General Considerations for Modeling Attention Defect Hyperactivity Disorder 605411 Diverse clinical symptoms with unknown etiology

ADHD is a clinically heterogeneous neuropsychiatric disorder with symptomatic components of hyperactivity, inattention, and impulsivity that usually present during childhood but can remain into adulthood. There are no objective laboratory measures for the diagnosis of ADHD and, similarly, there is no one definitive animal model of ADHD. This is largely due to a reliance on assessment of behavioral phenotypes that likely result from one or more genetic or neurodevelopmental disturbances across interacting neuronal networks, as well as an incomplete understanding of neurotransmitter systems that subserve these fundamental behavioral functions. Nonetheless, individual behavioral symptoms are readily assessed in laboratory animals,18 and recent molecular biological19 and functional imaging studies20 are shedding light on the etiology of the disorder.

There are many advantages to developing appropriate animal models of any disorder: a simpler system may be easier to interpret than the complex clinical syndrome, potential treatment groups are genetically homogeneous, and testing environments can be tightly controlled. Thus, the researcher can avoid complications associated with many clinical studies such as comorbidities, previous drug exposure, and heterogeneous environmental conditions. Ideally, animal models of ADHD should closely resemble the clinical disorder in as many ways as possible, including etiology, pathophysiology, behavioral phenotype, and response to pharmacotherapies that are clinically effective. Thus, to be considered as a valid ADHD animal model, one must be able to show that: (1) the model is based on a valid etiological theory such as a proposed pathophysiology or genetic mutation (construct validity); (2) behavioral deficits in the model closely resemble those commonly observed in the clinic (face validity); and (3) the model can selectively predict efficacy of known and unknown therapeutics or underlying aspects of the disorder (predictive validity).

For many years, rodents have been used to model ADHD. Manipulations to produce a behavioral phenotype similar to the disorder are numerous, including exposure to neurotoxins/environmental pollutants during development, neonatal anoxia, selective lesions of neurotransmitter systems, x-irradiation of selected brain regions, and genetic manipulations. Several of the more popular animal models are reviewed here.

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