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Sigma Proteins: Evolution of the Concept of Sigma Receptors pp 177–218Cite as

A Role for Sigma Receptors in Stimulant Self-Administration and Addiction

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 244))

Abstract

Sigma receptors (σRs) are structurally unique proteins that function intracellularly as chaperones. Historically, σRs have been implicated as modulators of psychomotor stimulant effects and have at times been proposed as potential avenues for modifying stimulant abuse. However, the influence of ligands for σRs on the effects of stimulants, such as cocaine or methamphetamine, in various preclinical procedures related to drug abuse has been varied. The present paper reviews the effects of σR agonists and antagonists in three particularly relevant procedures: stimulant discrimination, place conditioning, and self-administration. The literature to date suggests limited σR involvement in the discriminative-stimulus effects of psychomotor stimulants, either with σR agonists substituting for the stimulant or with σR antagonists blocking stimulant effects. In contrast, studies of place conditioning suggest that administration of σR antagonists or down-regulation of σR protein can block the place conditioning induced by stimulants. Despite place conditioning results, selective σR antagonists are inactive in blocking the self-administration of stimulants. However, compounds binding to the dopamine transporter and blocking σRs can selectively decrease stimulant self-administration. Further, after self-administration of stimulants, σR agonists are self-administered, an effect not seen in subjects without that specific history. These findings suggest that stimulants induce unique changes in σR activity, and once established, the changes induced create redundant, and dopamine independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of those pathways, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

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Notes

  1. 1.

    The designation of σR ligands as agonists or antagonists stems from initial conceptions of these proteins as G-protein coupled receptors. As the understanding of these proteins has evolved and it has become clear that they function as intracellular chaperones, there remain observations that ligands for these proteins have different effects and some can block the actions of others (Hayashi and Su 2007; Katz et al. 2016). Most of the designations of these ligands as agonists or antagonists are less than definitive and accrue from in vivo observations that might not meet the strictest pharmacological standards. Absent more definitive results we will designate compounds as agonists or antagonists according to common usage within the scientific community. Complicating the picture are studies indicating subtypes of σRs. Where necessary in discussions herein we use designations of σR subtype selectivity based on radioligand binding results which are shown in Table 1.

    Table 1 Affinities of various compounds in specifically binding to σ1, or σ2 receptors, as well as subtype selectivity
    Full size table
  2. 2.

    Full explanations and in-depth analyses of conditioning processes involved in the various behavioral procedures described in this chapter may be found in Catania (2013).

  3. 3.

    In some instances, there is a third, middle, compartment in which subjects are placed at the start of sessions. Time spent in this starting compartment is not typically considered, as the critical variable is time spent in the drug-paired compartment.

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Acknowledgments

Funding for the experiments originating in our laboratories was provided by the National Institute on Drug Abuse (NIDA) Intramural Research Program and by grants from the National Institute on Drug Abuse [Grant DA023205] and the National Institute of General Medical Sciences [Grant GM104932] to Christopher R. McCurdy. Takato Hiranita was supported in part by the NIDA IRP and by a fellowship from the Japan Society for the Promotion of Science. Weimin C. Hong was supported by startup funds from Butler University.

Subjects used in the studies published from the NIDA Intramural Research Program were maintained in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care, and those experiments were conducted in accordance with the guidelines of the institute’s Animal Care and Use Committee.

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Authors and Affiliations

  1. Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA

    Jonathan L. Katz, Takato Hiranita & Martin O. Job

  2. Department of Pharmaceutical Sciences, Butler University, Indianapolis, IN, 46208, USA

    Weimin C. Hong

  3. Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA

    Christopher R. McCurdy

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  1. Jonathan L. Katz
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  2. Takato Hiranita
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  3. Weimin C. Hong
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  4. Martin O. Job
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  5. Christopher R. McCurdy
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Corresponding author

Correspondence to Jonathan L. Katz .

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Editors and Affiliations

  1. Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

    Felix J. Kim

  2. Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Gavril W. Pasternak

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Katz, J.L., Hiranita, T., Hong, W.C., Job, M.O., McCurdy, C.R. (2016). A Role for Sigma Receptors in Stimulant Self-Administration and Addiction. In: Kim, F., Pasternak, G. (eds) Sigma Proteins: Evolution of the Concept of Sigma Receptors. Handbook of Experimental Pharmacology, vol 244. Springer, Cham. https://doi.org/10.1007/164_2016_94

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