W. A. Williams¹; R. E. Carson³; A. Heinz²; J. Bjork⁵; M. Enoch⁴; C. Geyer⁵; R. Rawlings⁵; D. Hommer⁵; D. Goldman⁴; P. Herscovitch⁶
1. Psychiatry, Yale Univ, New Haven, CT, USA.
2. Psychiatry, Humboldt Univ, Berlin, Germany.
3. PET Center, Yale Univ, New Haven, CT, USA.
4. Lab Neurogenetics, NIAAA, Bethesda, MD, USA.
5. Lab Clinical Studies, NIAAA, Bethesda, MD, USA.
6. PET Dept, NIH, Bethesda, MD, USA

Alcohol dependence (AD) is an etiologically heterogeneous syndrome determined by a complex interaction of genetic and environmental factors. We propose to investigate monoamine dysfunction in alcoholic patients by using acute tryptophan (TRP) depletion (ATD) and PET imaging.

Differences in 5-HT turnover (synthesis, metabolism, and release) in alcoholics may be involved in reinforcing responses to ethanol and alcohol seeking behaviors. To examine this question, we first studied 5-HT turnover and 5-HT1A receptor occupancy in healthy volunteers. We report the results of the first 5 subjects in this cohort. We hypothesize that diminished 5-HT release following ATD leads to decreased competition for 5-HT1A receptors by endogenous 5-HT, and greater 5-HT1A receptor binding of the radioligand [18F]FCWAY, a 5-HT1A receptor antagonist. ATD lowers brain 5-HT synthesis and release by decreasing plasma and brain TRP concentration. We administered a TRP-deficient amino acid mixture to acutely lower plasma TRP, the precursor for 5-HT synthesis. In humans, ATD decreases plasma TRP concentration, with a nadir occurring approximately 5 to 6 hr after drink administration. 5-hydroxyindoleacetic acid (5-HIAA), the principal metabolite of 5-HT and a neurochemical marker of neuronal 5-HT metabolism, also decreases.

[18F]FCWAY PET studies with concurrent CSF/plasma sampling were performed in 5 healthy volunteers, in a within-subject repeated measures design. The baseline PET scan was done before ATD on day 1. The active condition scan was done on day 2, 16 hr after ATD. The day 2 scan corresponds to the CSF 5-HIAA nadir. [18F]FCWAY was synthesized by the method of Lang. Dynamic scans were acquired over 2 hours on a GE Advance tomograph (3D mode; 6 mm resolution) following iv. bolus administration of 5 mCi of tracer. IMAGE PROCESSING. Dynamic PET images were motion-corrected, and converted to functional images of distribution volume (DV) using the metabolite-corrected arterial input function. Each subject’s MR image was registered to a Talairach template and this transformation was applied to the PET DV images. Cortical and subcortical regions of interest (ROIs), including the raphe, were drawn on structural MR images.

ROI analysis corrected for the free-fraction (f1) parent compound was performed. Comparing the day1 to day 2 scans, we found significant decreases in 5 subjects in 10 brain regions. The largest decrease, 25%, was localized to the raphe (p=0.023). The difference in f1, day1 vs day2, was -11.3% (p=0.012). In the raphe, there was a strong correlation (r=0.823) between day1 and day2 DV data, with intersubject variability being much greater than intrasubject variability.

Our data show a measurable effect of ATD on FCWAY/5-HT1A brain receptor binding. There were significant regional decreases in 5-HT1A receptor occupancy, post-ATD. This effect is opposite the hypothesized decrease in synaptic 5-HT/ligand receptor competition. We postulate that acute reduction in 5-HT turnover leads to a compensatory decrease in 5-HT1A auto- and hetero- receptor density. These effects may combine to produce lower FCWAY binding after ATD. It is unclear whether receptor density in other sub-cortical and cortical regions is behaving similarly. However, lower brainstem 5-HT1A receptor density could account for the marked reduction in FCWAY binding seen in the raphe. These findings in healthy subjects may have important implications for the pathophysiology of acute and chronic alcohol dependence.