General Issues

Early proposals that NE could have a causal role in ADHD, and hyperkinetic behavior in particular (228), were based on the effect of amphetamine to reduce NE activity during arousal. Now there is a widespread belief that children with ADHD are under- rather than overaroused, yet there is an increasing consensus that NE function has something to do with the symptoms (205). Evidence in this chapter shows that NE activity undoubtedly modulates attentional mechanisms both directly (tuning signal-to-noise ratios) and indirectly (via the control of mesocorticolimbic DA release). NE may influence other relevant behaviors depending on their dependence on cognitive mechanisms (e.g., environmental stimulation facilitating hyperkinesis) and the nature of the mechanisms underlying comorbid conditions. Crucial mechanisms include the control of catecholamine availability in the cortex (via the transporter) and phasic firing modes in the LC. Both of these should be targets for treatment.

Common to a consideration of the relative role of NE and 5-HT in ADHD is the increasing appreciation of a crucial role for the transporter in determining the availability of monoamines. Thus, cortical NE Ts can release DA (55), the DA transporter is regulated by a variety of substrates including 5-HT (229) and the NE T (compare knockout mice) modulates the perception of reinforcement (230). This latter finding has implications for understanding the aversion to accepting delays between response and reward, and the reinforcement gradients associated with the SHR and with ADHD subjects (231).

5-HT mechanisms are also relevant to the expression of features of ADHD by direct (transporter-mediated reuptake mechanisms) and indirect mechanisms (modulation of DA activity, especially in the initiation of behavioral responses). These have been underre-searched in view of more clearly established relations of 5-HT activity to the expression of externalizing responses more frequent in comorbid conditions. Now it is appreciated that 5-HT activity has a role in information processing (modulating gain) and cognitive impulsivity. The appreciation of these roles and the interactions of the three monoamines should make it easier to tailor treatment to the particular individual (im)balance of the pattern of cognitive, motivational, and motor bases to be found in a given patient.

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