Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning.

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Davids E, Zhang K, Tarazi FI, Baldessarini RJ

Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning.

Psychopharmacology (Berl). 2002 Feb;160(1):92-8. Epub 2001 Dec 18.

PubMed ID

11862378 [ View in PubMed

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Abstract

RATIONALE: The psychostimulant dl-threo-methylphenidate is commonly used to treat attention deficit-hyperactivity disorder (ADHD). Consistent with its effects in ADHD patients, racemic methylphenidate antagonizes behavioral hyperactivity in several animal models of ADHD, including juvenile rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of forebrain dopamine projections. The enantiomers of methylphenidate differ markedly in stimulant potency but have not been compared in the 6-OHDA lesion model. OBJECTIVE: Locomotor-inhibiting effects of methylphenidate enantiomers were compared in 6-OHDA-lesioned rats to test the hypothesis that d-methylphenidate is more potent than dl- and l-methylphenidate. METHODS: Selective dopamine lesions were made using 6-OHDA (100 microg, intracisternal, IC) on postnatal day (PD) 5 after desipramine (25 mg/kg, SC) pretreatment to protect noradrenergic neurons. Effects of d-, l- and dl-threo-methylphenidate on locomotor activity of lesioned and sham control rats were quantified at PD 23-27. RESULTS: Lesioning yielded robust motor hyperactivity at PD 23-27. Both d- and dl-methylphenidate stimulated locomotor activity in intact rats, and inhibited activity in lesioned rats. l-Methylphenidate did not affect locomotor activity in either lesioned rats or controls. d-Methylphenidate (ED(50)=1.66 mg/kg) was 3.3 times more potent than dl-methylphenidate (ED(50)=5.45 mg/kg) in reducing locomotor hyperactivity in lesioned rats. In addition, pretreatment of lesioned rats with l-methylphenidate significantly reduced the motor inhibiting effects of d-methylphenidate. CONCLUSIONS: The more active enantiomer, as predicted, was d-methylphenidate, but the l-enantiomer interfered with its effects, suggesting that clinical potency of d-methylphenidate may be more than twice that of the racemate.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dexmethylphenidate	Sodium-dependent dopamine transporter	Protein	Humans	Yes	Inhibitor	Details
Dexmethylphenidate	Sodium-dependent noradrenaline transporter	Protein	Humans	Yes	Inhibitor	Details