Chapter Nine - Sigma (σ) Receptors as Potential Therapeutic Targets to Mitigate Psychostimulant Effects

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Abstract

Many psychostimulants, including cocaine and methamphetamine, interact with sigma (σ) receptors at physiologically relevant concentrations. The potential therapeutic relevance of this interaction is underscored by the ability to selectively target σ receptors to mitigate many behavioral and physiological effects of psychostimulants in animal and cell-based model systems. This chapter begins with an overview of these enigmatic proteins. Provocative preclinical data showing that σ ligands modulate an array of cocaine and methamphetamine effects are summarized, along with emerging areas of research. Together, the literature suggests targeting of σ receptors as an innovative option for combating undesired actions of psychostimulants through both neuronal and glial mechanisms.

Introduction

Sigma (σ) receptors have been proposed as therapeutic targets for many central nervous system (CNS) disorders, consistent with their high concentrations in the brain and spinal cord (Fishback et al., 2010, Hayashi et al., 2011, Kourrich et al., 2012, Zamanillo et al., 2013). It has been recognized since the 1980s that many classes of CNS medications such as antipsychotics, antidepressants, and dissociative anesthetics interact with these proteins (Su, 1982, Tam, 1983, Tam and Cook, 1984), although the cellular mechanisms and pathways through which σ ligands convey therapeutic benefits are only now beginning to be illuminated.

The significant affinity of many drugs of abuse, including cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, phencyclidine (PCP), and some opiates for σ receptors, raises the intriguing possibility that interactions with these proteins may serve as common targets for abused substances (Brammer et al., 2006, Matsumoto, 2009, Sharkey et al., 1988, Weber et al., 1986). Through these interactions, σ receptors are believed to convey and modulate some of the physiological and behavioral effects of abused substances and serve as potential therapeutic targets for mitigating their effects. This chapter focuses on the psychostimulants cocaine and methamphetamine, which are among the best studied drugs of abuse with regard to interactions with σ receptors.

The chapter begins with an overview of σ receptors, from a historical perspective to our contemporary understanding of these enigmatic proteins. Then, preclinical data with regard to their implications for cocaine and methamphetamine are addressed, and the chapter concludes with our clinical knowledge of this class of compounds.

Section snippets

Historical perspective

σ Receptors were first proposed as a type of opiate receptor based on the actions of (±)-SKF10,047 (N-allylnormetazocine) and related benzomorphans, with the name originating from the first letter “S” in SKF10,047, which was thought to be the prototypic ligand for this subtype (Martin, Eades, Thompson, Huppler, & Gilbert, 1976). Studies since then have shown that SKF10,047 interacts with at least three distinct binding sites: the kappa opioid receptor, the PCP binding site within the ionophore

Background

Cocaine continues to be among the most abused illicit substances. It is responsible for more serious intoxications and emergency room mentions than any other illicit drug (Substance Abuse & Health Services Administration, 2008). In the United States, it is estimated that over 36 million Americans have used cocaine at least once and that nearly 2 million individuals consider themselves current users of the drug (Substance Abuse & Health Services Administration, 2009).

Cocaine interacts with

Background

Among the psychostimulants, methamphetamine distinguishes itself as one of the most abused substances worldwide (United Nations Office on Drugs, 2010). In the United States, over 12 million Americans have used methamphetamine at least once in their life (Substance Abuse & Health Services Administration, 2009), and there are roughly 16 million users of methamphetamine worldwide, a number which exceeds that of combined heroin and cocaine users (United Nations Office on Drugs, 2010). In 2005, an

Clinical Implications

No selective σ receptor ligands are currently approved by the FDA for use in humans. Thus, this section summarizes efforts to repurpose nonselective medications with σ affinity for psychostimulant applications, efforts to develop more selective σ ligands for clinical use, and efforts to develop selective σ ligands as suitable CNS imaging agents.

Conclusion

The ability of psychostimulants such as cocaine and methamphetamine to interact with σ receptors provides a viable target for the discovery and development of new therapeutic and diagnostic tools. Preclinical studies to date demonstrate that σ receptor antagonists can mitigate many psychostimulant-induced changes in behavior and gene and protein expression. On the other hand, σ receptor agonists may have potential as replacement therapies to reduce drug taking and craving and to improve

Conflict of Interest

R. M. is a consultant and contract recipient for Avanir Pharmaceuticals for her expertise on σ receptors; none of the research related to her work for Avanir Pharmaceuticals is described in this chapter. N. K. is an employee of Takeda Pharmaceuticals. Her contribution to the work described herein represents her Ph.D. research on a topic distinct from her responsibilities at Takeda. The authors have no other potential conflicts of interest to declare.

Acknowledgments

Some of the research described herein was supported by the National Institute on Drug Abuse (DA017756, DA011979, DA013978, and DA023205). We appreciate the expert technical assistance of Buddy Pouw and Joshua Blyden for generating the data on cocaine metabolites. We also appreciate the contributions of Ashley Brandebura in preparing the tables.

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    Current address: Takeda Pharmaceuticals, San Diego, California, USA

    3

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