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

100 Review article A role for sigma receptors in stimulant self-administration and addiction Jonathan L. Katza, Weimin C. Honga, Takato Hiranitaa and Tsung-Ping Sub Sigma-1 receptors (σ1Rs) are structurally unique combination with dopamine uptake inhibitors, an effective intracellular proteins that function as chaperones. σ1Rs and specific blockade of stimulant self-administration is translocate from the mitochondria-associated membrane to obtained. Actions of stimulant drugs related to their abuse other subcellular compartments, and can influence a host of induce unique changes in σR activity and the changes targets, including ion channels, G-protein-coupled induced potentially create redundant and, once established, receptors, lipids, and other signaling proteins. Drugs binding independent reinforcement pathways. Concomitant to σRs can induce or block the actions of σRs. Studies targeting of both dopaminergic pathways and σR proteins indicate that stimulant self-administration induces the produces a selective antagonism of stimulant self- reinforcing effects of σR agonists, because of dopamine administration, suggesting new avenues for combination transporter actions. Once established, the reinforcing chemotherapies to specifically combat effects of σR agonists are independent of dopaminergic stimulant abuse. Behavioural Pharmacology 27:100–115 mechanisms traditionally thought to be critical to the Copyright © 2016 Wolters Kluwer Health, Inc. All rights reinforcing effects of stimulants. Self-administered doses of reserved. σR agonists do not increase dopamine concentrations in the Behavioural Pharmacology 2016, 27:100–115 nucleus accumbens shell, a transmitter and brain region considered important for the reinforcing effects of abused Keywords: chaperone protein, cocaine, drug abuse, methamphetamine, reinforcing effects, self-administration, sigma receptors drugs. However, self-administration of σR agonists is blocked by σR antagonists. Several effects of stimulants aPsychobiology and bCellular Pathobiology Sections, Intramural Research Program, Department of Health and Human Services, National Institute on Drug have been blocked by σR antagonists, including the Abuse, National Institutes of Health, Baltimore, Maryland, USA reinforcing effects, assessed by a place-conditioning Correspondence to Jonathan L. Katz, Psychobiology Section, Intramural Research procedure. However, the self-administration of stimulants is Program, Department of Health and Human Services, National Institute on Drug largely unaffected by σR antagonists, indicating Abuse, National Institutes of Health, Baltimore, MD 21224, USA E-mail: [email protected] fundamental differences in the mechanisms underlying these two procedures used to assess the reinforcing Received 9 July 2015 Accepted as revised 16 November 2015 effects. When σR antagonists are administered in Introduction the spinal dog preparation. The prototype agonist for The present paper focuses on the involvement of sigma these effects was the benzomorphan derivative, SKF receptors (σRs) in psychomotor stimulant abuse and the 10,047. Subsequent studies of the pharmacology of SKF potential of the plasticity of these receptors to be 10,047 indicated differences in the pharmacology of its involved in changes that occur with long-term use that enantiomers, and that the psychotomimetic effects of are the basis for phenomena that come under the SKF 10,047 were not antagonized by the opioid-receptor umbrella of the term ‘addiction’. There have been a antagonist, naloxone (Vaupel, 1983). Confusion with number of excellent comprehensive and recent reviews regard to the pharmacology of various putative σR that have focused more broadly on σRs (e.g. Maurice and ligands, including SKF 10,047, resulted from affinity for Su, 2009; Zamanillo et al., 2012), as well as a number of the 1-(1-phenylcyclohexyl)piperidine (PCP) binding site previous reviews on the behavioral effects of various within the N-methyl-D-aspartate (NMDA) glutamate ligands for the σR (e.g. Leonard, 2004; Skuza and receptor complex (Quirion et al., 1987) and similar Wedzony, 2004). The interested reader is referred to behavioral effects of putative σR drugs and PCP those papers for a more comprehensive overview and an (Holtzman, 1982). The subsequent identification and introduction to the literature on the behavioral pharma- characterization of more selective ligands, including cology of σRs. dizocilpine for the PCP site (Wong et al., 1986) and 1,3 di- o-tolylguanidine (DTG) for sigma sites (Weber et al., The scientific literature on σRs traces back to the pro- 1986), allowed for pharmacological identification of σR posal by Martin et al. (1976) that σRs were a subtype of sites that were unique compared with other known opioid receptors that were responsible for the ‘psycho- binding sites in the central nervous system (see tomimetic’ effects of various opioid agonists observed in Matsumoto et al., 2007 for a review). 0955-8810 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FBP.0000000000000209 Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved. σRs in stimulant self-administration and addiction Katz et al. 101 Pharmacological and molecular studies have dis- an endogenous ligand for σ1Rs (Fontanilla et al., 2009). tinguished two subtypes of σRs. The σ1R has been Drugs identified as σ1R agonists induce dissociation of cloned and characterized as a 25 kDa single polypeptide σ1Rs and BiP (Hayashi and Su, 2007a, 2007b; Hayashi having no homology with any other known mammalian et al., 2011). In addition, ligands that can block the effects protein. Recent studies have indicated that σ1Rs are of those compounds that induce chaperone actions in an expressed throughout the CNS and have been implicated agonist–antagonist manner exist (Hayashi and Su, 2007a, in a variety of physiological functions and disease states 2007b; Hayashi et al., 2011; Fig. 1). σ – (Maurice and Su, 2009). The 2R, an 18 21 kDa protein, σ was first proposed on the basis of photoaffinity labeling One major locus of 1R clustering is a subdomain of the studies using a DTG analog (Hellewell and Bowen, ER that is associated with mitochondria [mitochondria- 1990). Recently, progesterone receptor membrane associated ER membrane (MAM); Hayashi and Su, 2007a, 2007b; Fig. 1]. At the MAM, the ER directly component-1 was identified as the potential molecular 2 + entity of σ2R (Xu et al., 2011). Although there is ongoing provides Ca to the mitochondria through IP3 receptors debate on the bona fide identity of the σ2R (Ruoho, and transports phospholipids and sterols to the mito- et al. 2 + 2013), this finding will significantly drive further chondria (Hayashi , 2009). The Ca provided to the explorations on the identity and physiological function of mitochondria activates the tricarboxylic acid cycle and et al. σ σ2Rs. ATP synthesis (Rizzuto , 1999). 1Rs chaperoning IP3 receptors at the MAM enhance Ca2 + influx from the Current understanding of sigma-1 receptors: MAM to the mitochondria (Hayashi and Su, 2007a, structure, molecular function, and subcellular 2007b), thus likely regulating mitochondrial bioener- distribution getics and generation of reactive oxygen species (ROS; The σ1R is predominantly expressed at the endoplasmic Fig. 1). reticulum (ER) and is an integral membrane protein with Other loci of σ1R clustering are the thin layers of ER N two transmembrane domains at the -terminus and the cisternae adjacent to the postsynaptic plasma membranes center of the protein (Hayashi and Su, 2007a, 2007b). of ventral horn spinal motor neurons (Mavlyutov et al., σ The 1R shares no homology with any mammalian pro- 2010). The postsynaptic clusters of σ1Rs are specific to – tein, but it shares 30% identity with a yeast C8 C7 sterol cholinergic synapses (Mavlyutov et al., 2010). Thus, in et al. isomerase (Hanner , 1996). The second transmem- specific neuron types, σ1Rs are constitutively expressed σ brane domain of the 1R shares over 80% identity with at the ER subdomains opposing the plasma membrane the sterol-binding pocket of sterol isomerase (Hanner (Fig. 1). Similar plasma membrane clustering of σ1Rs was et al. σ , 1996), supporting the hypothesis that the 1R observed in living NG108 neuroblastoma × glioma hybrid is a sterol-binding protein utilizing the membrane- cells when enhanced yellow fluorescent protein-tagged embedded domain for association with lipid ligands. σ1Rs were expressed (Hayashi and Su, 2007a, 2007b). The C-terminus of σ1R has chaperone activity that pre- vents protein aggregation (Hayashi and Su, 2007a, 2007b). It has been suggested that the chaperone domain Sigma-1 receptor regulation of plasma resides in the lumen of the ER, stabilizing ER lumenal or membrane proteins membrane proteins (Hayashi and Su, 2007a, 2007b). The The elucidation of the molecular mechanism by which σ chaperone activity of 1Rs is regulated by a direct σ1Rs regulate plasma membrane events is expanding as – protein protein interaction with binding immunoglobu- various novel roles for σ1R regulation of G-protein-cou- lin protein/78 kDa glucose-regulated protein (BiP/ pled receptors (GPCRs) and ion channels (Aydar et al., GRP-78), another ER chaperone (Hayashi and Su, 2007a, et al. σ 2 + 2002; Navarro , 2010) are documented. 1Rs toni- 2007b; Fig. 1). Depletion of Ca in the ER or activation cally regulate the activity of potassium, NMDA, and of Inositol trisphosphate (IP3) receptors through Gq- sodium channels (Aydar et al., 2002; Martina et al.,

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