The validity of dopamine transfer deficit theory in ADHD SHR model.
Introduction and Background
Attention deficit hyperactivity disorder (ADHD) is a disorder in which there is a persistent and developmentally abnormal level of overactivity, inattention and impulsivity. The physical cause or pathophysiology of this disease is currently unknown as the diagnosis is strictly based on relative or excessive increase in the symptoms such as overactivity, inattention or impulsivity which may otherwise also exist in normal individuals. The clinical symptoms considered for the detection of impulsivity in ADHD are often subjective or vague like ‘often blurts out answers before question have been completed’, ‘often has a difficulty awaiting turns’ and ‘often interrupts on others’ etc which is quite different from the basic science definition of impulsivity such as ‘an abnormally high preference of small, intermediate rewards over large delayed reward’ in a delay discounting task, ‘response during inter trial interval prior to the presentation of a cue associated with reward’ in a reaction time tasks. Till date no clear single gene has been successfully implicated exclusively in the aetiology of ADHD. However, significant associations of 4 different genes, D4 and D5 receptors and dopamine and serotonin transporters have been reported in several studies to play critical role in the aetiology. The list however is ever growing with some inclusions of inconclusive roles of DBH, HTR1B and SNAP-25 genes.
Developing animal models per se has not been easy for ADHD because of no clearly established pathological and etiological features and reliance upon heterogenous groups of symptoms found in variety of ADHD patients. This explains the existence of variety of models with none being able to mimic pathology, symptoms and response to the drugs.
Following behavioral paradigms are commonly used to model ADHD animals and test efficacy of drugs:
Delay discounting paradigm: Mainly for quantifying impulsivity checked by the tendency to choose small immediate reward over large delayed reward.
5-choice serial reaction time test: To test premature response to the stimulus for eg nose poke earlier than required in order to get rewards.
Stop signal reaction time task: To test the impulsivity in terms of withholding or inhibiting an already started motor response.
The spontaneously hyperactive rat (SRH), the most widely used ADHD model, has been shown to be impulsive when compared to their control strains such as WKY or wistar rats. They showed significantly more errors on delayed discounting task, episodic and reference memory task, habit learning and attentional and behavioral flexibility tasks than their respective controls strains. (Kantak et al., 2008). However, there was significant improvement on treatment with methylphenidate (Kantak et al., 2008). Another such research was able to show improvement on morris water maze task on treatment with atomoxetin (Liu et al., 2008)....