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

Davids, Eugen; Zhang, Kehong; Tarazi, Frank I.; Baldessarini, Ross J.

doi:10.1007/s00213-001-0962-5

Cited by 72 publications

(66 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, cocaine, as expected, was stimulatory. However, l-threo-MP neither stimulated locomotion nor, in contrast to the report of Baldessarini et al (2002), did this compound reduce cocaine-stimulated locomotion. A similar experiment using four pairs of mice per condition and drug doses of 6 mg/kg l-threo-MP and 10 mg/kg cocaine also did not find a reduction of cocaine-stimulated locomotor activity (data not shown).…”

Section: Effect Of L-threo-mp On Cocaine-induced Locomotor Activitycontrasting

confidence: 89%

See 1 more Smart Citation

Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

Ding

Gatley

Thanos

et al. 2004

Synapse

View full text Add to dashboard Cite

Methylphenidate (MP) (Ritalin) is widely used for the treatment of attention deficit hyperactivity disorder (ADHD). It is a chiral drug, marketed as the racemic mixture of d-and l-threo enantiomers. Our previous studies (PET and microdialysis) in humans, baboons, and rats confirm the notion that pharmacological specificity of MP resides predominantly in the d-isomer. A recent report that intraperitoneally (i.p.) administered l-threo-MP displayed potent, dose-dependent inhibition of cocaine-or apomorphine-induced locomotion in rats, raises the question of whether l-threo-MP has a similar effect when given orally. It has been speculated that l-threo-MP is poorly absorbed in humans when it is given orally because of rapid presystemic metabolism. To investigate whether l-threo-MP or its metabolites can be delivered to the brain when it is given orally, and whether l-threo-MP is pharmacologically active. PET and MicroPET studies were carried out in baboons and rats using orally delivered C-11-labeled d-and l-threo-MP ([methyl- ]CO 2 , derived from demethylation, was excluded by ex vivo studies in rats. When l-threo-MP was given i.p. to mice at a dose of 3 mg/kg, it neither stimulated locomotor activity nor inhibited the increased locomotor activity due to cocaine administration. These results suggest that, in animal models, l-threo-MP or its metabolite(s) is (are) absorbed from the gastrointestinal tract and enters the brain after oral administration, but that l-threo-MP may not be pharmacologically active. These results are pertinent to the question of whether l-threo-MP contributes to the behavioral and side effect profile of MP during treatment of ADHD. Synapse 53: 168 -175, 2004.

show abstract

Section: Effect Of L-threo-mp On Cocaine-induced Locomotor Activitycontrasting

confidence: 89%

“…These results are also in agreement with the recent report by Davids et al (2002). However, our data did not support the finding of an inhibitory effect of l-threo-MP on cocainestimulated locomotor activity that was recently reported by Baldessarini et al (2001).…”

Section: Discussionsupporting

confidence: 78%

Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

Ding

Gatley

Thanos

et al. 2004

Synapse

View full text Add to dashboard Cite

show abstract

“…1 Tables 2 and 3 show altered gene expression in the midbrain and striatum in rats exposed to neonatal treatment with 6-OHDA, bisphenol A, ). Yet, the degree of increment of SMA is lower than that in previous studies (Davids, 2002b;Zhang, 2001Zhang, , 2002 Multiple gene expression was examined by cDNA macroarray. Each value represents the ratio of gene expression level versus that ofrespective control value.…”

Section: Resultsmentioning

confidence: 74%

Effects of Neonatal Treatment With 6‐Hydroxydopamine and Endocrine Disruptors on Motor Activity and Gene Expression in Rats

et al. 2004

View full text Add to dashboard Cite

show abstract

“…0 S]-MPH) (Patrick et al, 1987;Aoyama et al, 1996;Davids et al, 2002). Hepatic metabolism of MPH is rapid and extensive, yielding mainly the de-esterified metabolite, ritalinic acid (Wargin et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Juvenile toxicity assessment of d,l‐methylphenidate in rats

Beckman¹,

Schneider²,

Youreneff³

et al. 2008

Birth Defects Research Pt B

View full text Add to dashboard Cite

BACKGROUND:The oral administration of d,l-methylphenidate (MPH) was designed to encompass the major part of postnatal development in the rat and to evaluate potential chronic effects. METHODS: Wistar Hannover rats were crossfostered on postpartum day 0 (day of birth) and were administered MPH at doses of 5, 50, and 100 mg/kg/day (mpkd) on postpartum days 7 to 70. Clinical signs, body weight, food consumption, developmental, behavioral, clinical/ anatomic pathology, toxicokinetic, and fertility evaluations were conducted. RESULTS: MPH-related effects on clinical signs, body weight, and behavior tests were noted. Increased locomotor activity and cage biting/chewing occurred at Z 5 mpkd (females) and Z 50 mpkd (males) and were absent after dosing ceased. Body weight parameters were decreased at Z 50 mpkd and were comparable to controls at 5 weeks' recovery. Open field motor activity tests conducted 2 weeks after dosing ceased revealed decreased peripheral beam breaks at Z 50 mpkd. Passive avoidance tests conducted 3 weeks after dosing ceased indicated decreased females reaching learning criterion at 100 mpkd. This is considered of nominal significance as there were no effects in the water maze test or retention in passive avoidance test. After multiple doses, females exhibited higher exposures than males and exposures were reduced in all groups in comparison to those after a single dose. CONCLUSIONS: These results suggest that MPH can produce enduring behavioral effects in rats. The no-toxicologic-effect-level was 5 mpkd, associated with AUC (0-24 h) racemate values in males and females, respectively, of 101 and 153 ng.h/mL after chronic dosing. Birth Defects Res (Part B) 83: 48-67, 2008.

show abstract

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

Abstract: 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.

Cited by 72 publications

References 42 publications

Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration

Effects of Neonatal Treatment With 6‐Hydroxydopamine and Endocrine Disruptors on Motor Activity and Gene Expression in Rats

Juvenile toxicity assessment of d,l‐methylphenidate in rats

Contact Info

Product

Resources

About