Figure 2 Horizontal (top two graphs) and vertical (bottom two graphs) activity recorded in an automated locomotor activity system in 1-min bins over a period of 30 min for SNAP-25 mice compared to CD-1 mice. SNAP-25 mice, whether naive or saline-treated, were significantly more active than CD-1 mice. Face validity

When neonatal rats are injected intracisternally with 100 mg 6-OHDA, on postnatal day 5, pronounced spontaneous hyperactivity is observed in a novel environment during a periadolescent development stage at postnatal days 21-30,62 but not at later stages of development at postnatal days 36 or 59. The nature of the hyperactivity suggests a lack of habituation to the novel environment of the activity test arena, since significant differences in spontaneous activity compared to sham control groups only become apparent during the later time bins (15-90 min) and not at earlier times (0-15 min).64 These findings are consistent with clinical ADHD since hyperactivity is generally only found in adolescence and usually resolves in adulthood (although the cognitive deficits do not). Similarly, ADHD patients exhibit difficulty habituating to novel situations and acting appropriately.65 Predictive validity

Psychostimulants effective in treating ADHD, such as methylphenidate and amphetamine, are also effective at alleviating the hyperactivity produced by 6-OHDA lesions.62'64 While the effects of both stimulants are dose-related, the best effect is seen with relatively high doses (e.g., 10mgkg_ 1 intraperitoneally for D-methylphenidate and 3 mgkg~1 intraperitoneally for amphetamine). Interestingly, a recent report described efficacy of atomoxetine against hyperactivity in 6-OHDA-lesioned rats.66 These effects of atomoxetine, a NET inhibitor currently labeled as a nonstimulant for the treatment of ADHD, were observed at a more reasonable dose of 1 mgkg_ 1 i.p. Construct validity

Consistent with clinical imaging data of dopamine hypofunction in the prefrontal cortex of ADHD patients, 6-OHDA lesioning in neonatal rats caused a loss of developing dopamine projections in the rat forebrain, as measured by decreased DAT binding.64 (DAT binding does not appear to correlate with the increased spontaneous motor activity in this model.) However, while motor hyperactivity induced by neonatal 6-OHDA lesions is mainly associated with destruction of mesolimbic dopamine pathways, behavioral responses of individual rats do not appear to be correlated with dopamine concentrations in any particular brain region.

Neonatal 6-OHDA lesions result in a remarkable resistance to the motor-impairing effect of alcohol (0.5-1.0gkg_ 1) as well as to the motor-suppressive effect of diazepam (5.0 mgkg_ 1), which may have clinical relevance since ADHD is a risk factor for alcohol abuse and antisocial behavior.65 However, learning deficits that are apparent soon after neonatal lesioning are maximal at weaning but disappear in adulthood.49 This is in contrast to the clinical situation, where learning impairments persist in many ADHD patients into adulthood, while the hyperactivity component generally remits.

Neonatal dopamine lesioning also induces neuronal adaptations that differ from responses to the same lesions in adult rats. For example, hyperinnervation of the striatum by serotonergic neurons during the periadolescent period is observed following early neonatal lesions but not following lesions in the adult.63,67 The functional significance of this is unclear, however, since serotonergic agents are generally not effective in treating symptoms of ADHD. In contrast to the adaptive changes seen in the serotonergic system, no major effects on the norepinephrine system are apparent following 6-OHDA lesioning.49 Since the calming effects of stimulants can be mimicked by NET inhibitors in lesioned rats, these data may be relevant to clinical ADHD, where such inhibitors also show efficacy, e.g., atomoxetine.

DA4 receptor polymorphisms have been repeatedly linked to ADHD so it is interesting to note that DA4 receptor upregulation correlated with 6-OHDA lesion-induced hyperactivity and that DA4 receptor antagonists ameliorated this hyperactivity in a dose-related manner, whereas DA2/DA3 receptor antagonists were without effect.62,68,69 Interestingly, mice lacking DA4 receptor that were lesioned with 6-OHDA on postnatal day 2 did not develop hyperactivity when tested between postnatal days 25 and 29; this was in contrast to lesioned wild-type controls, which did exhibit hyperactivity.70 Thus, the DA4 receptor appears to be important for hyperactivity and impaired behavioral inhibition in this model. Other Models Dorsal prefrontal cortex (dPFC) lesions

Lesions of the prefrontal cortex produce cognitive deficits such as impaired regulation of attention and impulsivity as well as disrupted working memory; these deficits are thought to be mediated by hypofunctioning catecholamine neurotransmitter systems.71 In a recent report describing pronounced deficits in attention in rats with lesions of the dPFC using a new combined attention memory task, the psychostimulant amphetamine reversed these deficits in a manner that was specific for attention.72 Importantly, the effective dose of amphetamine in this model was low, 0.2 mgkg_ 1 intraperitoneally, which is more in line with clinical expectations compared to efficacy with the same stimulant in 6-OHDA-lesioned rats. While this new model is quite laborious to conduct - taking 4-6 months to train rats to baseline performance - data generated may have important implications for the cognitive deficits seen in ADHD as well as in schizophrenia. Environmental toxins

Chronic exposure to lead or polychlorinated biphenyls can cause motor hyperactivity as well as cognitive impairment and impulsivity in rodents and may contribute to some instances of human ADHD. There are some older data indicating that psychostimulants such as methylphenidate and amphetamine may ameliorate some of these symptoms in mice, but these models have not been well characterized and the number of cases of ADHD caused by exposure to environmental toxins is likely small. Neonatal hypoxia

Anoxia in perinatal humans is a risk factor for developing ADHD. In rats, transient neonatal hypoxia produces behavioral symptoms similar to those observed in clinical ADHD, such as age-related hyperactivity, most pronounced in the periadolescent period, as well as longer-term deficits in cognitive functioning, possibly as a result of hippocampal damage. Complex age-related changes in neurotransmitter levels in the cortex and cerebellum as well as neurodegeneration in the hippocampus as a result of anoxia are not readily interpretable with respect to clinical relevancy.27 Animals selected for inattention and impulsivity

Using a 5-CSRTTsimilar to that described earlier, rats that are poor performers can be selected and preferentially bred for deficient sustained attention and increased impulsiveness.73 Methylphenidate treatment can improve accuracy in these otherwise poor performers; however, since these rats are not hyperactive to begin with, this model may only serve as a measure of the cognitive components of ADHD.73 Interestingly, local injection of a DA1 receptor agonist into the frontal cortex of poor performers (< 75% accuracy) in the 5-CSRTT enhanced attention74 (high-performers were impaired), which may be pertinent to the dopamine hypofunctioning evident in clinical ADHD. Summary

There is no one definitive animal model of ADHD, but rather several models that address different aspects of this complex behavioral syndrome. Interestingly, a factor common to many of the most frequently used models is a hypofunctioning dopamine system, especially in frontal cortex and striatal brain regions and associated pathways. Perhaps the most studied and best characterized is the SHR, which exhibits many of the behavioral and genetic aspects of ADHD and is responsive to drugs selective for different molecular targets that have proven efficacious in the clinic for treatment of ADHD. Other more recent genetically based (DAT knockout, SNAP-25 mutant) and cortical lesion (dPFC) models may also shed new light on the underlying pathology that causes ADHD. Finally, an important point to make at this juncture is the necessity to study the effects of new drugs using these models, which respond differentially to treatment due to altered neurotransmitter systems, compared to naive animals.

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