Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides.
Pharmacological and molecular biological tools were used to validate the involvement of sigma receptors in the actions of cocaine. Radioligand binding studies demonstrated significant levels of sigma receptors in the brain and heart, where cocaine interacts preferentially with the sigma(1) subtype. In behavioral pharmacological studies using mice, nine novel sigma receptor antagonists significantly attenuated cocaine-induced convulsions, while structural analogs with weak interactions with sigma receptors were ineffective. In contrast to the protection provided by the antagonists, a classical sigma receptor agonist exacerbated the convulsive effects of cocaine. The antagonists also attenuated cocaine-induced lethality, with the best compound protecting against death even when administered as a post-treatment. At doses where the antagonists had no effect on baseline locomotor activity, they significantly attenuated the locomotor stimulatory effects of cocaine, suggesting their ability to block the psychomotor as well as the toxic effects of cocaine. To further validate that the anti-cocaine effects were achieved by interfering with cocaine's access to sigma receptors, antisense oligodeoxynucleotides against sigma(1) receptors were shown to attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the studies support the involvement of sigma receptors, particularly the sigma(1) subtype, in the behavioral effects of cocaine.
Department of Pharmaceutical Sciences, P.O. Box 26901, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. rae-matsumoto@ouhsc.edu
Rae R
RR
Matsumoto
Kari A
KA
McCracken
Buddy
B
Pouw
Ying
Y
Zhang
Wayne D
WD
Bowen
D000818:Animals; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism
D005021:Ethylamines; D008024:Ligands; D020319:Oligodeoxyribonucleotides, Antisense; D011759:Pyrrolidines; D017480:Receptors, sigma; C085527:BD 1008; D003042:Cocaine