Naples high excitability and spontaneously hypertensive model different variants of attention-deficit hyperactivity disorder

Attention Deficit Hyperactivity Disorder (ADHD) is characterized by inattention, hyperactivity and impulsivity, and affects 1-3% of school children, across countries and cultures with a 4:1 male-to-female ratio. An altered mesocorticolimbic dopamine (DA) system is thought to be associated to different variants of ADHD. Prepuberal rats of the Naples High Excitability (NHE) and the Spontaneously Hypertensive (SHR) model the variant with altered executive functions and response inhibition respectively. As a matter of fact, the NHE show hyperactive mesocortical DA branch as demonstrated by hypertrophic DA neurons, high level of tyrosine hidroxylase (TH), high expression of DA D2 receptor density and higher expression of DA-related phosphoprotein (DARP32) in the mesencephalon. In contrast, the NHE show in comparison to random-bred controls more axonal varicosities, high DA transporter (DAT) density and lower DA D1 and D2 receptors in the prefrontal cortex (PFC). TH, DAT, DA D1 and D2 receptors and DARP32 demonstrate a non altered mesostriatal DA branch. Their basal profile is reversed by treatment with methylphenidate (MPH; 3 mg/Kg i.p. for 14 days). On the other hand, the SHR in comparison to Wystar-Kyoto controls (WKY), reveal altered mesolimbic and mesocortical branches without main changes in the mesencephalon. However, they show high responsiveness for TH expression and no responsiveness for DA D2 autoreceptors to MPH treatment. Conversely a higher basal DA tone is associated with high DAT density and higher DA D1 and D2 receptors in the PFC. In addition MPH treatment reverses the physiological high density of DA D1 and D2 receptors in the striatum. Furthermore DA re-uptake system is defective as shown in synaptosome preparations. Thus, both high and low functional states of mesocorticolimbic DA branches may be associated with impaired response inhibition, attention and executive function