DIFFERENCES BETWEEN ELECTRICALLY-STIMULATED, RITALIN-STIMULATED AND D-AMPHETAMINE-STIMULATED RELEASE OF [H-3]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 characteristi cs which make it a suitable animal model for Attention-Deficit Hyperac tivity Disorder (ADHD). The drugs of choice in the treatment of ADHD a re methylphenidate and D-amphetamine. Using an in vitro superfusion sy stem, we showed that both drugs released [H-3]dopamine (DA) (and metab olites) 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 r eleased significantly less [H-3]DA from nucleus accumbens slices obtai ned from SHR than from their normotensive Wistar-Kyoto (WKY) controls. Electrical stimulation released less [H-3]DA from prefrontal cortex a nd 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. Inhibiti on of the DA uptake carrier by low concentrations of methylphenidate i ncreased the electrically-stimulated release of [H-3]DA to the same ex tent in SHR and WKY tissue, suggesting that the DA transporter was not responsible for the differences between SHR and WKY. The present resu lts suggest that SHR may have impaired vesicular storage of DA causing leakage of DA into the cytoplasm, since SHR released less [H-3]DA fro m vesicular stores in response to methylphenidate or electrical stimul ation and released more [H-3]DA from cytoplasmic stores via the uptake carrier in response to D-amphetamine. Methylphenidate might be the dr ug of choice in the treatment of ADHD because it releases DA from vesi cular stores only and is less potent than D-amphetamine, thus making i t possible to adjust the dose and thereby 'normalise' reduced DA funct ion more precisely than is possible with D-amphetamine. There was no d ifference between SHR and WKY with respect to D-amphetamine-stimulated release of [C-14]acetylcholine (ACh) or methylphenidate-induced inhib ition of the electrically-stimulated release of [C-14]ACh from nucleus accumbens or caudate-putamen slices, suggesting that there is no majo r change in cholinergic transmission in SHR. (C) 1998 Elsevier Science B.V. All rights reserved.