Changes in the Cholinergic System between Bipolar Depression and Euthymia as Measured with [123I]5IA Single Photon Emission Computed Tomography

Abstract

Background The cholinergic system is substantially altered in individuals with major depression and is partially restored when depression remits. We quantified the availability of β2-subunit-containing nicotinic acetylcholine receptors (β2*-nAChR) in subjects with bipolar disorder. Methods Twenty-five subjects with bipolar disorder (15 depressed, 10 euthymic) and 25 sex- and age-matched control subjects had a [123I]5IA-85380 single photon emission computed tomography scan to quantify β2*-nAChR VT/fP (total volume of distribution, corrected for individual differences in metabolism and protein binding of the radiotracer). Average VT/fP was compared between groups and correlated with clinical characteristics. Postmortem analysis of β2*-nAChRs was conducted using equilibrium binding with [125I]5IA in subjects with bipolar disorder and matched control subjects. Results We showed significantly lower β2*-nAChR availability (20%–38%) in subjects with bipolar depression compared with euthymic and control subjects across all brain regions assessed (frontal, parietal, temporal, and anterior cingulate cortex, hippocampus, amygdala, thalamus, striatum). The postmortem binding study in which endogenous acetylcholine was washed out did not show a statistically significant difference in β2*-nAChR number in temporal cortex of the bipolar depressed and control groups (15% difference; p = .2). Conclusions We show that the alteration in the cholinergic system observed during a depressive episode appears to resolve during euthymia. We suggest that lower VT/fP observed in vivo may be due to a combination of higher endogenous acetylcholine levels during depression, which could compete with radiotracer binding to the receptor in vivo, and lower receptor number in bipolar depression. Identification of differences in cholinergic signaling in subjects with bipolar depression may improve our understanding of its etiology and reveal new treatment targets.

Expression of the 5-HT1A Serotonin Receptor in the Hippocampus Is Required for Social Stress Resilience and the Antidepressant-Like Effects Induced by the Nicotinic Partial Agonist Cytisine

“…Accumulating evidence also suggests that alteration of the cholinergic system may contribute to depression and be a target for antidepressant therapies. For example, human imaging studies of individuals with MDD or bipolar disorder show that ACh levels are high when individuals are actively depressed (Hannestad et al, 2013;Saricicek et al, 2012). These recent imaging studies are consistent with experiments showing that increasing ACh levels in human subjects by challenging with physostigmine, a drug that prevents breakdown of ACh, results in symptoms of anxiety and depression (Risch et al, 1981).…”

“…The idea that limiting cholinergic signaling could be antidepressant is in line with human studies indicating that blocking the breakdown of acetylcholine (ACh), thereby increasing ACh levels, can induce symptoms of depression. More recently, human imaging studies have suggested that ACh levels are high throughout the brain in patients who are actively depressed (Saricicek et al, 2012;Hannestad et al, 2013). Thus, although targeting the monoamine system is effective for treating depression in a significant subset of patients, emerging data suggest that abnormalities in the cholinergic system could be one of the etiological factors underlying the development of depression.…”

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

“…An increase in cholinergic tone can be observed in depressed patients (Hannestad et al, 2013;Saricicek et al, 2012). In contrast, treatment with the non-competitive non-selective antagonist mecamylamine can have an antidepressant-like effect in mice, which is correlated with a decrease in amygdala activity (Mineur et al, 2007).…”

“…Thus, it remains critical to identify the mechanisms underlying the development of mood disorders. Recent studies have suggested that individuals with uni-or bipolar illness have increased ACh levels throughout the brain when they are acutely depressed (Saricicek et al, 2012;Hannestad et al, 2013). A number of studies have also addressed the possibility that nAChRs could be involved in depression, because depressed individuals are twice as likely to smoke, have a harder time quitting, and can develop symptoms of depression during withdrawal (for reviews, see Moylan et al, 2012;Picciotto et al, 2012).…”

“…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).…”