THE EFFECTS OF ACUTE AND CHRONIC METHYLPHENIDATE TREATMENT ON STEREOTYPIC BEHAVIOR AND BASAL GANGLIA GENE EXPRESSION IN RATS. † 366

Methylphenidate (MPH) is frequently used in the treatment of Attention-Deficit / Hyperactivity Disorder, a common neurodevelopmental diagnosis in school-aged children. A concerning side effect is the induction of tics and other stereotypic behaviors. MPH is a dopamine re-uptake blocker with effects on mesocorticolimbic and mesostriatal dopamine (DA) systems. Mesocorticolimbic DA cell bodies are located in the ventral tegmental area(VTA) and project to the nucleus accumbens (NA) and frontal cortex. Mesostriatal DA cell bodies are located in the substantia nigra pars compacta(SNc) and project to the striatum (or caudate-putamen, STR). To identify neuronal subgroups involved in MPH effects, in situ hybridization histochemistry was performed after acute (at 7 wks) or chronic treatment(twice daily, 4-7 wks) with saline, low- (1.25 mg/kg) or high-dose (12.5 mg/kg) MPH in young rats. mRNA labelling for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis, and DA₂ receptors was quantified in the VTA and SNc, and glutamic acid decarboxylase ₆₇, the rate-limiting enzyme in GABA synthesis, DA₁ and DA₂ receptors and preproenkephalin labelling was quantified in the NA and STR. Locomotor activity, stereotypy and rearing were measured on days 1, 7, 14 and 21. After acute treatment, all behaviors were increased in the high-dose group (p's < 0.005) and there were no changes in mRNA labelling. With chronic treatment, activity was highest in the high-dose group (p= 0.0005), and effects were largest on day 1 (p's < 0.004). Stereotypy showed dose-dependent increases(p < 0.00005) without time effects. Rearing was increased in the high-dose group (p= 0.0006), with marginal effects on day 21. Chronic treatment with either dose resulted in increased tyrosine hydroxylase labelling in the VTA and SNC (p's < 0.05). High-dose treatment resulted in increased labelling for preproenkephalin in the STR (p < 0.01). Mazindol binding was unchanged suggesting that this was not due to loss of DA terminals. Chronic MPH treatment alters gene expression in VTA and SNc DA neurons and STR efferent neurons which express preproenkephalin. Supported by Tourette Syndrome Association, HD28815 and HD26979.