Peroxisome proliferator-activated receptor gamma activation relieves expression of behavioral sensitization to methamphetamine in mice.
Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcriptional factor that regulates lipid metabolism and inflammation. Behavioral sensitization is an experimental model of psychostimulant psychosis; it is elicited by repeated administration of psychostimulants and has recently been implicated in brain inflammation. We examined the involvement of PPARgamma, one of the isotypes of PPAR, in development of behavioral sensitization to the stimulant effect of methamphetamine (METH) (1 mg/kg, subcutaneously) in mice. Repeated administration of METH (once daily for 5 days) enhanced the locomotor-activating effect of METH, which was reproduced by METH challenge on withdrawal day 7 (test day 12). The protein level and the activity of PPARgamma were significantly increased in the nuclear fraction of whole brain after 5 days of METH administration (test day 5) and on withdrawal day 7 (test day 12). Both pioglitazone and ciglitazone (PPARgamma agonists; 0.5-5.0 microg, intracerebroventricularly (i.c.v.), once daily) prevented the expression of behavioral sensitization to METH challenge on withdrawal day 7, but not the sensitization that occurred during repeated administration of METH. In addition, the magnitude of expression of behavioral sensitization was augmented by treatments with GW9662 (a PPARgamma antagonist; 0.5-5.0 microg i.c.v., once daily) during the withdrawal period. The pioglitazone-induced alleviation of behavioral sensitization was synergistically facilitated by simultaneous i.c.v. injection of 9-cis-retinoic acid (1.0 microg), an agonist for the retinoid X receptor which is a ligand-activated nuclear receptor that forms heterodimers with PPAR. These results suggest that PPARgamma has a significant role in the expression of behavioral sensitization to METH in mice.
Maeda
Takehiko
T
Department of Pharmacology, Wakayama Medical University, Wakayama, Japan. tmaeda@wakayama-med.ac.jp
Kiguchi
Norikazu
N
Fukazawa
Yohji
Y
Yamamoto
Akihiro
A
Ozaki
Masanobu
M
Kishioka
Shiroh
S
D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077205:Pioglitazone; D011605:Psychoses, Substance-Induced / Q000188:drug therapy / Q000503:physiopathology*; D047488:Retinoid X Receptors / Q000819:agonists / Q000378:metabolism; D012201:Reward; D045162:Thiazolidinediones / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018765:Dopamine Uptake Inhibitors; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D008694:Methamphetamine; D000077205:Pioglitazone