Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1997-11

AUTHORS

Takao Aoyama, Koujirou Yamamoto, Hajime Kotaki, Yasufumi Sawada, Tatsuji Iga

ABSTRACT

Purpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed.Methods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis.Results. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model.Conclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine. More... »

PAGES

1601-1606

Identifiers

URI

http://scigraph.springernature.com/pub.10.1023/a:1012186519946

DOI

http://dx.doi.org/10.1023/a:1012186519946

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1046769279

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/9434281


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