Nonmetastatic nephrogenic hepatosplenomegaly and epilepsy.

Abstract

Because 5-HT_1A receptors located on the soma dendrites of serotonin (5-HT) neurons normally mediate an inhibition of 5-HT firing and release, the desensitization of these autoreceptors is essential for obtaining an enhancement of 5-HT transmission after treatment with 5-HT reuptake inhibitors (SSRIs). We have demonstrated previously, using immunoelectron microscopy with specific 5-HT_1A antibodies, that an internalization of 5-HT_1A autoreceptors is associated with their desensitization in rats given a single dose of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-<i>n</i>-propylamino)tetralin. Here, we examined the subcellular distribution of 5-HT_1A receptors in dendrites from nucleus raphe dorsalis (NRD) (autoreceptors) and hippocampus (heteroreceptors) after acute treatment with the antidepressant SSRI, fluoxetine (10 mg/kg, i.p.). In parallel experiments, the kinetics of <i>in vivo</i> binding of the 5-HT_1A positron emission tomography radioligand 4,2-(methoxyphenyl)-1-[2-(<i>N</i>-2-pyridinyl)-p-fluorobenzamido]ethylpiperazine ([¹⁸F]MPPF) was measured in these two brain regions by means of stereotaxically implanted β microprobes. One hour after treatment, there was a 36% decrease in 5-HT_1A immunogold labeling of the plasma membrane of NRD dendrites, and a concomitant increase in their cytoplasmic labeling, without any change in hippocampal dendrites. <i>In vivo</i> binding of [¹⁸F]MPPF was reduced by 35% in NRD and unchanged in hippocampus. Both effects were blocked by pretreatment with the 5-HT_1A receptor antagonist (<i>N</i>-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-<i>N</i>-(2-pyridinyl) cyclohexane-carboxamide) (1 mg/kg, i.p.). In brain sections of NRD and hippocampus, [¹⁸F]MPPF autoradiographic labeling did not differ between fluoxetine- and saline-treated rats. These immunocytochemical results confirmed that internalization of 5-HT_1A autoreceptors may account for their desensitization, and the microprobe results suggest that this prerequisite for antidepressant treatment efficacy could be amenable to brain imaging in humans.