Elsevier

Biological Psychiatry

Volume 63, Issue 12, 15 June 2008, Pages 1135-1140
Biological Psychiatry

Archival Report
Decreased [18F]MPPF Binding Potential in the Dorsal Raphe Nucleus After a Single Oral Dose of Fluoxetine: A Positron-Emission Tomography Study in Healthy Volunteers

https://doi.org/10.1016/j.biopsych.2007.11.016Get rights and content

Background

Brain serotonin-1A (5-HT1A) autoreceptors internalize when activated by agonist or by their endogenous ligand, serotonin. This positron-emission tomography (PET) study tested the hypothesis that 5-HT1A autoreceptor internalization might be indexed in vivo by a decrease in the specific binding of the 5-HT1A radioligand, 4-[18F]fluoro-N-[2-[1-(2-methoxyphenyl)-1 piperazinyl]ethyl-N-2-pyridinyl-benzamide ([18F]MPPF), in the dorsal raphe nucleus (DRN) of healthy adult men administered a single oral dose of the selective serotonin reuptake inhibitor, fluoxetine.

Methods

[18F]MPPF binding potential was measured in the DRN and other brain regions endowed with 5-HT1A receptors in eight healthy volunteers, 5 hours after the randomized, double-blind administration of fluoxetine (20 mg) or placebo.

Results

In every subject, [18F]MPPF binding potential was decreased in the DRN only (44% ± 22 SD), in response to fluoxetine.

Conclusions

Imaging the functional state of 5-HT1A autoreceptors (i.e., internalization) in the human brain, using [18F]MPPF/PET, may represent a promising avenue for investigating the neurobiology of serotonin-related disorders and notably of major depression.

Section snippets

Subjects

The study was carried out in accordance with the Declaration of Helsinki and was approved by the Montreal Neurological Institute Research Ethics Board. Eight men, 19 to 35 years old (mean: 25 ± 6) were recruited via advertisements on a local website. All were physically healthy and drug-free, as determined by a physical examination and standard laboratory tests, including a urine drug screen (Biosite Diagnosis, San Diego, California) on the morning of each PET scan. Personal history of

Results

All procedures were well tolerated by the subjects, who did not differ significantly between sessions (placebo vs. fluoxetine) for mood, subjective behavioral effects, and vital signs. Fluoxetine and norfluoxetine were detected in the plasma of every subject, 5 hours and 6 hours after fluoxetine intake, at similar levels at both time points (fluoxetine: 19.98 ± 7.39 ng/mL; norfluoxetine: 5.37 ± 3.41 ng/mL; means ± SD).

The rank order of regional distribution and range values of [18F]MPPF BP

Discussion

The selective decreases in [18F]MPPF BP here observed and measured with PET in the DRN of healthy human subjects administered a single oral dose of the SSRI fluoxetine were presumably imputable to 5-HT1A autoreceptor internalization, in keeping with earlier results in animals (6, 24, 25) showing that 5-HT1A autoreceptor internalization is associated with parallel decreases in the in vivo binding of the 5-HT1A receptor radioligand [18F]MPPF in the DRN.

Considering that the DRN nucleus is not

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