Novel approaches towards pharmacological enhancement of motivation
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Abstract
This work explores novel approaches towards pharmacological enhancement of motivatedbehaviour. A loss of motivation remains a severe unmet clinical need in a number ofneuropsychiatric and neurodegenerative disorders.The work described in this thesis, can be divided into two sections. Initially, a series ofexperiments were conducted that aimed to increase the likelihood of cross-species translationof motivation research. This was achieved by firstly optimising and validating a battery of tasksto assess effort-related behaviour, a preclinical measure of motivation, in rats for use within anoperant touchscreen platform. This will allow tasks to be performed with high face validity,across species. Secondly, we applied a highly translatable functional imaging measure, in vivooxygen amperometry, to explore whether a neural correlate of motivated behaviour could bedetected in rats.The second section describes the identification and exploration of a novel pharmacologicaltarget for treating apathy. By using a progressive ratio (PR) schedule of reinforcement,muscarinic acetylcholine receptor antagonists were found to facilitate motivated behaviour inintact mice. Furthermore, through the application of several compounds, these actions appearedto be driven by the M1 receptor subtype. Subsequently, nonpathological aging was examinedas a potential model of impaired motivation, based upon previous reports. However, the deficitwas found not to be reliable. Therefore, the effects of the muscarinic acetylcholine receptorantagonist biperiden was tested following administration of the dopamine receptor antagonisthaloperidol, a well-validated model of impaired motivation. Biperiden was able to successfully,reverse the effects of haloperidol on effort-based behaviour. This suggests that the drugbiperiden may be a therapeutic option in the treatment of apathy.
