Differential effects of acute and chronic fluoxetine on c-Fos expression in specific subpopulations of midbrain dopaminergic neurons

Previous studies have suggested adaptive changes to dopaminergic activity in the brain may be involved in treatment effects of selective serotonin re-uptake inhibitor antidepressants. However, the relative importance of functionally and anatomically distinct dopaminergic cell subgroups in these effects remains unclear. We therefore used dual-label immunohistochemistry for c-Fos and tyrosine hydroxylase to study effects of acute or chronic administration of fluoxetine in midbrain and pontine dopaminergic cells. Specifically, three groups of female juvenile BALB/c mice (n = 12 each) received either 18 mg/kg/day of fluoxetine in their drinking water for twelve days followed by acute i.p. injection of saline vehicle (chronic group), or received acute i.p. administration of 18 mg/kg of fluoxetine (acute group) or saline (control group). All mice were then subjected to a three-chamber social approach paradigm which induces novelty stress. Immunohistochemistry analysis was conducted in 23 subregions of the ventral tegmental area (VTA), substantia nigra, periaqueductal gray, and dorsal raphe nucleus. The number of activated dopaminergic neurons significantly varied between dopaminergic subnuclei but was not different between the treatment groups in most of the regions. Notable exceptions were the VTA midrostrocaudal interfascicular nucleus, where the number of activated dopaminergic neurons was significantly greater in acute fluoxetine-treated mice compared to controls, and the VTA rostral linear nucleus where this number was reduced in chronic fluoxetine-treated mice. These findings show highly selective effects of fluoxetine on stress-induced cellular activation in a range of dopaminergic cell groups and may provide novel insight into the dopaminergic circuitry involved in its clinical treatment effects.