Animal Models of Attention Deficit Hyperactivity Disorder 605421 The spontaneously hypertensive rat SHR

The most widely accepted animal model of ADHD is the SHR, a strain that was originally developed from Wistar Kyoto (WKY) rats in Japan more than 40 years ago. Unexpectedly, when selecting for hypertension, hyperactivity was also observed. Since then, the SHR has been studied extensively from face, predictive, and construct validity perspectives.

6.05.4.2.1.1 Face validity

SHRs exhibit many behavioral features characteristic of ADHD. Hyperactivity in the SHR strain is observed across multiple behavioral paradigms, including single- and multiple-compartment open-field as well as automated spontaneous locomotor tests. The nature of the hyperactivity is dependent on the test environment, with maximal disturbances compared to control rat strains observed in unfamiliar environments and more modest hyperactivity observed in the home cage.27

Excessive responding is also seen using fixed-interval/extinction schedules.21 Fixed-interval schedules (pressing a lever for a food pellet that is only rewarded after a fixed interval of time has expired) are useful for studying rate-dependent learning, also a measure of reward, which is impaired in ADHD. A typical 'scallop' pattern is usually observed during baseline responding in control rat strains such that responses are typically low during the early part of the interval and higher in the later part of the interval, closer to the time for the food reward. The SHR 'scallop' is shifted considerably to the left compared to other strains such as the WKY rat, demonstrating a different reactivity to the food reward, as well as motor impulsiveness. When extinction periods are added (effectively a time-out period), the SHR shows component differences in sensitivity to the stimulus change as well as decreased sustained attention.21

Response inhibition and cognitive function are also impaired in the SHR in five-trial inhibitory avoidance22 (Figure 1) and 5-CSRTT28 when compared with age- and sex-matched controls from WKYand other rat strains. Interestingly, these components of behavioral dysfunction correspond to the clinically observed symptoms of hyperactivity, impulsivity, and inattention/cognitive impairment, making the SHR a good model for studying multiple facets of ADHD. For example, in

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