Anti‐Muscarinic Drug Effects on Murine Cognition: A Pilot Study

Abstract

The importance of cholinergic activity in proper memory function has been well documented with reported memory improvement in mice associated with increased hippocampal cholinergic activity and neurogenesis (Dobryakova, et al, 2014; Jeong, et al, 2014). In the TgCRND8 mouse Alzheimer's Disease (AD) model, Proulx, et al, (2015) demonstrated a disruption in corticothalamic pathways of the prefrontal cortex, suggesting that AD was associated with a loss of intact cholinergic function. Many drugs used as mild sedatives, such as diphenhydramine (DPH), possess significant anti‐muscarinic action, an action that can produce cognitive impairment in mice (Budzynska, et al, 2015). This study tested memory changes by use of a Barnes Maze (BM), a nonstress measure of the ability of mice to remember the location of an escape box. Naïve mice were divided into 5 cohorts (C) and trained using the BM. They received either no drug (Control, C‐1), or oral administration of GDW (Sham, C‐2), atropine (ATR, 0.5 mg/kg, C‐3), DPH, (0.5 mg/kg, C‐4) or DAU 5884 (DAU, 0.25 mg/kg, C‐5). After 3 months treatment was stopped in 50% of mice in each cohort, but testing continued.Results demonstrated a decrease in the ability of mice treated with ATR and DPH to find the escape box measured by increased time and/or distance travelled to escape. Only the ATR treated mice travelled a greater distance to the escape compartment, but both the ATR and the DPH treated mice took more time to find the escape compartment. There was a suggested recovery of memory when treatment was stopped, as seen in time and distance returning towards control. Results are compatible with previous studies with suggested clinical relevance to the choice of sedative agents with anti‐muscarinic effects likely to cause cognitive function decline, especially in the elderly. Additionally, the data supports previous studies indicating that use of M3 selective anti‐muscarinic agents for treatment in patients with overactive bladder to improve quality of life create minimal risk of cognitive decline.