Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats.
Exposure to methamphetamine causes behavioral sensitization in experimental animals. However, the precise mechanism of this behavioral sensitization has not yet been fully elucidated. Accordingly, we evaluated the pharmacokinetic properties of methamphetamine in rats behaviorally sensitized to methamphetamine following its repeated administration (6 mg/kg, i.p., once a day for 5 days followed by a 21-day drug abstinence period). In the sensitized rats, methamphetamine (0.8 mg/kg)-induced locomotor activity was significantly enhanced, suggesting the successful establishment of behavioral sensitization to methamphetamine. Significant increases in the concentrations of methamphetamine in plasma and brain dialysate, as well as the delayed disappearance of methamphetamine from plasma, were observed in the sensitized rats after intravenous injection of methamphetamine (5 mg/kg). The tissue to plasma concentration ratio (Kp) of methamphetamine in lung and heart decreased in the sensitized rats. The renal excretion of methamphetamine, which is sensitive to several cations, was also decreased in the sensitized rats. Moreover, in the sensitized rats, the expression of organic cation transporter 3 (OCT3) mRNA was decreased in kidney, brain and heart as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Taken together, these results suggest that the behavioral outcome of sensitization to methamphetamine might, in part, be due to the increased levels of methamphetamine in plasma and brain extracellular areas, as well as an altered tissue distribution of methamphetamine associated with changes in the cation transport system.
Kitaichi
Kiyoyuki
K
Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, 461-8673, Nagoya, Japan.
Morishita
Yuki
Y
Doi
Yuko
Y
Ueyama
Jun
J
Matsushima
Miyoko
M
Zhao
Ying-Lan
YL
Takagi
Kenzo
K
Hasegawa
Takaaki
T
D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism*; D002331:Carnitine / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D002927:Cimetidine / Q000494:pharmacology; D015314:Dialysis Solutions / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008657:Metabolic Clearance Rate; D008694:Methamphetamine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D009043:Motor Activity / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074058:Solute Carrier Family 22 Member 5; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution; D010130:p-Aminohippuric Acid / Q000494:pharmacology
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D015314:Dialysis Solutions; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D008694:Methamphetamine; D019789:Tetraethylammonium; D002927:Cimetidine; D002331:Carnitine; D010130:p-Aminohippuric Acid