Sigma receptors are unique proteins located in many areas of the body, including the brain and the heart, which are target organs for the actions of cocaine. The research team interfered with cocaine's access to sigma receptors by treating mice with antagonists or antisense oligodeoxynucleotides. An antagonist is a chemical compound that competes with drugs such as cocaine for occupancy of the receptor. Antisense oligodeoxynucleotides reduce the number of receptors in the body by decreaseing the formation of new receptors. When old receptors are degraded, they are not replaced.
The researchers showed that when mice were treated with sigma receptor antagonists and then exposed to cocaine, they were less likely to experience the toxic effects of the drug. The effectiveness of the antagonists in preventing the toxic effects of cocaine appears related to their ability to interact with sigma receptors, rather than dopamine transporters. Additionally, the hyperactivity produced by cocaine was reduced in mice when they received antagonist treatments, showing a reduced sensitivity to the stimulant effects of cocaine.
When the researchers treated mice with antisense oligodeoxynucleotides to reduce the number of sigma receptors in the brain, the animals were much less responsive to cocaine. When exposed to cocaine, antisense-treated mice exhibited behaviors similar to placebo-exposed mice, instead of toxic or locomotor stimulant effects.
The result with either strategy (antagonist or antisense oligodeoxynucleotide) is a reduction in sites in the body through which cocaine can produce its actions.
A similar relationship between cocaine and sigma receptors was demonstrated in a separate study in which mice were administered a series of rimcazole analogs that were synthesized in the laboratory of Dr. Amy Newman at the National Institute on Drug Abuse Intramural Research Program. After cocaine exposure, mice were observed for the loss of the ability to right themselves and to control movements. The compounds were shown to attenuate the effects of cocaine through sigma receptors. When the compounds were ranked according to their effectiveness, there was a significant correlation between their protective effects and their affinities for sigma receptors, rather than dopamine transporters.
WHAT IT MEANS: These findings indicate that sigma receptors may mediate some of the toxic and behavioral effects of cocaine. Sigma receptor antagonists may be possible pharmacotherapeutic agents for treating cocaine abuse.
These studies were published by Dr. Matsumoto and colleagues in the June 2002 and the November 2001 issues of Neuropharmacology.