Experimental investigations on dopamine transmission can provide clues on the mechanism of the therapeutic effect of amphetamine and methylphenidate in ADHD.

The aim of this review is to compare the experimental evidence obtained from in vitro studies on the effect of amphetamine and methylphenidate on dopamine transmission with the results obtained in animal models of attention deficit hyperactivity disorder (ADHD). This comparison can extend the knowledge on the mechanism of action of the drugs used in the therapy of ADHD and provide insight into the etiology of ADHD. In particular, we considered the results obtained from in vitro methods, such as synaptosomes, cells in culture, and slices and from in vivo animal models of ADHD, such as spontaneous hypertensive rats (SHR) and the Naples high-excitability (NHE) rat lines. The different experimental approaches produce consonant results and suggest that in SHR rats, in contrast to Wistar Kyoto rats (WKY), amphetamine and depolarization by high K+ might release different pools of dopamine-containing vesicles. The pool depleted by amphetamine might represent dopamine that is stored in large dense core vesicles, whereas dopamine released by high K+ might be contained in small synaptic vesicles (SSV). The sustained dopamine transmission observed in the nucleus accumbens of SHR but not WKY rats can be supported by an elevated synthesis and release, which also might explain the stronger effect of methylphenidate on dopamine release in SHR but not in WKY rats. This hypothesis might enlighten the common therapeutic effect of these drugs, although their action takes place at different levels in catecholaminergic transmission.