Higher Serotonin 1A Binding in a Second Major Depression Cohort: Modeling and Reference Region Considerations

Abstract

Background Serotonin 1A receptors (5-HT1A) are implicated in major depressive disorder (MDD). We previously reported higher 5-HT1A binding potential (BPF=Bavail/KD) in antidepressant naïve MDD subjects compared to controls while other studies report lower BPND(BPND=fNDBavail/KD). Discrepancies can be related to differences in study population or methodology. We sought to replicate our findings in a novel cohort and determine whether choice of reference region and outcome measure could explain discrepancies. Methods Nine new controls and 22 new not recently medicated (4 years, NRM) MDD subjects underwent positron emission tomography with [11C]WAY100635. BPF and BPND were determined using a metabolite and free fraction corrected arterial input function. BPND was also determined using cerebellar gray matter (CGM) and cerebellar white matter (CWM) reference regions as input functions. Results BPF is higher in the new NRM cohort (p=0.037) compared to new controls, which is comparable to the effect in the previous cohort (p=0.04). We combined the cohorts to examine the effects of the reference region and outcome measure. In the combined cohort, BPF is higher in the NRM compared to controls (p=0.0001). Neither BPND using CWM (p=0.86) nor VT (p=0.374) differs between groups. When CGM is used, the NRM group has lower 5HT1A BPND compared with controls (p=0.03). CGM VT is higher in NRM compared to controls (p=0.007). Conclusions Choice of reference region and outcome measure can produce different 5-HT1A findings in MDD. Higher 5-HT1A BPF in MDD was found with the method with fewest assumptions about nonspecific binding and a reference region without receptors.

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

“…The G-allele of this SNP impairs the binding of the repressor, Nuclear Deaf-1 Related factor (NUDR), in a raphe cell line. Possibly as a result, G-allele carriers have higher levels of 5-HT1A autoreceptors, an increased risk for depression, and paradoxically, decreased amygdala reactivity (Albert and Lemonde, 2004;Fakra et al, 2009;Parsey et al, 2010). However, no study has assessed the brain region-specific impact of this polymorphism on 5-HT1A receptor expression during development.…”

Increased Serotonin-1A (5-HT1A) Autoreceptor Expression and Reduced Raphe Serotonin Levels in Deformed Epidermal Autoregulatory Factor-1 (Deaf-1) Gene Knock-out Mice

“…Based on our results, the human 5-HT1A G/G(Ϫ1019) genotype would be predicted to result in opposite changes in 5-HT1A receptor RNA and protein levels in pre-and postsynaptic brain regions. Recent studies support an up-regulation of 5-HT1A autoreceptors in antidepressant-free depressed patients with the G/G genotype (21,22,50), but not in healthy subjects (51). This suggests that compensatory mechanisms may be recruited in healthy subjects to normalize 5-HT1A autoreceptor expression whereas they are incompletely effective in depressed subjects.…”

“…However, the effect of the G/G genotype on postsynaptic 5-HT1A receptors is less clear. The G/G genotype in depressed subjects was associated with no change or increased 5-HT1A receptors in some regions such as the hippocampus (21,22,50), which could reflect a compensatory up-regulation due to lower serotonergic neurotransmission in these subjects (52) or a decrease in forebrain Deaf-1 levels, leading to reduced transcription of the 5-HT1A heteroreceptors (53). Several studies report reduced 5-HT1A RNA or binding in the prefrontal cortex of subjects with major depression (24,(53)(54)(55)(56), consistent with reduced transcription of the 5-HT1A receptor.…”

Transcriptional regulation of the 5-HT1Areceptor: implications for mental illness

“…An increase in 5-HT 1A autoreceptor expression has been reported in the rostral raphe region of post-mortem tissue from a depressed suicide victim compared with control subjects, but with reduced 5-HT 1A autoreceptor levels in caudal raphe regions [99,100]. Positron emission tomography (PET) imaging studies in living depression patients using the 5-HT 1A antagonist [ 11 C]WAY100635 also show a prominent 50 per cent increase in 5-HT 1A autoreceptors in antidepressant-free or naive depressed subjects [101][102][103], as well as a twofold increase in male bipolar depression patients [104]. An upregulation of 5-HT 1A autoreceptors is likely to reduce serotonergic neurotransmission, as associated with human depression and suicide ( figure 1).…”

“…Discrepancies in PET imaging results from different groups may be accounted for by methodological differences in reference tissue [101,119], or by confounds such as limited resolution (e.g. for raphe sub-regions), medication status or ligand competition with receptorbound 5-HT in vivo.…”