In Vivo Labeling of Serotonin Uptake Sites with [3H]Paroxetine

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Abstract
Previous work has shown that [3H]paroxetine is a potent and selective in vitro label for serotonin uptake sites in the mammalian brain. In the present study, [3H]paroxetine was tested in mice as an in vivo label for serotonin uptake sites. Maximum tritium concentration in the whole brain (1.4% of the intravenous dose) was reached 1 h after injection into a tail vein. Distribution of the tracer at 3 h after injection followed the distribution of serotonin uptake sites known from previous in vitro binding studies (r= 0.85). The areas of highest [3H]paroxetine concentration, in decreasing order, were: hypothalamus > frontal cortex > olfactory tubercles > thalamus > upper colliculi > brainstem > hippocampus > striatum > cerebellum. Preinjection of carrier paroxetine (1 mg/kg) significantly decreased [3H]paroxetine concentration in all areas except in the cerebellum, which is known to contain a relatively low number of specific binding sites. Kinetic studies showed highest specific [3H]paroxetine binding (tissue minus cerebellum) at 2 h after injection and slow clearance of activity thereafter (half‐time of dissociation from the hypothalamus, 215 min). The specificity of in vivo [3H]paroxetine binding was studied by preinjecting monoamine uptake blockers or receptor antagonists 5 min before administration of [3H]paroxetine. Serotonergic or muscarinic cholinergic receptor antagonists and dopamine or norepinephrine uptake blockers did not reduce the in vivo binding of [3H]paroxetine. In contrast, there was an excellent correlation (r= 0.99) between the in vivo inhibitory potencies of serotonin uptake blockers in this study and previously published in vitro data on inhibition of [3H]serotonin uptake in brain synaptosomes. In addition, [3H]paroxetine binding in the hypothalamus was found to be stereospecifically inhibited, (Z)‐norzimelidine displaying a greater than fourfold higher potency than the E isomer. These studies indicate that [3H]paroxetine is a potent and selective agent for the in vivo labeling of cerebral serotonin uptake sites.