Document Detail


The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats.
MedLine Citation:
PMID:  17988657     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Organic cation transporter-3 (OCT3) is expressed in several tissues including the brain. We have previously demonstrated that rats with behavioral sensitization to methamphetamine (METH) increased the brain penetration of METH with decreased expression of OCT3 in brain. Considering the earlier in vitro studies demonstrating that 1) OCT3 could transport dopamine (DA) and 2) the specific transport via OCT3 could be inhibited by METH, these results suggest that decreased OCT3 might decrease the efflux of METH and/or DA from brain, subsequently causing the development of behavioral sensitization. Thus, in the present study, behavioral task related to DA and pharmacokinetic experiment were performed using rats treated with antisense against OCT3 (OCT3-AS) since no specific ligands for OCT3 are still available. The continuous infusion of OCT3-AS into the third ventricle significantly decreased the expression of OCT3 in choroid plexus (CP) epithelial cells. Both METH-induced hyperlocomotion and METH-induced extracellular DA levels in nucleus accumbens and prefrontal cortex were significantly increased in OCT3-AS-treated rats. Moreover, the concentrations of METH were significantly increased in cerebrospinal fluid as well as extracellular areas at the nucleus accumbens in OCT3-AS-treated rats. These results suggested that decreased OCT3 elevated the concentration of METH and/or DA in brain, subsequently enhancing dopaminergic neuronal transmission and increasing METH-induced hyperlocomotion. In summary, OCT3 at the CP could regulate the effect of METH by controlling the levels of METH and/or DA in brain. Thus, these results suggest that OCT3 may be a new molecular target to treat METH-related disorders such as drug abuse and schizophrenia.
Authors:
Hironao Nakayama; Kiyoyuki Kitaichi; Yukiko Ito; Katsunori Hashimoto; Kenji Takagi; Toyoharu Yokoi; Kenzo Takagi; Norio Ozaki; Tuneyuki Yamamoto; Takaaki Hasegawa
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-10-06
Journal Detail:
Title:  Brain research     Volume:  1184     ISSN:  0006-8993     ISO Abbreviation:  Brain Res.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-06     Completed Date:  2008-04-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0045503     Medline TA:  Brain Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  260-9     Citation Subset:  IM    
Affiliation:
Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Animals
Behavior, Animal / drug effects*
Central Nervous System Stimulants / metabolism*,  pharmacology*
Dopamine / metabolism
Male
Methamphetamine / metabolism*,  pharmacology*
Motor Activity / drug effects
Nucleus Accumbens / drug effects,  metabolism
Oligonucleotides, Antisense / pharmacology
Organic Anion Transporters, Sodium-Independent / physiology*
Prefrontal Cortex / drug effects,  metabolism
Rats
Rats, Wistar
Time Factors
Chemical
Reg. No./Substance:
0/Central Nervous System Stimulants; 0/Oligonucleotides, Antisense; 0/Organic Anion Transporters, Sodium-Independent; 0/organic anion transport protein 3; 537-46-2/Methamphetamine

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