Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071

Abstract

Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and, in patients with Parkinson's disease (PD), to impairments in gait and balance and the resulting risks for falls. Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. Here, we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that a M1 PAM amplifies such transient signaling and thereby rescues attentional performance. Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period. The post-dSAT period served to assess the capacity for recovering performance following a disruptive event. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance. Administration of TAK-071 (0.1, 0.3mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose). Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, but also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d') in lesioned rats and facilitated the adoption of a more liberal response bias (B˝D) in all female rats. These findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.