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.

Background: Important tools in the study of prefrontal cortical -dependent executive functions are cross-species behavioural tasks with translational validity. A widely used test of executive function and attention in humans is the continuous performance task. Optimal performance in variations of this task is associated with activity along the medial wall of the prefrontal cortex, including the anterior cingulate cortex, for its essential components such as response control, target detection and processing of false alarm errors. Methods: We assess the validity of a recently developed rodent touchscreen continuous performance task that is analogous to typical human continuous performance task procedures. Here, we evaluate the performance of mice with quinolinic acid -induced lesions centred on the anterior cingulate cortex in the rodent touchscreen continuous performance task following a range of task parameter manipulations designed to challenge attention and impulse control. Results: Lesioned mice showed a disinhibited response profile expressed as a decreased response criterion and increased false alarm rates. Anterior cingulate cortex lesions also resulted in a milder increase in inter-trial interval responses and hit rate. Lesions did not affect discriminative sensitivity d′. The disinhibited behaviour of anterior cingulate cortex -lesioned animals was stable and not affected by the manipulation of variable task parameter manipulations designed to increase task difficulty. The results are in general agreement with human studies implicating the anterior cingulate cortex in the processing of inappropriate responses. Conclusion: We conclude that the rodent touchscreen continuous performance task may be useful for studying prefrontal cortex function in mice and has the capability of providing meaningful links between animal and human cognitive tasks.

RationaleAcross species, effort-related motivation can be assessed by testing behaviour under a progressive ratio (PR) schedule of reinforcement. However, to date, PR tasks for rodents have been available using traditional operant response systems only.ObjectivesTouchscreen operant response systems allow the assessment of behaviour in laboratory rodents, using tasks that share high face validity with the computerised assessments used in humans. Here, we sought to optimise a rat touchscreen variant of PR and validate it by assessing the effects of a number of manipulations known to affect PR performance in non-touchscreen paradigms.MethodsSeparate groups of male Sprague-Dawley rats were trained on PR schedules with either linear (PR4) or exponential (PREXP) schedules of reinforcement. PR performance was assessed in response to manipulations in reward outcome. Animals were tested under conditions of increased reward magnitude and following reward devaluation through a prefeeding procedure. Subsequently, the effects of systemic administration of the dopamine D2/D3 receptor antagonist raclopride and the psychostimulant d-amphetamine were examined as traditional pharmacological methods for manipulating motivation.ResultsRats reinforced under PR4 and PREXP schedules consistently showed differential patterns of response rates within sessions. Furthermore, both PR4 and PREXP schedules were sensitive to suppression by prefeeding or raclopride administration. Performance under both schedules was facilitated by increasing reward magnitude or d-amphetamine administration.ConclusionsTaken together, these findings mirror those observed in lever-based PR paradigms in rats. This study therefore demonstrates the successful validation of the rat touchscreen PR task. This will allow for the assessment of motivation in rats, within the same touchscreen apparatus used for the assessment of complex cognitive processes in this species.

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