Exploring the Role of 5-HT in Amphetamine-Induced Depression of Visual Responses in the Superior Colliculus

The research presented in the current thesis had two principal motivators. First, to elucidate the mechanism by which D-amphetamine depresses visual responses in the superficial layers of the superior colliculus (SC). Then, to identify a candidate substance that has a similar mechanism of action at the level of the superficial SC to D-amphetamine, but with a safer profile in terms of side effects and abuse potential. D-amphetamine is a current frontline pharmaceutical used in the treatment of ADHD, and when tolerated well, is highly efficacious in improving sustained attention and alleviating the symptoms of ADHD. Despite this efficacy, the use of D-amphetamine in the treatment of ADHD has been criticised due to its abuse potential and aversive side-effects. Thus, there is a need to identify new efficacious interventions for ADHD that lack the abuse potential of psychostimulants. A fruitful strategy when taking this approach is to identify substances that have a common mechanisms of action to psychostimulants in terms of the systems they interact with Data presented in the current thesis show that D-amphetamine induces a depression of the superficial SC response to visual stimuli in vivo, which can be reversed by antagonising 5-HT. The SSRI fluoxetine was identified as a candidate drug with potential to depress SC visual responses with a similar profile to D-amphetamine. It was shown that when administered in the presence of a substance that antagonises autoregulator processes at the level of the dorsal raphe nucleus, fluoxetine depresses aspects of the SC response to visual stimuli in a manner that is comparable to the effects of D-amphetamine. Given the novelty of these results in light of mixed evidence of the efficacy of treating ADHD with SSRIs, it is proposed that the viability of targeting 5-HT transmission in the pharmacotherapy of ADHD should be re-examined.