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 [(123)I]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 [(125)I]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.

Keywords: Acetylcholine; SPECT; bipolar disorder; depression; tobacco smoking; β(2)*-nAChR.

Figure 1

Bars illustrating in vivo V_T/f_P in bipolar depressed (n = 15), bipolar euthymic (n = 10), and control (n = 25) subjects. Lower V_T/f_P was observed across all brain regions in bipolar depressed compared with bipolar euthymic and control subjects (Hotelling’s trace F = 2.5, p = .004). V_T/f_P, receptor availability.

Figure 2

(A) Illustration of in vivo V_T/f_P in euthymic smokers with (n = 5) and without (n = 5) bipolar disorder and nonsmokers with (n = 5) and without (n = 5) bipolar disorder. No significant upregulation was observed in V_T/f_P in bipolar euthymic sample (Hotelling’s trace F = 5.6, p = .16). As we have shown previously, there was higher V_T/f_P in control smokers compared to nonsmokers (Hotelling’s trace F = 10.0, p = .04), and this was significant in the anterior cingulate, frontal, and parietal cortices (F_5,5 = 6.0,p = .04; F_5,5 = 10.7,p = .01; and F_5,5 = 8.8, p = .02, respectively, with a trend in the temporal cortex F₅₅ = 4.0, p = .08). (B) Calculated B_max (fmoles/mg protein) for [¹²⁵I]5IA binding in homogenates of temporal cortex samples in control nonsmokers (n = 3), control smokers (n = 5), nonsmokers with bipolar disorder (n = 3) and smokers with bipolar disorder (n = 5). No significant differences were detected as an effect of diagnosis (F_1,14 = 2.13, p = .17), but nicotinic acetylcholine receptors upregulation was greater in control smokers than in smokers with bipolar disorder (F_1,14 = 104.4, p < .0009). V_T/f_P, receptor availability.