Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning.
BACKGROUND
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.
Davids
Eugen
E
Department of Psychiatry & Neuroscience Program, Harvard Medical School and Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, MA 02478, USA.
Zhang
Kehong
K
Tarazi
Frank I
FI
Baldessarini
Ross J
RJ
D000818:Animals; D001345:Autoradiography; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D008774:Methylphenidate / Q000737:chemistry / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D019275:Radiopharmaceuticals / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013563:Sympathectomy, Chemical; D013565:Sympatholytics
D000697:Central Nervous System Stimulants; D019275:Radiopharmaceuticals; D013565:Sympatholytics; D008774:Methylphenidate; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D016627:Oxidopamine; D003042:Cocaine