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

Abstract

Background Modulation of nicotinic acetylcholine receptors (nAChRs), specifically α4β2 subunit containing nAChRs, may be effective in the treatment of patients with major depressive disorder (MDD). Using [123I] 5-I-A-85380 single photon emission computed tomography (SPECT), we studied β2 subunit containing nAChR (β2*-nAChR) availability in patients with MDD. In order to understand the molecular basis of the change in receptor availability, we also studied β2*-nAChR binding in postmortem samples of human brains of MDD subjects. Methods 23 medication-free, early-onset, non-smoking subjects with familial MDD (8 acutely depressed (aMDD), 15 euthymic, recovered MDD subjects (rMDD)), and 23 age- and gender-matched, non-smoking controls had one [123I] 5-I-A-85380 SPECT scan and a magnetic resonance imaging (MRI) scan. β2*-nAChR availability was quantified as VT/fP. β2*-nAChR binding was analyzed in postmortem samples of the prefrontal cortex in 14 subjects with MDD and age-matched controls with [125I] 5-I-A-85380. Results β2*-nAChR availability in aMDD and rMDD subjects was significantly lower across all brain regions than in respective controls and lower in aMDD subjects than in rMDD subjects. MDD patients showed significant correlations between β2*-nAChR availability and lifetime number of depressive episodes, trauma and anxiety scores. There were no differences in β2*-nAChR number between groups in the human postmortem study. Conclusion β2*-nAChR availability is decreased in patients with MDD. The difference between β2*-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 increased endogenous acetylcholine.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

“…This result illustrates an enhanced cholinergic tone in the VTA after SD, as suggested in human depressed subjects. 20 Hence, SD alters the spontaneous activity of DA neurons, their sensitivity to nicotine and increases the cholinergic tone in the VTA. If SD and nicotine 29 induce similar alterations within the DA system, then nAChRs may be important mediators of these enduring changes and a promising therapeutic target.…”

“…For example, changes in nAChRs availability have been observed in patients suffering from post-traumatic stress disorders or depression. [19][20][21] Chronic social defeat stress (SD) parses the enduring behavioral abnormalities induced by stress and is believed to capture features of depressive-like states. 22 SD triggers an increase in DA VTA neuronal activity 23 that drives social avoidance.…”

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

“…Many etiological factors could underlie depressive disorders, including alterations in monoaminergic function, but several studies have implicated dysregulation of the cholinergic system in depression in human subjects (Janowsky et al, 1972;Risch et al, 1981). Recent human SPECT imaging studies show that depressed unipolar and bipolar subjects have increased levels of ACh throughout the brain (Saricicek et al, 2012;Hannestad et al, 2013). In humans, blocking the degradation of ACh can induce depressive symptoms even in individuals with no history of illness (Janowsky et al, 1972;Risch et al, 1981), whereas in mice, blocking ACh breakdown in the hippocampus alone is sufficient to induce depression-and anxiety-like behaviors (Mineur et al, 2013).…”

“…The cholinergic system has been a recent focus for development of novel antidepressant medications (Drevets et al, 2013;Mineur and Picciotto, 2010;Picciotto et al, 2012;Saricicek et al, 2012). Acetylcholine signals through muscarinic and nicotinic acetylcholine receptors (mAChRs and nAChRs, respectively) and many studies of depression have focused on mAChR signaling (Cannon et al, 2011;Riemann et al, 1994); however, blockade of either mAChRs or nAChRs can reverse the depression-like effects of increased cholinergic signaling in mice (Mineur et al, 2013) and it is likely that multiple receptors can mediate the effects of cholinergic signaling on depression (Drevets et al, 2013).…”

Measuring α4β2∗Nicotinic Acetylcholine Receptor Densityin Vivowith [18F]nifene PET in the Nonhuman Primate

“…5 Similar experiments could also improve understanding and treatment of depressive disorder. 4 Future toxicological and pharmacological measurements of nifene are needed to determine if nifene doses inducing significant receptor occupancies would be ethical in humans. The 0.6 nmol/kg dose used for the present experiments resulted in a4b2* nAChR occupancies of roughly 70%; however, saturation of these receptors has been reported with no adverse side effects in 2-[ 18 F]FA smoking studies.…”