The role of the cannabinoid type 1 receptor and down-stream cAMP/DARPP-32 signal in the nucleus accumbens of methamphetamine-sensitized rats.
Blockade of the cannabinoid type 1 (CB(1)) receptor could suppress methamphetamine self-administration; however, the cellular mechanism remains unclear. In this study, we intended to investigate the significance of brain CB(1) receptors on the development of behavioral sensitization to methamphetamine. Male Sprague-Dawley rats treated with chronic methamphetamine (4 mg/kg, i.p.) for either 7 or 14 days developed behavioral sensitization to methamphetamine (1 mg/kg) at withdrawal day 7. A progressive decrease in numbers of CB(1) receptor (both Bmax and mRNA) but increase in binding affinity (Kd) was noticed during withdrawal days 3 to 7. Microinjection of CB(1) antagonist [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] into the nucleus accumbens (NAc) at withdrawal day 7, significantly suppressed the behavioral sensitization to methamphetamine. In NAc brain slices preparation, acute incubation with CB(1) agonist (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP 55940) dose-dependently enhanced cAMP accumulation in sensitized rats; no change was noticed in control groups. Consequently, treatment of CP 55940 induced a dose-dependent (10 nmol/L-10 micromol/L) phosphorylation on down-stream dopamine and cAMP-regulated phosphoprotein of Mr 32 000 (DARPP-32)/Thr34 in sensitized rats, while only 10 micromol/L CP 55940 was able to enhance the phosphoDARPP-32/T34 in control groups. Alternatively, both basal activity of calcineurin (PP-2B) and CP 55940-induced changes in the amount of PP-2B in the NAc were both decreased in sensitized rats, but not in controls. Overall, we demonstrated that brain CB(1) receptor and its down-stream cAMP/DARPP-32/T34/PP-2B signaling are profoundly altered in methamphetamine-sensitized animals.
Chiang
Yao-Chang
YC
Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Chang-Gung University and Molecular Imaging Center, Chang Gung Hospital, Kwei-Shan, Tao-Yuan, Taiwan, Republic of China.
Chen
Jin-Chung
JC
D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003511:Cyclohexanols / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology
D003511:Cyclohexanols; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D008694:Methamphetamine; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP; D019703:Calcineurin