Dopaminergic modulation of cognition in ADHD
Dopaminergic modulation of cognition in adults with Attention-Deficit Hyperactivity Disorder (ADHD)
Cambridge and Peterborough NHS Foundation Trust (CPFT) and University of Cambridge - Joint Sponsorsh
Dopamine is a key neurotransmitter and regulates cognitive functions dependent on fronto-striatal circuitry. Dopamine dysregulation is central to the pathophysiology of Attention-Deficit Hyperactivity Disorder (ADHD), a prevalent and debilitating condition of childhood onset, which persists into adulthood in 40-60% of cases. ADHD is associated with cognitive deficits, readily observable using objective translational tests.
In the frontal lobes, Catechol-O-methyltransferase (COMT) is the enzyme largely responsible for the inactivation of synaptic dopamine. A common functional polymorphism in the COMT gene (Val substitution at codon 158) results in a ~40% increase in enzymatic activity and thereby reduced cortical dopamine levels. Val carriers exhibit less efficient prefrontal neural signalling and/or relative deficits in executive cognitive functioning.
Tolcapone is a COMT inhibitor that has been found to modulate cognition in healthy volunteers (Apud et al., 2007), especially in individuals with the Val allele of COMT. Unlike stimulant medications, translational research indicates that tolcapone exerts little or no effects on cortical noradrenaline function. The cognitive effects of tolcapone in ADHD have yet to be studied. Given that tolcapone represents a useful dopaminergic probe, and that ADHD is a prototypical disorder of dopaminergic dysregulation and cognitive impairment, this study will examine the effect of single doses of this medication on cognition in ADHD. Cognitive effects of tolcapone will be contrasted to those of single doses of caffeine, the latter being an active control condition associated with enhanced arousal and attentional processing and effects on striatal dopamine release.
East of England - Cambridge South Research Ethics Committee
Date of REC Opinion
1 Oct 2014
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