Involvement of sigma (sigma) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies.
Methamphetamine interacts with sigma (sigma) receptors, suggesting that the drug produces some of its physiological and behavioral effects through these sites. Therefore, in the present report, receptor binding and pharmacological studies were performed to characterize the interaction between methamphetamine and sigma receptors. Of the two major sigma receptor subtypes, sigma1 and sigma2, competition binding studies showed that methamphetamine has a 22-fold preferential affinity for the sigma1 subtype. Saturation binding studies using the sigma1 selective radioligand [3H]+-pentazocine showed that in the presence of methamphetamine, there was a significant change in Kd, but not Bmax, suggesting competitive interactions. In behavioral studies, pretreatment of Swiss Webster mice with the sigma1 receptor antagonists, BD1063 or BD1047, significantly attenuated the locomotor stimulatory effects of methamphetamine. Mice that were administered an antisense oligodeoxynucleotide to down-regulate brain sigma1 receptors also exhibited a reduced locomotor stimulatory response to methamphetamine, as compared to control mice receiving mismatch oligonucleotides. Together, the data suggest that sigma1 receptors are involved in the acute actions of methamphetamine and that antagonism of this subtype is sufficient to prevent the locomotor stimulatory effects of methamphetamine.
Nguyen
Emily C
EC
Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK 73190, USA.
McCracken
Kari A
KA
Liu
Yun
Y
Pouw
Buddy
B
Matsumoto
Rae R
RR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D007700:Kinetics; D008297:Male; D008694:Methamphetamine / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D000097605:Sigma-1 Receptor
D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D020319:Oligodeoxyribonucleotides, Antisense; D010879:Piperazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C106107:sigma-2 receptor