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Novel approaches towards pharmacological enhancement of motivation



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Hailwood, Jonathan Michael 


This work explores novel approaches towards pharmacological enhancement of motivated behaviour. A loss of motivation remains a severe unmet clinical need in a number of neuropsychiatric and neurodegenerative disorders. The work described in this thesis, can be divided into two sections. Initially, a series of experiments were conducted that aimed to increase the likelihood of cross-species translation of motivation research. This was achieved by firstly optimising and validating a battery of tasks to assess effort-related behaviour, a preclinical measure of motivation, in rats for use within an operant 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 vivo oxygen amperometry, to explore whether a neural correlate of motivated behaviour could be detected in rats. The second section describes the identification and exploration of a novel pharmacological target for treating apathy. By using a progressive ratio (PR) schedule of reinforcement, muscarinic acetylcholine receptor antagonists were found to facilitate motivated behaviour in intact mice. Furthermore, through the application of several compounds, these actions appeared to be driven by the M1 receptor subtype. Subsequently, nonpathological aging was examined as a potential model of impaired motivation, based upon previous reports. However, the deficit was found not to be reliable. Therefore, the effects of the muscarinic acetylcholine receptor antagonist biperiden was tested following administration of the dopamine receptor antagonist haloperidol, 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 drug biperiden may be a therapeutic option in the treatment of apathy.





Bussey, Timothy John


Muscarinic, Motivation, Translational, Touch Screen, Apathy


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Medical Research Council funded CASE studentship