Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation.
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Authors
Heath, Christopher J
Phillips, Benjamin U
Saksida, Lisa
Bussey, Timothy
Publication Date
2019-05Journal Title
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN
0893-133X
Publisher
Springer Nature
Volume
44
Issue
6
Pages
1068-1075
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Hailwood, J., Heath, C. J., Phillips, B. U., Robbins, T., Saksida, L., & Bussey, T. (2019). Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44 (6), 1068-1075. https://doi.org/10.1038/s41386-018-0281-8
Abstract
Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4). However, scopolamine and tropicamide also produced increases in non-specific activity levels, whereas biperiden did not. A series of control tests suggests the effects of the mAChR antagonists were sensitive to changes in reward value and not driven by changes in satiety, motor fatigue, appetite or perseveration. Subsequently, a sub-effective dose of biperiden was able to facilitate the effects of amphetamine upon PR performance, suggesting an ability to enhance dopaminergic function. Both biperiden and scopolamine were also able to reverse a haloperidol-induced deficit in PR performance, however only biperiden was able to rescue the deficit in effort related choice (ERC) performance. Taken together, these data suggest that the M1 mAChR may be a novel target for the pharmacological enhancement of effort exertion and consequent rescue of motivational impairments. Conversely, M4 receptors may inadvertently modulate effort exertion through regulation of general locomotor activity levels.
Keywords
Animals, Mice, Inbred C57BL, Mice, Disease Models, Animal, Biperiden, Haloperidol, Scopolamine, Tropicamide, Receptor, Muscarinic M1, Receptor, Muscarinic M4, Muscarinic Antagonists, Antipsychotic Agents, Behavior, Animal, Motivation, Psychomotor Performance, Apathy, Cognitive Dysfunction
Sponsorship
MRC (1505392)
Identifiers
External DOI: https://doi.org/10.1038/s41386-018-0281-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286996
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