title: A Role for Sigma Receptors in Stimulant Self-Administration and Addiction.
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.
authors.affiliation: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA. jkatz@intra.nida.nih.gov.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
authors.affiliation: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA.
authors.forename: Takato
authors.initials: T
authors.lastname: Hiranita
authors.affiliation: Department of Pharmaceutical Sciences, Butler University, Indianapolis, IN, 46208, USA.
authors.forename: Weimin C
authors.initials: WC
authors.lastname: Hong
authors.affiliation: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Job
authors.affiliation: Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS, 38677, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D004192:Discrimination, Psychological / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D055030:Drug Users / Q000523:psychology*; D006801:Humans; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration; D015398:Signal Transduction; D019966:Substance-Related Disorders / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D017480:Receptors, sigma
keywords: Chaperone protein; Cocaine; Drug abuse; Methamphetamine; Reinforcing effects; Self-administration; Sigma receptor (σR)