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 to impairments in gait and balance, and the resulting risks for falls, in patients with Parkinson's disease (PD). 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 an M1 PAM amplifies such transient signaling, thereby enhancing and rescuing 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 assessing their capacity for recovering performance. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance recovery. Administration of TAK-071 (0.1, 0.3 mg/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, and 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. Collectively, 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.

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071

“…In addition to evidence suggesting relatively superior attentional control of complex movement in female rats, we also found that falls in male rats were associated with their relatively higher body weights (Kucinski et al 2019;Koshy Cherian et al 2019;Kucinski et al 2017;Kucinski et al 2018). Furthermore, we previously documented beneficial attentional effects of TAK-071 in male and female rats with basal forebrain cholinergic lesions, and also in female, but not male, control rats (Kucinski et al 2020). As the present experiments were designed to determine whether these effects generalize to complex movement control, as assessed specifically by traversal of the zigzag rod, only female rats were used to optimize the documentation of such effects.…”

“…Evidence describing the effects of semi-chronic administration of TAK-071 on plasma and brain concentrations appears unavailable. Finally, for the present experiment, the two doses were selected based on our prior study indicating efficacy of these doses, administered over 6 days, in rats with cholinergic lesions and performing a sustained attention task (Kucinski et al 2020).…”

“…As a result, such a treatment would be expected to benefit the ability of DL rats to more effectively employ task cues as well as utilize proprioceptive information to optimize dynamic surface traversal, and to respond to movement errors by rapidly adapting gait and balance to continue forward traversal. We tested this hypothesis using the M1 PAM TAK-071 because of this compound's relatively high selectivity for neuronal M1 receptors (Kurimoto et al 2019;Sako et al 2018) and based on our prior finding that this drug improves the attentional performance of rats with BF cholinergic lesions (Kucinski et al 2020). In addition to testing fall propensity in rats traversing the rotating rod of the MCMCT, we also assessed their ability to traverse a rotating zigzag rod which even more severely taxes the attentional control of balance and complex movements (Kucinski et al 2019;Kucinski et al 2018).…”

Make a Left Turn: Cortico‐Striatal Circuitry Mediating the Attentional Control of Complex Movements

“…As mentioned, we found that an M1 PAM improved the attentional performance of rats with partial losses of the cortical cholinergic input system. 55 More recently, we also observed that such a treatment benefits the complex movement control of DL rats (see earlier for a description of these rats as a model of the dual cortical cholinergic-striatal dopaminergic losses that characterize PD fallers). The M1 PAM was particularly effective in testing conditions that interfered with the execution of relatively rhythmic, stable walking patterns and thus required nearly continuous reprogramming of gait and balance.…”

Forebrain Cholinergic Signaling: Wired and Phasic, not Tonic, and Causing Behavior

“…The interpretation of evidence from behavioral, neurophysiological as well as human imaging studies on the role of cholinergic signaling will be more constrained and eventually heuristically more powerful by abandoning intuitive notions about "tonic" cholinergic control of brain states and focusing instead on the role of fast cholinergic signaling for precise computational processes. Moreover, the search for effective pro-cholinergic, pro-cognitive treatments may benefit significantly from moving away from drugs the effects of which conform with views about tonic cholinergic activity and function, such as AChEIs, to drugs that enhance and rescue transient cholinergic signaling or their post-synaptic processing (e.g., Howe et al, 2010;Moran et al, 2018;Uslaner et al, 2018;Kucinski et al, 2019).…”