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putamen but not from nucleus accumbens or prefrontal cortex slices in SHR compared with control mice (30). In another study, dopamine release secondary to electrical stimulation was significantly lower in caudate-putamen and prefrontal cortex slices of SHR compared with control mice. These findings were attributed to increased autoreceptor- mediated inhibition of dopamine release in caudate-puta- men slices but not in the prefrontal cortex. Another study showed that the altered presynaptic regulation of dopamine in SHR led to the down-regulation of the dopamine system (31). The authors hypothesized that this may have occurred early in development as a compensatory response to abnor- mally high dopamine concentrations.

Other SHR studies implicated an interaction between the noradrenergic and dopaminergic system in the nucleus accumbens, but they ruled out the idea that a dysfunctional locus ceruleus and A2 nucleus impairs dopaminergic trans- mission in the nucleus accumbens through 2-adreno- ceptor–mediated inhibition of dopamine release (32). Papa et al. used molecular imaging techniques to assess the neural substrates of ADHD-like behaviors in the SHR rat (33). Their data showed the corticostriatopallidal system to me- diate these behaviors. King et al. showed that exposure to excess androgen levels early in development led to decreased catecholamine innervation in frontal cortex and enhanced expression of ADHD-like behaviors (34). Carey et al. used quantitative receptor autoradiography and computer-as- sisted image analysis to show a higher density of low-affinity D1 and D5 dopamine receptors in the caudate-putamen, the nucleus accumbens, and the olfactory tubercle of SHR (35). Stimulant treatment normalized these receptors by de- creasing the number of binding sites and increasing affinity to the control level.

In contrast to the large body of evidence implicating dopaminergic and noradrenergic systems in ADHD, evi- dence implicating serotonergic systems is mixed. Although the tertiary amines (imipramine and amitriptyline) are more selective for the serotonin transporter than the norepineph- rine transporter (36), the secondary amines (desipramine, nortriptyline, and protriptyline) are more selective for the norepinephrine transporter (36). Moreover, measures of se- rotonin metabolism appear minimally related to the clinical efficacy of the stimulants (22), a finding consistent with the lack of efficacy of serotonergic drugs for treating ADHD. This suggests that the anti-ADHD efficacy of the TCAs stems from their actions on catecholamine reuptake, partic- ularly that of norepinephrine.

Despite these equivocal findings, work by Gainetdinov et al. suggests that we cannot rule out a role for serotonergic systems in the pathophysiology of ADHD (37). These au- thors studied knockout mice lacking the gene encoding the dopamine transporter (DAT). These mice have elevated do- paminergic tone, are hyperactive, and show decreased loco- motion in response to stimulants. Gainetdinov et al. showed

Chapter 43: Pathophysiology of ADHD


that the effects of stimulants were mediated by serotonergic neurotransmission (37).

The anti-ADHD efficacy of nicotine and ABT-418 sug- gests that nicotinic dysregulation may also play a role in the pathophysiology of ADHD. Patients with ADHD are more likely to smoke and have an earlier age of onset of smoking than persons who do not have ADHD (38–40). In addition, maternal smoking during pregnancy appears to increase the risk of ADHD in the children (41), and in utero exposure to nicotine in animals confers a heightened risk of an ADHD-like syndrome in the newborn (42,43). That nico- tine dysregulation could play an important role in the path- ophysiology of ADHD is not surprising considering that nicotinic activation enhances dopaminergic neurotransmis- sion (44,45).


Satterfield and Dawson were among the first to propose that ADHD symptoms were caused by frontolimbic dysfunction (46). These investigators suggested that weak frontal cortical inhibitory control over limbic functions could lead to ADHD. A review of the neurologic literature showing simi- larities in disinhibited behavior between adult patients with frontal lobe damage and children with ADHD provided further evidence that the frontal lobes could be involved in the pathophysiology of the disorder (47). Two sources of data have tested the frontolimbic hypothesis of ADHD: neuropsychological studies and neuroimaging studies.

Neuropsychological Studies

Neuropsychological tests indirectly assess brain functioning by assessing features of human perception, cognition, or behavior that have been clinically or experimentally linked to specific brain functions (48). Although limited in their ability to localize brain dysfunction, these tests have several advantages. Many of these tests have been standardized on large populations, thus making it straightforward to define deviant performance. Because of the extensive use of these tests in brain-damaged populations, performance on many of these tests can lead to hypotheses, albeit weak, about the locus of brain dysfunction. Being noninvasive and inexpen- sive, neuropsychological tests are frequently used to generate hypotheses about brain dysfunction.

Given that inattention is a one of the defining clinical features of ADHD, many neuropsychological studies of the disorder have assessed the attention of children with ADHD. The most commonly used measure of attention is the continuous performance test, which requires subjects to sustain their attention to subtle sensory signals, to avoid being distracted by irrelevant stimuli, and to maintain alert- ness for the duration of the session. Most of these studies

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