Differences between electrically-, ritalin- and D-amphetamine-stimulated release of [3H]dopamine from brain slices suggest impaired vesicular storage of dopamine in an animal model of Attention-Deficit Hyperactivity Disorder

The spontaneously hypertensive rat (SHR) has behavioural characteristics which make it a suitable animal model for Attention-Deficit Hyperactivity Disorder (ADHD). The drugs of choice in the treatment of ADHD are methylphenidate and D-amphetamine. Using an in vitro superfusion system, we showed that both drugs released [H-3]dopamine (DA) (and metabolites) from prefrontal cortex, nucleus accumbens and caudate-putamen slices, but methylphenidate was from 7- to 17-fold less potent than D-amphetamine. The similarity in the drug effects on SHR and WKY [H-3]DA release is in accordance with the fact that there is no 'paradoxical effect' of psychomotor stimulants on ADHD behaviour. Methylphenidate released significantly less [H-3]DA from nucleus accumbens slices obtained from SHR than from their normotensive Wistar-Kyoto (WKY) controls. Electrical stimulation released less [H-3]DA from prefrontal cortex and caudate-putamen slices of SHR, while D-amphetamine, in contrast to methylphenidate, released more [H-3]DA from prefrontal cortex, nucleus accumbens and caudate-putamen slices of SHR compared to WKY. Inhibition of the DA uptake carrier by low concentrations of methylphenidate increased the electrically-stimulated release of [H-3]DA to the same extent in SHR and WKY tissue, suggesting that the DA transporter was not responsible for the differences between SHR and WKY. The present results suggest that SHR may have impaired vesicular storage of DA causing leakage of DA into the cytoplasm, since SHR released less [H-3]DA from vesicular stores in response to methylphenidate or electrical stimulation and released more [H-3]DA from cytoplasmic stores via the uptake carrier in response to D-amphetamine. Methylphenidate might be the drug of choice in the treatment of ADHD because it releases DA from vesicular stores only and is less potent than D-amphetamine, thus making it possible to adjust the dose and thereby 'normalise' reduced DA function more precisely than is possible with D-amphetamine. There was no difference between SHR and WKY with respect to D-amphetamine-stimulated release of [C-14]acetylcholine (ACh) or methylphenidate-induced inhibition of the electrically-stimulated release of [C-14]ACh from nucleus accumbens or caudate-putamen slices, suggesting that there is no major change in cholinergic transmission in SHR. (C) 1998 Elsevier Science B.V. All rights reserved.