Previous studies in alcohol-preferring rodents have demonstrated a deficit in serotonin (5-HT) transmission, shown by low brain 5-HT content, a decrease in 5-HT cells and fibers, and a compensatory upregulation of 5-HT1A
). Microdialysis studies of ethanol-naïve alcohol preferring and non-preferring rodents have shown either higher levels of serotonin in the preferring rodent or no difference between the two groups (24
). However, ethanol pretreatment has been shown to result in decreased basal extracellular 5-HT levels in alcohol preferring rodents (24
). Previous post-mortem studies in alcohol dependent subjects have shown a significant decrease in the SERT in multiple brain areas including the hippocampus, anterior cingulate, dorsal striatum, amygdala, and hypothalamus (8
). Based on these findings, our hypothesis was that alcohol dependence would be associated with a decrease in serotonin transmission, which would be reflected as a decrease in SERT and 5-HT1A
receptor binding in the midbrain combined with a decrease in SERT and compensatory upregulation of the 5-HT1A
receptor in the projection fields. However, we did not find any specific alterations in 5-HT1A
receptor or SERT binding in alcohol dependent subjects compared to matched controls.
Our study does not replicate previous studies from two groups but agrees with a third group with respect to SERT binding. Using SPECT and [123
I]β-CIT, Heinz et al (9
) reported a 30% reduction of SERT binding in the midbrain in male, but not female, alcohol dependent participants. In a subsequent study, this group reported a decrease in midbrain SERT only in alcoholics who were homozygous for the long allele of the promoter of the SERT gene compared to healthy controls with the same genotype (32
Since these studies were conducted with the SPECT radiotracer [123I]βCIT measurement of the SERT was limited to the midbrain. Another group, using PET and the radiotracer [11
C]McN5652, reported a significant decrease in the distribution volume of [11
C]McN5652 in the midbrain, cortical brain regions, and reference region (cerebellum) in alcohol dependence (12
). However, only the midbrain was significantly reduced when the authors reported on the specific binding of [11
C]McN5652. More recently, a third group (13
) used [11
C]DASB, a radiotracer for SERT imaging with an improved signal to noise ratio (33
), in a study of alcohol dependence and reported no difference in any brain region, including the midbrain.
Thus, two groups have reported a decrease in midbrain SERT in alcoholism while this study and that of Brown et al (13
) did not. The reason behind this discrepancy is not clear, but may relate to differences in stage of withdrawal, data analysis, specifically of the midbrain regions, or patient heterogeneity. Duration of abstinence was somewhat varied between the studies (2 weeks in this study and the study of Brown et al, 3 to 5 weeks in the studies of Heinz et al, and 2 to 27 years in the study of Szabo et al). However, it should be noted that the two negative studies had the same duration of abstinence, whereas there was more variability in the studies showing decreased SERT binding. Thus, for the time of abstinence to explain this discrepancy, it would be necessary to hypothesize that the SERT is normalized early in abstinence, then decreases at 3 weeks of abstinence and remains decreased for years.
Due to a lack of clear borders for defining the raphe nuclei, it is possible that differences in methods of analysis of the midbrain region may explain the different findings. However, this study examined two methods of defining the raphe, and neither resulted in a difference between the two groups. Heterogeneity of the disease may play a role. Heinz et al showed an effect of genotype and depressive symptomatology may be an important factor (9
). However, it should be noted that the study of Szabo et al did not include depressed alcohol dependent subjects (12
). In addition, Brown et al. investigated the correlation between alcoholism, aggression, and SERT binding and found no effect. Gender is not likely to explain this discrepancy. Heinz et al showed an effect in males only, and a re-analysis of this data without the 2 females did not change our outcome. A limitation of this study is that genotyping was not performed. A recent PET study reported that [11
C]DASB BP in the midbrain was significantly increased in the midbrain of subjects homozygous for the long allele of the serotonin transporter (34
), although another study did not see a difference in the midbrain (35
). The study above of Heinz et al reported that SERT binding was reduced only in alcohol dependent subjects who were carriers of the long allele (32
), so that this factor could have affected our results. Finally, differences between tracers resulting from differences in the levels of endogenous transmitter between groups are possible, since both negative studies used the same radiotracer. Studies in the same cohorts with both tracers can inform us whether the discrepancies are related to illness heterogeneity or tracer’s properties.
We observed a correlation between indices of severity of disease and levels of binding of the SERT in some brain regions that were a priori hypothesized to show alterations of radiotracer binding. These correlations were of small magnitude in general but reached statistical significance on occasion. The meaning of these correlations, in the absence of overall alterations of receptors, is unclear and they should be taken with caution.
Lastly, an important point is that this study used an indirect estimate of intrasynaptic serotonin, by measuring SERT and the 5-HT1A receptor binding. In theory, low intrasynaptic serotonin should result in upregulation of the 5-HT1A receptor, and low SERT binding should reflect a decrease in serotonergic fibers, as has been shown in animal studies (1
). Ideally, one would measure intrasynaptic serotonin using PET imaging in conjunction with a pharmacologic probe that alters serotonin transmission. However, to date it has not been feasible to measure intrasynaptic serotonin directly using PET, although attempts to do this have been made (36
). Thus, the discrepancy in the studies reported above may simply result from the limitations associated with such indirect measures of serotonin transmission.