Theme: Mechanisms

Project Description

Attention-deficit/hyperactivity disorder (ADHD) is associated with diverse cognitive difficulties, including differences in attention, executive function, memory and reward processing. While the role of dopaminergic and noradrenergic neurotransmission in ADHD is well established, increasing evidence also implicates serotonergic mechanisms, although their contribution to cognitive dysfunction remains poorly understood

This DPhil project will investigate whether signalling through the serotonin 4 (5-HT4) receptor influences cognition and its underlying neural circuitry in adults with ADHD. The 5-HT4 receptor is an exciting and relatively understudied target. It is expressed in brain regions central to cognition, including hippocampal, striatal and cortical circuits, and can modulate dopamine and acetylcholine signalling. Studies in humans using prucalopride, a selective 5-HT4 receptor agonist, have demonstrated effects on learning, memory and hippocampal function, and preclinical research suggests that 5-HT4 stimulation can also improve attentional performance. Despite these promising findings, selective 5-HT4 receptor stimulation has not yet been directly investigated in people with ADHD.

The core of the project will be a randomised, double-blind, placebo-controlled experimental medicine study in unmedicated adults with ADHD, using prucalopride as a pharmacological probe of the 5-HT4 receptor. Participants will complete detailed neurocognitive assessments examining sustained attention, response inhibition, working and episodic memory, processing speed, reward learning and decision-making. 

This project offers the opportunity to address fundamental and clinically relevant questions about the neurobiology of ADHD while gaining interdisciplinary expertise in psychopharmacology, cognitive neuroscience and neuroimaging. The precise DPhil programme will be developed with the successful student according to their interests, with opportunities for additional experimental, computational or pharmacoepidemiological studies.