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

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Abstract

Rationale

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.

Objectives

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.

Results

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, 0.3 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, 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.

Conclusions

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.

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Acknowledgments

We thank Dr. Arthur Simen (Takeda, Cambridge, MA) for numerous discussions of this project and Dr. Cindy Lustig (University of Michigan) for comments on a draft of the paper. AKC is now at PsychoGenics (NJ). A preprint of this manuscript was posted at https://www.biorxiv.org/content/10.1101/606343v1.

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Authors and Affiliations

  1. Department of Psychology, University of Michigan, 530 Church Street, Ann Arbor, MI, 48103, USA

    Aaron Kucinski, Kyra B. Phillips, Ajeesh Koshy Cherian & Martin Sarter

  2. Department of Psychology, University of Michigan, 530 Church Street, Ann Arbor, MI, 48109, USA

    Martin Sarter

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  1. Aaron Kucinski
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Contributions

AK and AKC conducted the experiments. AK and KBP analyzed the data and conducted the histological analyses. MS designed the experiment. AK, KBP, and MS wrote the paper.

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Correspondence to Martin Sarter.

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The research described in this manuscript was supported by a grant from Takeda Pharmaceutical Company Ltd. Dr. Sarter received compensation as a consultant for Takeda.

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Kucinski, A., Phillips, K.B., Koshy Cherian, A. et al. Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071. Psychopharmacology 237, 137–153 (2020). https://doi.org/10.1007/s00213-019-05354-5

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