Chemical Modulation of Fronto-Executive Mechanisms: Neuropsychiatric Implications

Abstract

Event Abstract Back to Event Chemical Modulation of Fronto-Executive Mechanisms: Neuropsychiatric Implications Trevor W. Robbins1* 1 University of Cambridge, Behavioural and Clinical Neuroscience Institute, United Kingdom I will review evidence from studies of experimental animals and humans that the monoaminergic neurotransmitters dopamine, noradrenaline and serotonin (5-HT) exert differential control over executive mechanisms of the prefrontal cortex. Reversal learning is well-known to have an orbitofrontal substrate from based on effects of lesions in humans, monkeys and rodents, and from functional neuroimaging data in human volunteers. In previous studies we have reported modulation of reversal learning performance in humans by tryptophan depletion in human volunteers. These findings are relevant to neuropsychiatric syndromes such as obsessive-compulsive disorder, as functional imaging of such patients and their first-degree relatives shows a reduced BOLD response within the orbitofrontal cortex during reversal learning. Profound serotonin depletion in the orbitofrontal cortex produced by intra-cerebral 5,7 dihydroxytryptamine in the marmoset produces impaired reversal and serial reversal learning performance that has a perseverative quality. By contrast orbitofrontal dopamine depletion has no effect on reversal or serial reversal learning. However, if visual discrimination performance is extinguished it does not enhance resistance to extinction, although serotonin depletion enhances the proportion of responses to the formerly reinforced stimulus. By contrast, whilst orbitofrontal dopamine loss has no effect on stimulus preference or perseveration in responding to a particular discriminative stimulus it has a profound effect greatly to retard extinction performance. These data thus reflect a double dissociation of chemical neuromodulatory influences within the orbitofrontal cortex and suggest that different forms of compulsive behavior can follow its dysmodulation. By contrast, noradrenergic manipulations affect performance on the extra-dimensional shift paradigm and stop-signal performance that depends on PFC networks including the right ventrolateral cortex in humans. Finally, we speculate that neuromodulatory interventions at the level of the striatum may also affect lateral PFC processing through striato-thalamic-cortical ‘loops’ and this is illustrated from the effects of a D2 receptor agonist in stimulant abusers in a functional MRI paradigm.