five-trial inhibitory avoidance, SHR pups continue to transfer to a darkened chamber (which they prefer) from a brightly illuminated chamber (which is aversive to a rodent) over five trials spaced only 1 min apart, despite the presence of a mild footshock upon crossing. This is measured as relatively low transfer latencies, that are higher in pups from other strains.22 Similarly in the 5-CSRTT, SHR adults exhibit impaired sustained visual attention, although this aspect has been attributed to the hypertension that is evident in older adult SHRs. Of course, SHRs also have impaired cognitive function in a number of other tests, including the water maze,28-30 a measure of spatial learning and memory, the radial arm31'32 and Y-maze,33 measures of spatial working memory, as well as other operant-based tasks such as the delayed nonmatching to position test,28 a measure of short-term or working memory, and the lateralized reaction time task, a behavioral measure of visuospatial divided attention.34 Predictive validity

Juvenile SHRs, that do not exhibit the potential confound of hypertension that develops later in the adult SHR, respond to stimulant drugs that are clinically efficacious for treating ADHD, such as methylphenidate (Ritalin). Locomotor hyperactivity and decreased delayed reinforcement in SHRs are reportedly attenuated in a dose-related manner by low doses of methylphenidate,33,35 while impaired spontaneous alternation behavior in the Y-maze, which may be gender-specific (worse in male rats) was restored by methylphenidate treatment.33 Similarly, increased impulsivity assessed in an elevated plus maze was also lowered by methylphenidate,33 although it is difficult to dissociate this from potential anxiety-related measures. Impaired response inhibition/attention in five-trial inhibitory avoidance is effectively reversed by doses of methylphenidate,22 producing plasma levels (approximately 4-17 ngmL_ 1) similar to those efficacious in the clinic (approximately 8-10ngmL_ 1). Similarly, non-stimulants with different mechanisms, such as the NNR agonist, ABT-418, that are effective in clinical trials for ADHD36 also reverse impairments in response inhibition/ attention in five-trial inhibitory avoidance22 at efficacious plasma levels consistent between SHRs (3.5 ngmL_ 1) and humans (8-30 ngmL_ 1). Similar data were also obtained very recently with the selective a4b2 NNR agonist, ABT-089, currently in development for treating cognitive dysfunction in neurological disorders such as ADHD. Further, in adults with ADHD, nicotine administration improves cognitive function and behavioral inhibition to a level at least as comparable with methylphenidate.38 Nicotine also reverses behavioral impairments in SHRs tested in the Y-maze, an effect that is blocked by the a4b2 NNR antagonists mecamylamine and dihydro-^-erythroidine.39 SHRs are also reportedly sensitive to D-amphetamine, demonstrating reduced motor activity and impulsiveness.27 Construct validity

Diagnosis of ADHD is based on behavioral symptoms, following DSM IV criteria. As with ADHD, similar behavioral impairments observed in SHRs are believed to have a genetics-based etiology. In recent years in humans diagnosed with ADHD, several genetic studies have identified candidate genes that are consistent with the widely held belief that hypofunction of the mesocortical dopaminergic system contributes to the main symptoms of ADHD. In three genomewide scans of three different samples from US, Dutch, and German populations, the DAT1 candidate gene was linked to ADHD symptomatology.19 In adult SHRs, the DAT is significantly overexpressed in the striatum when compared with control WKY rats, while dopamine levels in the striatum and frontal cortex are decreased. Increases in D1 receptors occur in some brain regions in SHRs, which is presumably linked to deficient activation of the dopaminergic system.27 This is consistent with stimulant efficacy in both ADHD patients and SHRs, given that mechanisms of action proposed for drugs such as methylphenidate and amphetamine include increased release of dopamine. Increased neuronal uptake of norepinephrine, which is also evident in SHRs,40 has been implicated in mediating hypertension rather than ADHD-related abnormal behavior. SHRs also appear to have impaired vesicular storage of dopamine, causing leakage of the neurotransmitter into the cytoplasm. Striatal dopamine release is also impaired.

Cholinergic function is also disrupted in SHRs. NNRs containing the a4 subunit are decreased in multiple brain regions, especially the frontal cortex in prehypertensive juvenile SHRs, worsening with age.30,32,41 This finding appears unrelated to the hypertension that also develops with age, since treatment of SHRs with the antihypertensive agent hydralazine prevented the development of hypertension in adult SHRs but did not affect the reduced expression of 41

nicotinic receptors.

Understanding And Treating ADHD

Understanding And Treating ADHD

Attention Deficit Disorder or ADD is a very complicated, and time and again misinterpreted, disorder. Its beginning is physiological, but it can have a multitude of consequences that come alongside with it. That apart, what is the differentiation between ADHD and ADD ADHD is the abbreviated form of Attention Deficit Hyperactive Disorder, its major indications being noticeable hyperactivity and impulsivity.

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