Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder

Abstract

Background: Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of β2-subunit-containing nAChRs (β2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied β2*-nAChR binding in postmortem brain samples from depressed subjects.

Method: The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one [123I]5-I-A-85380 SPECT scan and an MRI scan. The availability of β2*-nAChRs was quantified as VT/fP. Postmortem analysis of β2*-nAChR binding was conducted with [123I]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects.

Results: The β2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, β2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in β2*-nAChR number between groups in the postmortem study.

Conclusions: Depressed patients have lower β2*-nAChR availability than do healthy subjects. The difference between β2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.

Figure 1

Comparison of β₂*-nAChR availability throughout the brain in acutely depressed (n=8) and recovered depressed patients (n=15) and respective control subjects (n=8 and n=15 respectively). (Main effect of group: F _3,42=8.7, p= 0.0001; Group*region interaction: F_30,420=0.00005). For acute MDD (N=8) and respective controls (N=8) main effect of group F_1,14=15.8, p=0.0014; group*region interaction: F_10,140=2.52, p=0.008. For recovered MDD (N=15) and respective controls (N=15) main effect of group F_{1, 28}=7.9, p=.009 and group*region interaction F_{10, 280}, p=.03. For acute MDD and recovered MDD main effect of group F_1,21=10.0, p=.005, group*region interaction F_10,210=1.34, p=0.21.