Rate Dependent Effects of Pharmacological Manipulation of Dopaminergic System on 5CCPT Performance Measures

Abstract

Rationale Clinical studies suggest that an individual’s response to drug administration depend on his or her baseline rates of behaviour (rate dependence). However, factors such as regression to the mean and mathematical coupling can contribute to rate dependence and these are often unrecognised in drug studies. Oldham’s method (1962) controls for the influence of these factors on rate dependence. Here, we compared the traditional analytical method of handling data as one group with correlational analyses (including Oldham’s method) to determine whether changes in performance following drug administration depend on baseline rate of behaviour. Methods Lister-Hooded female rats (240±10g at the start of training) were trained to target (>70% accuracy, < 30% omission and < 40% false alarms) in a standard 5C-CPT task. 5C-CPT performance was then tested under direct or indirect dopaminergic receptor agonists using a Latin-square within-subjects design. One method was used to assess baseline dependence: Oldham’s method, which correlates between the average of pre- and post-treatment and the parameter change. Results Low doses of the dopaminergic reuptake inhibitor, GBR12909, improved selective attention (accuracy) while higher doses promoted waiting impulsivity in a baseline-dependent manner. The selective D1 receptor agonist SKF38393 and the indirect dopaminergic and noradrenergic agonist amphetamine improved waiting impulsivity in a baseline-dependent manner, whereas the selective D3 receptor agonist PD 128907 had no effect on this measure. PD 128907 did, however, increase compulsive behaviour and reduce accuracy in a rate dependent manner. Amphetamine altered attentional measures in a rate-dependent manner. As expected, low doses of amphetamine produced a tendency toward improving attentional performance in a baseline-dependent manner, while higher doses impaired attentional processes. Conclusions These findings indicate that activation of D1 receptors improves waiting impulsivity while activation of D3 receptors impairs compulsive behaviour. This thesis highlights rate-dependent effects of pharmacological manipulations of the dopaminergic system on 5C-CPT performance measures. This is the first study to take advantage of the variation in individual baseline performance to demonstrate the presence of a rate-dependent relationship between baseline performance and the magnitude of change following direct or indirect activation of dopaminergic system. Adopting a correlative analysis (e.g., Oldham’s method) may be particularly effective in revealing drug effects on behaviour and improve our understanding of the neurochemical basis of sustained attention and inhibitory response control as measured by 5C-CPT.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gigg (Supervisor) & Joanna Neill (Supervisor)