Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour

Rationale: Altered serotonergic and dopaminergic function have been widely implicated in behavioural disorders associated with impulsivity and risk-ta king, However, little research has addressed the specific cognitive consequ ences of changed monoaminergic function that might contribute to the produc tion of impulsive behaviour. Objectives and methods: We compared the effect s of rapid plasma tryptophan depletion, acute doses of the mixed indirect c atecholamine agonist, methylphenidate (40 mg), and acute doses of the alpha (1)/alpha(2) agonist, clonidine (1.5 mu g/kg), on aspects of visual dis cri mination learning involving either acquisition of altered stimulus-reward a ssociations (i.e. updating the affective valence of exteroceptive stimuli) or the control of attention towards relevant as opposed to irrelevant stimu lus dimensions. Results: Relative to subjects who received placebo, subject s with reduced tryptophan exhibited a deficit in the ability to learn chang ed stimulus-reward associations, but were still able to shift an acquired a ttentional set away from a now-irrelevant stimulus dimension towards a newl y relevant dimension. By contrast, subjects who received methylphenidate we re able to learn effectively about changing stimulus-reward associations, b ut showed an enhanced ability to shift an attentional bias, in combination with slowed response times. Subjects who received clonidine showed neither of these changes. Conclusions: These results suggest that reduction in cent ral serotonin leads to altered neuromodulation of the cortical and subcorti cal regions (e.g. orbitofrontal cortex, striatum and anterior temporal stru ctures) that mediate important aspects of associative learning whereby exte roceptive stimuli acquire altered incentive motivational value. On the othe r hand, facilitation of catecholamine neurotransmitters may disrupt the all ocation of attention between relevant and irrelevant features of the enviro nment, perhaps through altered modulation of the dorsolateral prefrontal co rtex. The implications of these results for understanding the differential neuromodulation of cognitive functions are discussed.