Testing paradigms utilized by different laboratories can vary but tend to revolve around using so-called standard assays, e.g., open-field/automated locomotor activity in a novel environment and general tests of cognitive function, e.g., the water maze, radial arm maze, or passive avoidance paradigm. While versions of the open field are sensitive to showing the hyperactivity component of ADHD and are useful for demonstrating face validity, standard tests of cognitive function are arguably less demonstrative in that behavioral domains affected in ADHD (e.g., decreased response inhibition or impulsivity, inattention) are not specifically addressed. Therefore, more sophisticated tests are desirable. Three such tests of varying degrees of complexity are used routinely by others or us. These include: (1) fixed-interval/ extinction schedule operant responding, where rodents are required to withhold responding (usually pressing on a lever) for a defined time period (up to several minutes) for a food or drink reward - motor-based impulsiveness is operationalized as bursts of responses with short interresponse times prior to the end of the fixed interval, i.e., poor response inhibition21; (2) five-trial inhibitory avoidance, in which juvenile rats are required to withhold transferring from a brightly illuminated 'safe' compartment of a shuttle-like apparatus to a darkened compartment, where they receive a very mild (0.1 mA) footshock - the test is usually conducted sequentially for five trials (maximum 180 s long) spaced 1 min apart and impulsiveness is operationalized in this instance as low latencies to transfer to the darkened compartment, i.e., poor response inhibition22; and (3) 5-CSRTT, in which selective attention, impulsivity, motivation, and motor function can all be evaluated individually.23 The 5-CSRTT is perhaps the single most relevant assay since sustained attention as well as the other afore-mentioned behaviors can be assessed. Originally designed as a preclinical correlate of the CPTof attention used in clinical studies, the 5-CSRTT relies on visual cues that predict a food reward that is only delivered when the rodent correctly chooses the location of a short-duration (typically less than 1 s during testing) light stimulus. Sustained attention is operationalized as percent correct or incorrect (errors of commission) choices or the number of missed responses (errors of omission) over a test session (usually 30min or 100 trials long), while impulsivity is measured by assessing the number of responses between trials (termed the 'limited hold' period). Latencies to respond as well as number of missed responses provide additional information on motor function. All of these measures are assessed over the same time period in a rat that is on a food-restricted diet for motivational purposes. The 5-CSRTT can also be conducted in nonhuman primates,24 although research using monkeys in this regard lags considerably behind that conducted in rodents. A downside of the 5-CSRTT, as well as fixed-interval tests, is that training schedules of 8 weeks or more are typical, although three or four compounds can usually be sequentially evaluated in the same animals using a cross-over design25 typical of similar studies in the clinic. In contrast, the five-trial inhibitory avoidance is usually conducted acutely over a period of 15 min, although the test is labor-intensive and can take 2-4 weeks to generate a full dose-response curve when evaluating the effects of a novel drug.26
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