Targeting sigma receptors: novel medication development for drug abuse and addiction

Abstract

Psychostimulant abuse is a serious health and societal problem in industrialized and developing countries. However, the identification of an effective pharmacotherapy to treat it has remained elusive. It has long been known that many psychostimulant drugs, including cocaine and methamphetamine, interact with sigma receptors in the brain and heart, offering a logical target for medication development efforts. However, selective pharmacological agents and molecular biological tools have only recently become available to rigorously evaluate these receptors as viable medication development targets. The current review will summarize provocative preclinical data, demonstrating the ability of sigma receptor antagonists and antisense oligonucleotides to ameliorate cocaine-induced convulsions, lethality, locomotor activity and sensitization, and conditioned place-preference in rodents. Recent studies suggest that the protective effects of sigma receptor antagonists also extend to actions produced by methamphetamine, 3,4-methylenedioxymethamphetamine, ethanol and other abused substances. Together, the data indicate that targeting sigma receptors, particularly the σ₁-subtype, may offer an innovative approach for combating the effects of cocaine, and perhaps other abused substances.

Keywords::

• cocaine
• ethanol
• MDMA
• methamphetamine
• morphine
• phencyclidine
• sigma receptors

Financial & competing interest disclosure

Some of the work described herein was supported by NIH grants DA017756, DA011979, DA013978 and DA023205 from the National Institute on Drug Abuse. US patent application number 60/956,249 and international patent application number PCT/US08/73478 have been filed in relation to some of the work described herein. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript