Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder

Background: Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the beta(2) subunit, may be effective in treating patients with major depressive disorder. Using [I-123]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of beta(2)-subunit-containing nAChRs (beta(2)*-nAChRs) in depressed patients. To understand its molecular basis, the authors also Studied beta(2)*-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 [I-123]5-I-A-85380 SPECT scan and an MRI scan. The availability of beta(2)*-nAChRs was quantified as V-T/f(P), Postmortem analysis of beta(2)*-nAChR binding was conducted with [I-123]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects. Results: The beta(2)*-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, beta(2)*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in beta(2)*-nAChR number between groups in the postmortem study. Conclusions: Depressed patients have lower beta(2)*-nAChR availability than do healthy subjects. The difference between beta(2)*-nAChR availability in vivo and in postmortem 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.