The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [11C] Raclopride Binding in Tau Mouse Models of Alzheimer's Disease

Abstract

Psychosis that occurs over the course of Alzheimer's disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human-mutant-tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [¹¹C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment-on both tau and behavior-that may have relevance to AD and other tauopathies.

Keywords: Alzheimer’s disease; hopping; locomotion; psychosis; scopolamine; tau.

Figure 1

Percent changes in mean open field velocity (A,B) and hopping (C,D) (% change shown with 95% confidence interval) and differences in hopping frequency (C1,D1) (mean with 95% confidence interval shown) following 1 week of treatment with scopolamine (n = 15) or reboxetine (n = 15), in comparison with saline (n = 15), in P301L/COMTKO (A,C,C1) and htau (B,D,D1) mice. ANOVA followed by pairwise comparison * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns = non-significant.

Figure 2

Mean change in the amplitude (mV, 95% confidence interval shown) of acoustic startle response to a 120 dB stimulus following 1 week of treatment with scopolamine (n = 15) or reboxetine (n = 15), in comparison with saline (n = 15), in (A) P301L/COMTKP and (B) htau mice. ANOVA followed by pairwise comparison *** p < 0.001, ns = non-significant.

Figure 3

(A) Quantification of total soluble tau (DA31, μg/mg of protein) in the striatum of P301L/COMTKO mice treated for 1 week with scopolamine or saline determined via t-test, * p < 0.05 (B) Linear regression of distance traveled in the open field versus the total soluble tau in 30 mice (treated with either scopolamine or saline in behavioral experiments) with 95% CI shown, R² = 0.25, p < 0.01. Multiple linear regression of scopolamine treatment status (red = scopolamine, black = saline) with the distance traveled and tau revealed significant interaction between scopolamine treatment, tau concentration, and distanced traveled p = 0.002.

Figure 4

Differences in ¹¹C-raclopride binding in scopolamine-treated P301L/COMTKO mice relative to saline-treated P301L/COMTKO mice. (A) Using the SPM voxel-wise analysis, a significant decrease in ¹¹C-raclopride binding was detected in the scopolamine mice in the regions (yellow, t = 2.457 and p < 0.01) that overlapped with the caudate-putamen (red) and nucleus accumbens (black). Represented are two-dimensional displays of the decreased regions, caudate-putamen, and nucleus accumbens overlaid on a standard mouse MRI template (B). The ¹¹C-raclopride relative uptakes were reduced in the scopolamine-treated mice, compared to saline mice (p < 0.05; Student t test), in the caudate-putamen (left) and nucleus accumbens (right) Mean values of ¹¹C-raclopride PET in these regions were measured and normalized by the mean value of cerebellum in each image. Error bars represent standard deviations of the means; * p < 0.05.