptake inhibitor (fluoxetine; 5 mg/kg/d for 6 d) inhibited MPTP-activated glial activation as assessed by Mac-1 and GFAP immunostaining. Fluoxetine was also found to prevent MPTP-induced neuroinflammation (increases in reactive oxygen species and proinflammatory cytokines, such as TNF-α, IL-1β, and inducible NO synthase). In the LPS-injected rat substantia nigra, fluoxetine (10 mg/kg/twice a d for 6 d) dramatically reduced neuroinflammation (reactive oxygen species and proinflammatory cytokines). This is in line with recent findings that fluoxetine inhibits the expression of proinflammatory cytokines, such as TNF-α, and IL-1β in the rat cerebral ischemia model of middle cerebral artery occlusion (1) and kainaic acid-treated mouse hippocampus (2). Contrary to citalopram, Taler and his colleagues (3, 4) reported that paroxetine and sertraline, another serotonin uptake inhibitor, reduced secretion of TNF-α in human T lymphocytes and rat splenocytes. It is therefore likely that anti-inflammtory actions of paroxetine may not be specific to neuroinflammation, and not all of serotonin uptake inhibitors possess anti-inflammtory properties.
Striatal serotonin levels were measured in MPTP-treated mice to determine the relationship between anti-inflammatory effects of the fluoxetine and serotonin system. Results (MPTP: 14.6 ± 2.5 μg/mg protein, n = 6; MPTP + fluoxetine: 15.3 ± 1.3 μg/mg protein, n = 6) show that, whereas fluoxetine prevented MPTP-induced neuroinflammation, it failed to increase serotonin levels in the striatum. These results carefully suggest that the anti-inflammatory effect of paroxetine is not mediated by increases in synaptic serotonin, although serotonin levels are not provided.
