The Sigma-1 Receptor As a Regulator of Dopamine Neurotransmission: a Potential Therapeutic Target for Methamphetamine Addiction

JPT-07178; No of Pages 16 Pharmacology & Therapeutics xxx (2018) xxx–xxx

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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction

Danielle O. Sambo, Joseph J. Lebowitz, Habibeh Khoshbouei ⁎

University of Florida, College of Medicine, Department of Neuroscience, Gainesville, FL 32611, United States article info abstract

Keywords: Methamphetamine (METH) abuse is a major public health issue around the world, yet there are currently Sigma-1 receptor no effective pharmacotherapies for the treatment of METH addiction. METH is a potent psychostimulant that Dopamine increases extracellular dopamine levels by targeting the dopamine transporter (DAT) and alters neuronal Dopamine transporter activity in the reward centers of the brain. One promising therapeutic target for the treatment of METH addiction Methamphetamine is the sigma-1 receptor (σ1R). The σ1R is an endoplasmic reticulum-localized chaperone protein that is activated by cellular stress, and, unique to this chaperone, its function can also be induced or inhibited by different ligands.

Upon activation of this unique “chaperone receptor”,theσ1R regulates a variety of cellular functions and pos-

sesses neuroprotective activity in the brain. Interestingly, a variety of σ1R ligands modulate dopamine neurotrans-

mission and reduce the behavioral effects of METH in animal models of addictive behavior, suggesting that the σ1R may be a viable therapeutic target for the treatment of METH addiction. In this review, we provide background on

METH and the σ1R as well as a literature review regarding the role of σ1Rs in modulating both dopamine neuro-

transmission and the effects of METH. We aim to highlight the complexities of σ1R pharmacology and function as

Contents

1. Introduction...... 0 2. Methamphetamine...... 0 3. Sigma-1receptor...... 0 4. Sigma-1receptorandthedopaminergicsystem...... 0 5. Sigma-1receptorandmethamphetamine...... 0 6. Discussion...... 0 Conﬂictofintereststatement...... 0 References...... 0

1. Introduction up to 35 million people use amphetamine-type stimulants (ATSs) worldwide (Salamanca, Sorrentino, Nosanchuk, & Martinez, 2014). Methamphetamine (METH) is one of the most commonly used Although there have been clinical trials for drugs targeting the dopami- illicit drugs in the world (Krasnova & Cadet, 2009), with reports that nergic, serotonergic, and opioid systems (Karila et al., 2010), there are

Abbreviations: AC927, 1-(2-phenylethyl)piperidine; AMPH, amphetamine; ATS, amphetamine-type stimulants; AZ66, 3-(4-(4-cyclohexylpiperazin-1-yl)pentyl)-6- flourobenzo(Abadias et al., 2013)thiazol-2(3H)-one; BD1008, N-(Brammer et al., 2006)-N-methyl-1-pyrrolidineethanamine; BD1047, N-(Brammer et al., 2006)-N-methyl-2- (dimethylamino)ethylamine; BD1063, 1-(Jones et al., 1998)-4-methylpiperazine; BiP, Binding immunoglobulin Protein; BMY 14802, alpha-(4-fluorophenyl)-4-(5-fluoro-2- pyrimidinyl)-1-piperazine-butanol; CM156, 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione; CPP, conditioned place preference; DA, dopamine; DAT, dopamine transporter; DMT, N,N-dimethyltryptamine; DTG, 1,3-di-O-tolylguanidine; MDMA, methylenedioxy-methamphetamine; METH, methamphetamine; MS-377, (R)-(+)-1-(4- chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl2-pyrrolidinone L-tartrate; NE-100, 4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine; NMDA, N-methyl-D- aspartate; PCP, phencyclidine; PD, Parkinson's disease; PKC, protein kinase C; PRE-084, 2-(4-Morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride; SA4503, 1-(3,4- dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride; SKF-10,047, N-allylnormetazocine ((−)-ANMC); SN, substantia nigra; VMAT2, vesicular monoamine transporter-2; VTA, ventral tegmental area; σ1R, sigma-1 receptor; σ2R, sigma-2 receptor. ⁎ Corresponding author at: 1149 S Newell Drive Bldg 59, PO Box 100244, Gainesville, FL 32611, United States. E-mail address: Habibeh@ufl.edu (H. Khoshbouei).

Two isoforms of σRs are known to exist, σ1Randσ2R; however, the function, are inhibited (Panenka et al., 2013), and levels of stress σ1R has been more thoroughly characterized in the literature (Bowen, hormones including cortisol and adrenocorticotrophic hormone can 2000; Quirion et al., 1992). In addition to responding to cellular stress, increase up to 200% (Harris, Reus, Wolkowitz, Mendelson, & Jones, the σ1R is a ligand-operated chaperone protein that can be activated 2003). Most notably, METH administration also elicits a suite of rein- or inhibited by different ligands in an agonist-antagonist manner forcing effects including euphoria, arousal, heightened awareness,

(Hayashi & Su, 2003b; Tsai, Hayashi, Mori, & Su, 2009). Several σ1R- reduced fatigue, behavioral disinhibition, positive mood, increased targeting drugs are proposed as possible treatments for human diseases self-confidence, and acute cognitive improvement (Courtney & Ray, including neurodegeneration, psychiatric disorders, neuropathic pain, 2014). Conversely, METH can also induce acute negative psychological and drug abuse (Hayashi, 2015). Importantly, multiple FDA-approved effects including anxiety, insomnia, aggressive behavior, paranoia, and drugs that are widely used for the treatment of schizophrenia and de- psychosis (Rawson & Condon, 2007). At high doses, METH can elevate pression have high affinity for the σ1R, supporting the therapeutic the body temperate to potentially lethal levels, resulting in convulsions, potential of drugs targeting σ1Rs. While several studies have reported coma, stroke, or even death (Rawson & Condon, 2007). that σR ligands attenuate some of the behavioral effects of cocaine and Like other drugs of abuse, prolonged METH use often results in METH in rodent models, the mechanisms by which σR ligands produce drug tolerance, typically leading to increased dosage and frequency these effects are largely unknown. With the ongoing synthesis of novel, of use (Rawson & Condon, 2007). Long-term chronic METH use often highly selective σ1R ligands every year and the increased understanding leads to the development of symptoms including violent behavior, of the protein's function, the σ1R remains a highly attractive therapeutic anxiety, cognitive impairment, and insomnia (Rawson & Condon, target for METH addiction. 2007). Additionally, many chronic METH users report psychotic symptoms similar to those of schizophrenia, namely paranoia, auditory 2. Methamphetamine hallucinations, mood disturbances, delusions, and abnormal speech (Hsieh, Stein, & Howells, 2014). Additional adverse physiological con- 2.1. Patterns of methamphetamine use sequences of prolonged METH use include cardiovascular problems, pulmonary disease, and infections from repeated intravenous injec- Methamphetamine (METH) is a widely abused, highly addictive tions (such as HIV) (Rawson & Condon, 2007). Patterns of METH psychostimulant that belongs to a class of synthetic drugs called abuse may also lead to other negative repercussions including disrupted amphetamine-type stimulants (ATSs). This class includes amphetamine personal relationships, unemployment, and incarceration (Hsieh et al., (AMPH), METH, methylenedioxy-methamphetamine (MDMA), and 2014). other designer drugs (Chomchai & Chomchai, 2015). AMPH and METH were once widely distributed as over-the-counter drugs for the 2.3. Methamphetamine regulation of extracellular dopamine myriad of “positive” effects that quickly became causative for their use (increased wakefulness, appetite suppression, etc.) (Vearrier, The administration of ATSs results in an acute increase in the mono- Greenberg, Miller, Okaneku, & Haggerty, 2012). The intended beneficial amines dopamine (DA), norepinephrine, and serotonin in the brain use of these drugs, however, was offset by their highly addictive poten- (Azzaro & Rutledge, 1973; Halpin, Collins, & Yamamoto, 2014). Both tial, ultimately leading to ATSs becoming among the most abused the rewarding and addictive properties of ATSs are primarily attributed drugs in the world. The 2016 United Nations Office on Drugs and to their ability to increase extracellular DA levels (Sonders, Zhu, Crime World Drug Report estimated that over 35 million people use Zahniser, Kavanaugh, & Amara, 1997). In both humans and animal AMPHs and prescription stimulants across the world (UNODC, 2016). models, blockade of DA receptors decreases the euphoric effects of METH specifically has surpassed the other ATSs in popularity, produc- AMPH, demonstrating the importance of DA in the rewarding effects tion, and trafficking. While AMPH and METH share similar mechanisms of the drug (Davis & Smith, 1975; Gunne, Anggard, & Jonsson, 1972; of action as well as behavioral effects, the drugs have differing molecular Jonsson, Anggard, & Gunne, 1971; Yokel & Wise, 1975). In 1988, Di structures and cellular effects (Goodwin et al., 2009; Saha et al., 2014), Chiara and Imperato reported that while administration of cocaine, and METH is more commonly associated with recreational use and morphine, methadone, ethanol, and nicotine in rats increased extra- drug addiction. METH can be synthesized by the reduction of everyday cellular DA levels in the striatum up to 400%, AMPH treatment in- over-the-counter nasal decongestants that contain ephedrine or creased extracellular DA levels up to 1000% (Di Chiara & Imperato, pseudoephedrine, and the relative accessibility of these starting mate- 1988), demonstrating the profound capacity of ATSs to activate the rials led to the expansion of small scale METH laboratories across DA system. Human imaging studies have similarly reported increased the United States (Ciccarone, 2011; Panenka et al., 2013). Despite DA levels after the administration of amphetamines (Volkow et al., attempts to limit sales of these products with the 2005 Combat 1999; Volkow, Fowler, Wang, Swanson, & Telang, 2007). The mecha- Methamphetamine Epidemic Act, larger-scale illicit METH manufac- nism by which METH increases DA levels in the brain – a direct interac- turers emerged (Maxwell & Brecht, 2011; SAMHSA, 2006). In 2014, tion with its primary target the dopamine transporter (DAT) - has been there was a global peak in ATS law enforcement seizures worldwide, well characterized. with METH accounting for the largest share of ATS seizures and increasing an estimated 21% from the previous year (UNODC, 2016). Despite 2.4. Methamphetamine interactions with DAT widespread efforts to decrease METH production, METH use continues to be a major public health problem worldwide. Dopamine (DA) is important for regulating processes including reward, motivation, movement, working memory, and cognition (Chinta 2.2. Effects of methamphetamine use & Andersen, 2005). The main source of DA in the brain is midbrain dopaminergic neurons, which includes the substantia nigra (SN) and Upon administration, there are several acute physiological effects ventral tegmental area (VTA). The dopamine transporter (DAT) is a associated with METH use. By promoting the release of epinephrine transmembrane protein located on dopaminergic neurons that

Please cite this article as: Sambo, D.O., et al., The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction, Pharmacology & Therapeutics (2018), https://doi.org/10.1016/j.pharmthera.2018.01.009 D.O. Sambo et al. / Pharmacology & Therapeutics xxx (2018) xxx–xxx 3 primarily functions to take up DA released into the extracellular space. firing activity above baseline (Shi, Pun, Zhang, Jones, & Bunney, 2000). Upon reuptake, dopamine can then be sequestered into synaptic vesi- This increase in firing activity is inhibited by DAT blockers, suggesting cles via the vesicular monoamine transporter-2 (VMAT-2) for storage it occurs via a DAT-dependent mechanism (Ingram, Prasad, & Amara, until the next exocytosis event (Giros, Jaber, Jones, Wightman, & 2002; Lin, Sambo, & Khoshbouei, 2016; Saha et al., 2014). DAT also Caron, 1996). DAT knockout mice display hyperactivity, cognitive defi- carries a channel-like current uncoupled to DA transport (DeFelice & cits, altered psychostimulant responses, and persistently high levels of Blakely, 1996; Kahlig et al., 2005; Lester, Mager, Quick, & Corey, 1994). extracellular DA with low tissue DA content (Giros et al., 1996), AMPHs increase this DAT-dependent inward positive current (Fischer highlighting the requirement of DAT for regulating DA homeostasis as & Cho, 1979; Saha et al., 2014) leading to membrane depolarization well as the actions of psychostimulants. and increased firing activity of dopaminergic neurons. Importantly, Both cocaine and ATSs increase extracellular DA levels through previous studies revealed that repeated METH exposure in rodents de- direct interactions with DAT. While cocaine increases extracellular DA creases the sensitivity of D2 autoreceptors, which in turn could increase levels by blocking DAT and preventing DA reuptake, METH interacts METH-mediated, DAT-dependent firing activity (White & Wang, 1984; with DAT to increase extracellular DA levels through a variety of mech- Wolf, White, Nassar, Brooderson, & Khansa, 1993). anisms (Fig. 1). As a substrate for the transporter, METH enters DA neu- AMPHs are also known to internalize the transporter in a protein ki- rons directly through DAT and consequently decreases DA uptake via nase C (PKC)-dependent manner. This is presumably via AMPH-induced competitive inhibition (Fleckenstein, Metzger, Gibb, & Hanson, 1997). increases in intracellular Ca2+ (Gnegy et al., 2004; Goodwin et al., 2009) Once inside the neuron, METH disrupts vesicular stores of DA, resulting that in turn activate PKC (Giambalvo, 1992), or AMPH-induced mem- in the release of DA into the cytoplasm of the neuron (Sulzer & Rayport, brane depolarization (Richardson et al., 2016). By promoting DAT inter- 1990). Importantly, METH also induces the reverse transport of DA from nalization, AMPHs decrease DA transport by limiting available DAT at the cytosol to the extracellular space via DAT-mediated, action potential the membrane for uptake (Cowell, Kantor, Hewlett, Frey, & Gnegy, independent DA efflux (Sulzer et al., 1995). This is thought to occur via 2000; Melikian & Buckley, 1999). Over the past several years, other sig- the facilitated exchange diffusion model in which forward transport naling pathways involved in DAT trafficking have also been identified, of AMPHs is followed by a counter movement of DA outside the cell including a role for Ca2+/calmodulin-dependent protein kinase II, (Fischer & Cho, 1979; Khoshbouei, Wang, Lechleiter, Javitch, & Galli, MAP/ERK, and membrane depolarization (Fog et al., 2006; Moron 2003). This model is supported by evidence showing that compounds et al., 2003; Richardson et al., 2016). Collectively, these effects of that release DA from vesicular stores without affecting DAT activity do AMPHs on DAT activity result in a robust increase in extracellular DA not produce DA efflux, demonstrating the importance of the inward levels that contribute to the highly addictive properties of the drug. transport of AMPH (Jones, Gainetdinov, Wightman, & Caron, 1998). This process is voltage-dependent and highly regulated by AMPH- 2.5. Other mechanisms induced increases in intracellular Na+ and Ca2+ as well as proteins interacting with DAT (Khoshbouei et al., 2003). In addition to DAT-mediated increases in extracellular DA through Beyond competitive inhibition of DA uptake and reverse DA trans- disrupting DAT activity, METH also decreases the activity of monoamine port, ATSs also impact the electrophysiological properties of DA neurons oxidase, resulting in decreased dopamine metabolism and thus prolonged through a DAT-dependent mechanism. AMPH-mediated DA release ac- elevated extracellular DA levels (Sulzer, Sonders, Poulsen, & Galli, tivates D2 autoreceptors which inhibit the firing activity of DA neurons 2005). Importantly, METH also affects others neurotransmitter systems (Bunney, Walters, Roth, & Aghajanian, 1973). Pharmacological blockade outside of the monoamines. ATSs have been shown to activate the en- of these autoreceptors, however, reveals AMPH-mediated increases in dogenous opioid system, also contributing to the rewarding effects of

Dopamine-(DA) DAT- METH Internalization

VMAT Increased- Cytosolic- DA

DAT

Decreased- DAT DA-Uptake DA-Efflux Currents

Fig. 1. METH-stimulated, DAT-mediated increase in extracellular dopamine. Molecule and protein images are courtesy of Servier Medical Art, licensed under CC BY 3.0.

the drugs (Chiu, Ma, & Ho, 2005; Jones & Holtzman, 1994; Shen et al., depressive-like phenotype has been observed in σ1R knockout mice, 2010). Additionally, studies have demonstrated that METH increases supporting a role for σ1Rs in psychiatric disease (Rousseaux & Greene, levels of glutamate, acetylcholine, and the neuropeptide neurotensin 2015; Sabino, Cottone, Parylak, Steardo, & Zorrilla, 2009). Although (Courtney & Ray, 2014). there are many unanswered mechanistic questions, the past 20 years

of research suggests that the σ1R is a viable target for the treatment of 2.6. Chronic effects on the dopaminergic system numerous pathological conditions.

High doses and persistent use of METH can lead to neurotoxic effects 3.1. Protein characterization on dopaminergic neurons. Human positron emission tomography (PET) imaging in METH abusers demonstrates decreases in striatal Because of their afﬁnity for the opioid-receptor targeting

DAT density, D2 dopamine receptor (D2R) availability, and VMAT-2 benzomorphan N-allylnormetazocine (SKF-10,047), sigma receptors density compared to non-METH users (Johanson et al., 2006; McCann (σR) were initially classified as the “σ opioid” receptor subtype in 1976 et al., 1998; Volkow, Chang, Wang, Fowler, Ding, et al., 2001; Volkow, (Martin, Eades, Thompson, Huppler, & Gilbert, 1976). A later study re- Chang, Wang, Fowler, Leonido-Yee, et al., 2001). The mechanisms vealed that the classic opioid receptor antagonist naltrexone failed to an- by which these dopaminergic markers are down-regulated are not un- tagonize the effects of SKF-10,047, leading researchers to distinguish the derstood, however evidence suggests that METH-mediated oxidative σR as a non-opioid receptor (Vaupel, 1983). SKF-10,047 was later shown stress may be responsible for neuronal toxicity (Berman, O'Neill, Fears, to have a similar behavioral profile as the dissociative drug phencyclidine Bartzokis, & London, 2008). Interestingly, human imaging studies have (PCP) as well as share binding to the N-methyl-D-aspartate (NMDA) re- revealed that prolonged METH abstinence (more than one year) can ceptor, creating further uncertainty about the σR's identity (Hayashi & improve these deficits in dopaminergic markers (Curtin et al., 2015; Su, 2004; Quirion et al., 1992). Eventually, the development of more se- Volkow, Chang, Wang, Fowler, Franceschi, et al., 2001). Despite the lective ligands revealing a distinct binding profile led to the recognition potential for improvement after abstinence, the connection between of σRs as a separate class of proteins (de Costa et al., 1989).

METH use and Parkinson's disease (PD) is an ongoing concern. Individ- At least two subtypes of σRs have been identified, sigma-1 (σ1)and uals with a history of METH use were reported to have nearly a three- sigma-2 (σ2), initially characterized based on their differential ligand af- fold increased risk for developing PD (Callaghan, Cunningham, Sajeev, finities (Maurice et al., 2002; Quirion et al., 1992). In general, σ1Rs have & Kish, 2010; Callaghan, Cunningham, Sykes, & Kish, 2012), however higher affinity and stereoselectivity for (+)-isomers of benzomorphans whether or not METH use directly causes PD remains unresolved whereas σ2Rs have more affinity for (−)-isomers (Hellewell et al., (Guilarte, 2001; Kish, Boileau, Callaghan, & Tong, 2017). 1994). Additionally, the subtypes display different molecular weights;

the σ1R is identified at 25–30 kDa and the σ2Rat18–21 kDa (Maurice 2.7. Treatment strategies et al., 2002). The σ1Rwasfirst cloned from guinea pigs in 1996 (Hanner et al., 1996) and later identified as a 223-amino acid protein Currently, there are few effective options for the treatment for METH with 90% homology across mammalian species (Su, Hayashi, Maurice, addiction. Psychosocial interventions are often employed consisting of Buch, & Ruoho, 2010). Interestingly, the σ1R has 33% identity and 66% either Cognitive-Behavioral Treatment (CBT) or Contingency Manage- homology with a yeast sterol C8-C7 isomerase involved in sterol biosyn- ment (CM) (Courtney & Ray, 2014). CBT involves teaching individuals thesis (Hanner et al., 1996; Su & Hayashi, 2003). Although the σ1Rwas how to reduce or discontinue drug use, whereas CM involves using later shown to bind cholesterol and to be involved in subcellular lipid positive reinforcement, such as money vouchers, to promote decreased distribution (Hayashi & Su, 2005; Palmer, Mahen, Schnell, Djamgoz, & drug use (Lee & Rawson, 2008). Unfortunately, these psychosocial treat- Aydar, 2007), it lacks sterol or cholesterol isomerase activity (Labit-Le ments have low rates of treatment induction as well as patient retention Bouteiller et al., 1998). Furthermore, the σ1R lacks enzymatic activity (Shearer, 2007). Currently, there is no FDA-approved drug treatment for and shares no sequence homology with any other known mammalian METH addiction, but several drugs are currently under clinical trial. proteins (Hayashi & Su, 2003b; Su et al., 2010), further complicating These drugs mainly target dopaminergic, serotonergic, GABAergic, efforts to categorize the protein. In 2016, the crystal structure of the and/or glutamatergic systems in the brain (Courtney & Ray, 2014). human σ1R was identified and shown to have a trimeric organization In addition to these known pathways involved in psychostimulant with a single transmembrane domain for each protomer (Schmidt addiction, there is growing interest in a unique target in the brain for et al., 2016). Because of these advances in characterizing the σ1R, the treatment of METH addiction called the sigma-1 receptor (σ1R), the σ1R has been more widely investigated throughout the field com- which will be the focus for the remainder of this review. pared to the σ2R. Only recently was the σ2R cloned and identified as TMEM97 (Alon et al., 2017), an ER membrane protein known to contrib- 3. Sigma-1 receptor ute to cholesterol homeostasis (Alonso et al., 2000; Bartz et al., 2009) and potentially other cellular functions (Derbez, Mody, & Werling,

The sigma-1 receptor (σ1R) is a ubiquitously expressed protein im- 2002; Sahn, Mejia, Ray, Martin, & Price, 2017; Walker et al., 1993). It is plicated for the treatment of a number of neurological conditions unclear how this recent development might alter the interpretation of including stroke, neurodegenerative disease, psychiatric disorders, previous σ2R studies. It should be noted that although several of the and neuropathic pain (Rousseaux & Greene, 2015). The σ1R is widely σR ligands discussed in this report and used in many other studies expressed throughout the central nervous system and peripheral have afﬁnity for both the σ1Randσ2R, the focus of this review is on organs. Within the brain, σ1Rs are highly concentrated within the limbic σ1Rs. This is important to consider as the two subtypes may differ in cel- system and brainstem (Maurice, Martin-Fardon, Romieu, & Matsumoto, lular activity and thus overall function.

2002). At the cellular level, the σ1R is located at the endoplasmic reticulum (ER) membrane where it possesses chaperone activity in response 3.2. Pharmacology to misfolded proteins. A unique property of this chaperone, however, is that it can also be regulated by different ligands in an agonist-antagonist A variety of drugs bind to σ1Rs, including benzomorphans and PCP manner. Upon activation, the σ1R acts as intracellular signaling modula- as described above. Although there is no known explicit endogenous tor, regulating a variety of cellular functions. Despite the σ1R's wide ex- ligand, neurosteroids including progesterone and dehydroepiandros- pression and numerous functions, σ1R knockout mice are viable and terone (DHEA) have afﬁnity for the σ1R(Su, London, & Jaffe, 1988). do not display any overt phenotype. In part, this could be due to com- Additionally, N,N-dimethyltryptamine (DMT), an endogenous compensatory mechanisms occurring during development. Interestingly, a pound also used recreationally as a hallucinogen, has been shown to

bind to the σ1R(Fontanilla et al., 2009). DMT is generally recognized as (Hayashi, Maurice, & Su, 2000) where they are highly localized in targeting serotonin receptors, but DMT's afﬁnity for the σ1R suggests a cholesterol-rich areas of the ER adjacent to the mitochondria called potential role for σ1Rs in its psychedelic effects and further implicates the mitochondrial-associated membrane (MAM). Additionally, σ1Rs the σ1R in psychiatric disease (Rousseaux & Greene, 2015). have also been localized to the plasma membrane, nuclear envelope, In addition to these compounds, a wide range of unrelated and struc- and post-synaptic thickenings of neurons (Alonso et al., 2000; Su turally diverse ligands used both recreationally and therapeutically et al., 2010). As described above, the σ1R is constitutively bound to in humans have high afﬁnity for the σ1R. This includes the drugs of BiP, and agonists dissociate σ1R from BiP allowing σ1R translocation abuse cocaine (Sharkey, Glen, Wolfe, & Kuhar, 1988) and METH within the cell. In addition to agonist activation, ER Ca2+ depletion has

(Nguyen, McCracken, Liu, Pouw, & Matsumoto, 2005), the antipsychotic also been shown to dissociate the σ1R from BiP, suggesting a role of 2+ drug haloperidol (Su, 1982), and antidepressants such as fluoxetine the σ1R as a sensor of ER Ca levels (Hayashi & Su, 2007). A recent (Prozac®) (Safrany & Brimson, 2016) and sertraline (Zoloft®) (Narita, study showed that mutations in the σ1R gene linked to neurodegenera- Hashimoto, Tomitaka, & Minabe, 1996). Importantly, fluoxetine has tive diseases resulted in aberrant cellular localization of the σ1R, been reported to reach serum concentrations at clinically relevant supporting the importance of proper σ1R localization in its physiological doses that can bind σ1Rs (Di Rosso, Palumbo, & Genaro, 2016; Safrany function (Wong et al., 2016). & Brimson, 2016), thus the actions of these drugs and potentially While the precise localization of σ1Rs is poorly understood, multiple many other clinically used drugs could be in part due to their interac- independent studies have demonstrated that σ1Rs exist within or adja- tions with the σ1R. Additionally, anticonvulsants, cytochrome P450 cent to the plasma membrane. Subcellular fractionation in rat brain 3 inhibitors, and monoamine oxidase inhibitors also have reported σ1R homogenates revealed (+)[ H]SKF-10,047 binding sites within non- affinity (Maurice et al., 2002). It is still unclear if and how the σ1R synaptic plasma membrane fractions (Hayashi & Su, 2003a; McCann contributes to the actions of many of these drugs, but these findings & Su, 1990). Treatment with selective σ1R ligands increased the detec- have generated great interest in the potential clinical role of the σ1R tion of σ1Rs in the plasma membrane fraction using this method, and has also led to the generation of several novel drugs selectively supporting the hypothesis that σ1R activation promotes its transloca- targeting σ1Rs. Table 1 summarizes drugs mentioned in this review tion from the ER to other cellular compartments such as the membrane with their affinities for σ1R, σ2R, and DAT. (Hayashi et al., 2000). A 2013 study by Kourrich et al. suggested that the Defining σ1R ligands as agonists or antagonists has been compli- σ1R is directly incorporated within the plasma membrane via an assay cated for various reasons. Several ligands with σ1Raffinity remain detecting C- and N-terminal tags on the σ1R putatively at the membrane uncharacterized as either agonists or antagonists (Gonzalez-Alvear & (Kourrich et al., 2013). In contrast, Mavlyutov et al. used electron

Werling, 1994). One widely accepted metric for determining σ1Rago- microscopy in motor neurons as well as ganglion cells to identify σ1Rlo- nist activity is the ability of the ligand to dissociate the σ1R from its con- calization to subsurface cisternae of the ER near but not integral to the stitutive binding partner protein, Binding immunoglobulin Protein plasma membrane (Mavlyutov, Epstein, Andersen, Ziskind-Conhaim,

(BiP). Agonists dissociate σ1R from BiP whereas antagonists either in- & Ruoho, 2010; Mavlyutov, Epstein, & Guo, 2015). These ER subsurface crease the association or block the effect of agonists (Hayashi & Su, cisternae, also referred to as cortical ER, are areas of the ER that come

2007). Interestingly, several selective σ1R ligands show no effect when in close contact with the plasma membrane and provide direct com- administered alone and only modulate stimulated cellular responses munication between ER and membrane proteins (Berridge, 1998; (Hayashi & Su, 2003a), limiting the feasibility of classifying ligands as Kosaka, 1980; Rosenbluth, 1962; Spacek & Harris, 1997). Importantly, agonists versus antagonists based cellular effects. Additionally, modula- the σ1R has been shown to interact with and modulate the activity tion of these responses is often dose-dependent as a number of studies of various membrane proteins (Pabba, 2013; Rousseaux & Greene, have shown opposing effects depending on whether high or low doses 2015), supporting the notion that a population of σ1Rs are capable of were used (Rousseaux & Greene, 2015); this makes it challenging to translocating to the area at or near the plasma membrane where they compare diverse studies using different doses of the same σ1Rligands. can directly or indirectly modulate the activity of transmembrane Another proposed method of determining agonist versus antagonist ac- proteins. tivity is that σ1R agonists mimic the effects of σ1R overexpression while σ1R antagonists mimic σ1R knockdown (Mei & Pasternak, 2002), 3.4. Cellular functions although this requires further validation. Additionally, the possibility that some σ1R antagonists may act as partial or inverse agonists is a σRs regulate a variety of second messenger signaling pathways, in- developing concept within the field. It is important to consider that cluding cyclic guanosine monophosphate (cGMP), inositol phosphates, many σ ligands to-date have dual or partial affinity for both σ receptor kinases, and Ca2+ (Matsumoto, Liu, Lerner, Howard, & Brackett, 2003). subtypes making it difficult to distinguish which target is primarily σ1Rs modulate these effects in a manner distinct from traditional contributing to the effects of the drugs. Furthermore, ligands may act ionotropic or metabotropic receptors by translocating between cellular as an agonist of one subtype but an antagonist of the other, and the compartments. Fig. 2 broadly summarizes the existing theories for the cellular responses to agonism and antagonism of the σ2Rarenot cellular function of σ1R. Overall, the σ1R is considered pro-survival defined. Adding additional complexity, it was recently shown that under cellular stress (Hayashi & Su, 2007; Pabba et al., 2014). As an ER drugs thought to be highly selective for the σ1R can also directly influ- chaperone protein, it attenuates protein misfolding and stabilizes + ence the activity of voltage-gated K channels, potentially explaining other ER proteins (Hayashi & Su, 2007). σ1R interactions with the IP3R the effects on neuronal physiology without a direct role of the σ1R type 3 at the MAM have been well characterized and are hypothesized 2+ (Liu et al., 2017). Lastly, the in vitro pharmacokinetics of many of these to regulate IP3R-mediated Ca mobilization from the ER to the mito- selective σR ligands is undetermined, with the half-life and brain con- chondria. This in turn promotes cell survival by upregulating Ca2+- centrations of these drugs after administration unknown. Given this dependent enzymes involved in the tricarboxylic acid (TCA) cycle complexity, further investigation is required to properly characterize (Hajnoczky, Robb-Gaspers, Seitz, & Thomas, 1995; Hayashi & Su, and categorize σR ligands and allow for proper interpretation across 2007). Thus, by promoting cellular metabolism, the σ1R is believed to studies utilizing these drugs. promote cell survival. 2+ Numerous reports indicate that the σ1R also regulates Ca homeo- 3.3. Cellular localization stasis outside of the MAM. A study utilizing different chemical classes

of selective σ1R agonists, pregnenolone sulfate, (+)-pentazocine, and The cellular localization of the σ1R is dynamic in nature. σ1Rs PRE-084, revealed no effect of these drugs alone but reported a potenti- exist predominantly in the endoplasmic reticulum (ER) membrane ation of bradykinin-induced Ca2+ release from the ER. Interestingly, the

Table 1

Ligand afﬁnities for σ1R, σ2R, and DAT (Ki,nM).

Ligand Activity σ1R σ2R DAT Reference Stimulants and psychiatric drugs Cocaine Agonist n.d. n.d. 164 Izenwasser, Newman, and Katz (1993) 5190 19,300 77 Garces-Ramirez et al. (2011) 1347 48,170 n.d. Lever et al. (2016) Fluoxetine Agonist 240 16,100 n.d. Narita et al. (1996) Haloperidol Antagonist 7.0 n.d. n.d. Su (1982) 1.9 79.8 n.d. Bowen, dCBR, Hellewell, Walker, and Rice (1993) n.d. n.d. 5232 Izenwasser et al. (1993) 3.3 270.0 n.d. Takahashi et al. (1999) 2.2 16.0 9578 Moison et al. (2003) 0.9 7.9 n.d. Lever, Gustafson, Xu, Allmon, and Lever (2006) 1.2 18.1 n.d. Lever et al. (2014) 1.4 72.8 n.d. Lever et al. (2016) Methamphetamine ??? 2160a 46,670a n.d. Nguyen et al. (2005) 4390 15,900 n.d. Hiranita, Mereu, Soto, Tanda, and Katz (2013), Hiranita, Soto, Tanda, Kopajtic, and Katz (2013) MDMA ??? 3057 8889 10,320 Brammer, Gilmore, and Matsumoto (2006) Sertraline Agonist 57 5297 n.d. Narita et al. (1996) Selective σ ligands (+)-3-PPP Agonist 49.3 120.0 n.d. Bowen et al. (1993) n.d. n.d. 1784 Izenwasser et al. (1993) AC927 Antagonist 30.0 138.0 2939 Matsumoto, Shaikh, Wilson, Vedam, and Coop (2008) AZ66 Antagonist 2.4 0.5 872 Seminerio et al. (2012) 4.7 1.4 1950 Katz et al. (2016) BD1008 Antagonist 2.0 8.0 n.d. McCracken, Bowen, and Matsumoto (1999) 2.1 16.6 2510 Garces-Ramirez et al. (2011) BD1047 Antagonist 0.9 47.0 n.d. Matsumoto et al. (1995) 3.0 48.0 3220 Garces-Ramirez et al. (2011) BD1063 Antagonist 9.2 449.0 n/a Matsumoto et al. (1995) 6.0 440.0 16,820 Brammer et al. (2006) 9.0 625.0 8020 Garces-Ramirez et al. (2011) 8.8 626.0 8020 Katz et al. (2016) 9.7 762.0 n.d. Lever et al. (2016) BMY-14802 Antagonist 265.0 391.0 n.d. Weigl, Bedurftig, Maier, and Wunsch (2002) CM156 Antagonist 1.3 0.6 1175 Xu et al. (2010) DTG Agonist 74.3 61.2 n.d. Bowen et al. (1993) 69.0 21.0 N10,000 Moison et al. (2003) 35.5 39.9 n.d. Lever et al. (2006) 57.0 22.0 93,500 Garces-Ramirez et al. (2011) 111.8 39.1 n.d. Lever et al. (2016) MR200 Agonist 1.5 21.9 N10,000 Moison et al. (2003) MS-377 Antagonist 73.0 6900.0 n.d. Takahashi et al. (1999) NE100 Antagonist 1.5b 633.0b n.d. Chaki, Tanaka, Muramatsu, and Otomo (1994) 2.5 121.0 3590 Hiranita et al. (2011) (+)-Pentazocine Agonist 6.7 1361 n.d. Bowen et al. (1993) 1.6 728.4 n.d. Lever et al. (2006) 4.6 224.0 n.d. Hiranita, Mereu, et al. (2013), Hiranita, Soto, et al. (2013) 5.1 2060.0 n.d. Lever et al. (2016) PRE-084 Agonist 44.0b n.d. n.d. Su et al. (1991) n.d. n.d. 5344 Izenwasser et al. (1993) 46.5 n.d. n.d. Cao et al. (2003) 48.5 12,700.0 n.d. Hiranita, Mereu, et al. (2013), Hiranita, Soto, et al. (2013) 53.0 32,100.0 19,600 Garces-Ramirez et al. (2011) SA4503 Agonist 17.4b 1784.0b n/a Matsuno, Nakazawa, Okamoto, Kawashima, and Mita (1996) 4.6 63.1 n.d. Lever et al. (2006) (+)-SKF-10,047 Agonist 28.7 33,654.0 n.d. Bowen et al. (1993) Other drugs DHEA-sulfate Agonist 15,129 n.d. n.d. Maurice, Roman, and Privat (1996) DMT ??? 14,750a 21,710a n.d. Fontanilla et al. (2009) PCP ??? 2541b n.d. n.d. Su (1982) Progesterone Antagonist 175 n.d. n.d. Maurice et al. (1996) 2.7 n.d. n.d. Su, London, et al. (1988), Su, Schell, Ford-Rice, and London (1988) Rimcazole Antagonist 908.0 302.0 224 Husbands et al. (1999) 96.6 883.0 238 Hiranita, Soto, Tanda, and Katz (2011) n.d.: not determined. a KD. b IC50.

different σ1R agonists differentially affected depolarization-induced response), the different modulatory responses of the different σ1R 2+ Ca increases, with PRE-084 potentiating the response and preg- ligands despite all drugs used being classiﬁed as σ1R agonists, and the 2+ nenolone sulfate and (+)-pentazocine attenuating it (Hayashi et al., ability of σ1Rs to regulate both ER Ca release as well as extracellular 2000). This study highlights a number of important concepts within Ca2+ inﬂux to support a diversity of cellular functions. The latter is 2+ σ1R biology, namely: the modulatory nature of selective σ1R ligands supported by reports showing σ1R-regulation of L-type Ca channel (i.e. the lack of effect when administered in the absence of a stimulated activity in hippocampal slices as well as retinal ganglion cells (Sabeti,

Fig. 2. Schematic of sigma-1 receptor cellular activity. (1) The sigma-1 receptor (σ1R) is constitutively bound to another endoplasmic reticulum protein Binding immunoglobulin Protein

(BiP). Upon activation, the σ1R dissociates from BiP where it can then translocate to other cellular compartments. (2) The σ1R has been shown to stabilize IP3 type 3 receptors at the mitochondrial associated membrane and promote calcium (Ca2+)inﬂux into the mitochondria. This promotes cellular metabolism and contributes to the pro-survival effects of the

σ1R. (3) The σ1R has also been shown to associate with and regulate the activity of different membrane proteins, including voltage-gated ion channels (VGICs), transporter proteins, and G-protein coupled receptors (GPCRs). The ER, mitochondria, and protein images are courtesy of Servier Medical Art, licensed under CC BY 3.0.

Nelson,Purdy,&Gruol,2007; Tchedre et al., 2008). Additionally, σ1R li- σ1R also associates with one of the ER stress-sensing proteins in- gands were reported to differentially influence both NMDA receptor volved in the unfolded protein response, inositol-requiring enzyme 2+ and nicotinic acetylcholine receptor mediated Ca signaling (Hayashi 1 (IRE1). Mori et al. found that like the σ1R, IRE1 is also enriched et al., 1995; Paul et al., 1993). More recently, activation of the σ1Rwas at the mitochondrial-associated membrane, and σ1R stabilizes IRE1 shown to inhibit store operated Ca2+ entry (SOCE), a ubiquitously thereby prevent its degradation under cellular stress (Mori, Hayashi, expressed pathway that facilitates Ca2+ influx into the cell in response Hayashi, & Su, 2013). 2+ to ER Ca depletion (Srivats et al., 2016). This attenuation by the σ1R Relevant to its potential role in psychostimulant addition, the 2+ was proposed to prevent excess Ca influx that may in turn lead to σ1R also associates with proteins directly involved in dopaminergic sig- apoptosis. Overall, these studies suggest that the σ1Rcaninfluence mul- naling. This includes the D1R in HEK cells co-expressing σ1R/D1R, where 2+ tiple intracellular Ca signaling pathways through a variety of mecha- researchers reported that σ1R ligands attenuated cocaine-induced D1R- nisms, potentially acting in parallel. mediated increases in cAMP levels and ERK1/2 phosphorylation in cells as well as striatal tissue (Navarro et al., 2010). The same group later

3.5. Protein interactions found that the σ1R interacts with the D2R, and cocaine binding to this complex inhibits downstream D2R-mediated signaling pathways The σ1R associates with and regulates the activity of diverse classes (Navarro et al., 2013). More recently, the σ1R/DAT association was re- of proteins both intracellularly and at the plasma membrane. This in- vealed in HEK cells co-expressing σ1R/DAT (Hong, Yano, et al., 2017). cludes several different voltage-gated ion channels (VGICs) where in- This association was shown to increase DA uptake at high concentration teractions with these channels can have either inhibitory or enhancing of σ1R agonist and enhanced cocaine binding to the transporter. In an effects on channel activity (Kourrich, Su, Fujimoto, & Bonci, 2012; independent study, our laboratory also conﬁrmed that the σ1R associ- Pabba, 2013). Some examples include σ1R associations with the Kv1.4 ates with DAT at or near the plasma membrane and that this association channel in Xenopus oocytes (Aydar, Palmer, Klyachko, & Jackson, is potentiated by combined treatment with a σ1R agonist and METH 2002), L-type Ca2+ channels in retinal ganglion cells (Tchedre et al., (Sambo et al., 2017). This study is further described in a later section

2008), Kv1.3 in a human embryonic kidney cell (HEK) line (Kinoshita, of the review. Overall, σ1R interactions with D1R, D2R, and DAT provide Matsuoka, Suzuki, Mirrielees, & Yang, 2012), and Kv1.2 channels in me- further support for the role of σ1R in modulating the dopaminergic neu- dium spiny neurons of nucleus accumbens (Kourrich et al., 2013). Inter- rotransmission and the effects of psychostimulants and also provide po- + actions between the σ1R and different ion channels, particularly K tential molecular mechanisms by which the σ1R mediates its effects. channels, support the hypothesis that the σ1R may act as a regulatory subunit for these channels (Aydar et al., 2002) and implicates the σ1R 4. Sigma-1 receptor and the dopaminergic system as an indirect regulatory of neuronal excitability.

In addition to VGICs, the σ1R has also been shown to interact with The role of σRs in dopaminergic neurotransmission has been of in- and modulate the activity of the NMDA receptor in the rat hippocampus terest since early ﬁndings that antipsychotics and other drugs involved (Balasuriya, Stewart, & Edwardson, 2013; Pabba et al., 2014) as well in dopaminergic signaling have afﬁnity for σRs (Iyengar et al., 1990; as the μ opioid receptor expressed in HEK cells (Kim et al., 2010). In ad- Wachtel & White, 1988). σRs are expressed in dopaminergic regions in- dition to interactions with BiP, IP3R, and STIM1 described above, the σ1R cluding the striatum, substantia nigra (SN), and ventral tegmental area forms a complex with other ER-localized proteins including ankyrin B. (VTA) (Gundlach, Largent, & Snyder, 1986; Hayashi et al., 2010; McLean

σ1R agonist treatment dissociated ankyrin from the IP3R, potentiating & Weber, 1988). Using immunohistochemistry, σ1Rs were identiﬁed in 2+ IP3-mediated intracellular Ca signaling (Hayashi & Su, 2001). The dopaminergic neurons (Francardo et al., 2014). Despite several reports,

4.1. Effects on dopamine release the σ1R agonist (+)-pentazocine increased tyrosine hydroxylase activity (Booth & Baldessarini, 1991) and the σ1R agonist SA4503 increased Reports on the effects of σRs on DA release have yielded varying rein L-DOPA levels in the presence of DOPA decarboxylase inhibitors sults over the past several years. In 1990, Iyengar et al. first investigated (Kobayashi et al., 1997), suggesting a role of σRs in increasing DA synthe- the effect of σR ligands on DA release in the striatum and olfactory tu- sis. Currently, the molecular mechanisms by which σRligandspromote bercles and found that local administration of the benzomorphan σRag- DA release or synthesis are unknown. onists (+)-pentazocine and (+)-SKF 10,047 increased the levels of DA metabolites dihydrophenylacetic acid (DOPAC) and homovanillic acid 4.2. Electrophysiological effects on dopamine neurons (HVA) with no change in DA steady state levels (Iyengar et al., 1990). Benzomorphans (+)-N-allylnormetazocine and (+)-pentazocine In addition to dopamine release, the effects of σR ligands on the were later shown to increase the activity of tyrosine hydroxylase, the firing activity of dopaminergic neurons have also been examined. rate limiting enzyme for DA synthesis, in ex vivo rat striatal tissue Dopaminergic neurons display spontaneous baseline firing activity (Booth & Baldessarini, 1991). While this implied a role for σRs in DA (Grace & Bunney, 1984). Consistent with its ability to increase locomo- metabolism and synthesis, there was no distinction between the effect tor activity alone, the σ1R agonist (+)SKF-10,047 also increased the of σ1Randσ2R because the antagonist used to block these effects, basal firing activity of VTA DA neurons which was blocked by the σ1R BMY-14802, is not selective between the two subtypes. In 1993, antagonist rimcazole (Ceci, Smith, & French, 1988). Proposed as a po-

Patrick et al. showed that systemic administration of σRagonists(+)- tential antipsychotic drug, the σ1/2R antagonist BMY 14802 reversed pentazocine and 1,3-Di-(2-tolyl)guanidine (DTG) increased striatal DA the effect of apomorphine (a D2R agonist) on inhibiting the firing ac- levels in freely moving rats. In this study, only higher doses of the σ1R tivity of SN and VTA dopaminergic neurons (Wachtel & White, 1988). selective ligand (+)-pentazocine had an effect whereas lower doses of In vivo extracellular recordings in the SN revealed intravenous adminis- the non-discriminant σ1/2RagonistDTGweresufficient to increase DA tration of the σ1/2R agonist (+)-3-PPP decreased neuronal firing rate levels. This suggested that activation of the σ2R, rather than the σ1R, in- which was reversed by treatment with BMY 14802 (Steinfels & Tam, duced DA release in these rats (Patrick, Walker, Perkel, Lockwood, & 1989). These early studies suggest a role for the σR in dopaminergic

Patrick, 1993). This conclusion was further substantiated in later studies neuron firing activity or D2R-mediated inhibition of firing activity, how- revealing systemic injection of only higher doses of (+)-pentazocine in- ever relatively non-specific ligands were utilized. In vivo recordings in creased striatal DA levels (Gudelsky, 1995) and intra-nigral injections of the SN and VTA dopaminergic neurons of rats intravenously injected

σ1/2R agonist DTG increased extracellular levels of dopamine metabo- with the selective σ1R agonist SA4503 showed no change on the lites DOPAC and HVA in the striatum (Bastianetto, Rouquier, Perrault, spontaneous firing activity but significantly decreased the number of & Sanger, 1995). The effect of σR ligands on DA release was later spontaneously active neurons in the SN and increased the number of shown to be biphasic in a study where intra-striatal administration of spontaneously active neurons in the VTA (Minabe, Matsuno, & Ashby (+)-pentazocine, (−)-pentazocine, or DTG all initially increased DA Jr., 1999). Further studies are required to more conclusively determine levels followed by a prolonged decrease (Gudelsky, 1999). Supporting the role of the σ1Rinthefiring activity of dopamine neurons. Addition- the inhibitory effect of σR on DA release, intra-striatal application ally, the mechanisms involved in this regulation are not characterized, of the σ1/2R agonist MR200 as well as DTG decreased DA levels in the but σ1R associations with different ion channels may serve as potential striatum (Moison et al., 2003). mechanisms that have yet to be investigated. Later efforts to clarify the role of the σR subtype on DA release were made possible with the development of more selective σ1R ligands. In 4.3. Role in Parkinson's disease 1997, Kobayashi et al., showed that acute oral administration of the selective σ1R agonist SA4503 increased DA levels in the rat frontal cortex, The established role of σ1Rs in dopaminergic physiology has also led but interestingly not the striatum or midbrain (Kobayashi, Matsuno, to the investigation of the therapeutic potential of the σ1R in Parkinson's Murai, & Mita, 1997). This was further supported by a more recent disease (PD). Human PET imaging revealed lower binding of a 11 study showing a range of doses of SA4503 as well as the σ1Rantagonists radiolabeled σ1Rtracer([ C]SA4503) on the side of the anterior puta- BD1047 and BD1063 failed to evoke [3H]DA overflow in preloaded men that exhibited lower radiolabeled DAT substrate binding rat striatal slices (Rodvelt, Lever, et al., 2011), however the frontal (Mishina et al., 2005). While this meant that the σ1R could be a plausible cortex was not examined in this report. In 2011, Garcés-Ramírez et al. marker of dopaminergic degeneration, there was no difference in the recapitulated the dose-dependent effects of σR ligands demonstrating binding measured between PD patients and controls, ruling out any po- again that DTG increased dopamine levels in the nucleus accumbens tential of σ1R imaging as a biomarker for early PD. at lower concentrations whereas the selective σ1R agonist PRE-084 Studies in animal models reported paradoxical results in regard only increased dopamine levels at higher doses. Furthermore, the PRE- to the role of σ1R as a neuroprotective target. In 6-hydroxydopamine 084-mediated increase in dopamine levels was not blocked by σ1R (6-OHDA) lesioned mice, five weeks of treatment with the σ1R agonist antagonists BD1063, suggesting potential off-target effects PRE-084 PRE-084 (0.3 mg/kg) produced a profound recovery of motor function at the dose used in this study (Garces-Ramirez et al., 2011). PRE-084 as well as DA neuronal protection (Francardo et al., 2014). The treat- was later tested at 1, 3.2, and 10 mg/kg and shown to have no effect ment also increased levels of BDNF, GDNF, and pERK and decreased on extracellular DA levels in the nucleus accumbens shell in saline- microglial activation. In an alternative model utilizing the neurotoxin treated animals as well as animals with a history of cocaine exposure MPTP, σ1R hetero- and homozygous knockout mice had reduced DA (Hiranita, Mereu, et al., 2013). cell loss and recovery of motor function subsequent to MPTP injection

Taken together, these studies suggest that σ2R activation, but not (Hong et al., 2015). This effect was attributed to σ1Rdeﬁciency induced σ1R activation, may regulate DA neurotransmission within the striatum. suppression of NMDA receptors. The observed neuroprotective σ1R The potential role of σ1R in cortical DA neurotransmission was observed knockout effect was recapitulated in wild-type mice using the σ1R in at least one report, suggesting potential brain region differences in antagonist NE-100. Further complicating these paradoxical ﬁndings, the actions of σRs. Furthermore, the time-dependency of these effects the σ1R knockout mouse was shown to undergo age-dependent dopa- may also contribute to whether potentiation or inhibition of DA release minergic neurodegeneration, suggesting that the σ1R knockout mouse is observed. The mechanisms by which the σRs promote dopamine may be suitable to serve as a unique animal model of PD (Hong,

Wang, Zhang, Zhang, & Chen, 2017). The aged σ1R KO mice exhibited relevant concentrations. METH's affinity for σRs was first demon- multiple pathological characteristics that mimic the hypothesized cas- strated in 1993 in whole rat brain membrane preparations showing cade leading to cell death in PD, and also exhibited measurable motor a concentration-dependent inhibition of [3H](+)-pentazocine binding defects. Taken together, these studies underscore the complexity of by METH (Itzhak, 1993). In 2005, Nguyen et al. determined the binding 3 the σ1R's role in neuronal function and disease, yet still provide ratio- affinity of METH for the σ1Randσ2R in rat brains labeled with [ H](+)- 3 nale for the therapeutic targeting of the σ1RinPD. pentazocine for σ1R selectivity or [ H]DTG in the presence of (+)- pentazocine for σ2R selectivity. METH displayed over 20-fold selectivity 5. Sigma-1 receptor and methamphetamine for the σ1Rovertheσ2R(Ki 2.16 ± 0.25 μM vs. 46.67 ± 10.34 μM, respectively) (Nguyen et al., 2005). The consequences of METH

Interest in the role of σRs in METH addiction stems from the early binding to the σ1R are currently unknown; however, Hayashi et al. observation that the σR agonist (+)SKF-10,047 induces psychotomi- demonstrated that METH treatment increased the association between metic effects in dogs (Martin et al., 1976). Additionally, the discovery the σ1R and BiP suggesting METH may have antagonist activity (Hayashi that antipsychotics such as haloperidol have high affinity for the σ1R & Su, 2007). A recent review by Yasui and Su posits that METH may and the known parallels between schizophrenia and METH-induced act as an inverse agonist (Yasui & Su, 2016). In addition to METH, both psychosis further provoked the investigation of the potential role of cocaine and MDMA also have affinity for the σ1R(Brammer et al., σRs in psychostimulant addiction. At least one Japanese study found 2006; Matsumoto, McCracken, Pouw, Zhang, & Bowen, 2002; Sharkey no link between known mutations in the σ1R gene and METH abuse, et al., 1988). concluding that σ1Rs are unlikely to play a major role in the suscepti- bility for METH addiction (Inada et al., 2004). Although no genetic link 5.3. Locomotor activity was observed in humans, a number of studies have revealed restorative effects of σR ligands in animal models of METH addiction. It should be Before σRs were identified as a unique class of proteins in the brain, noted that the effects of σR ligands have also been widely studied the “σ opioid receptor” agonist (+)SKF-10,047 was shown to induce in models of cocaine addiction. Although both METH and cocaine are psychotomimetic effects alone (Fujiwara, Kuribara, & Tadokoro, 1990; widely abused psychostimulants, the different cellular mechanisms, Martin et al., 1976). This finding, in addition to studies described pharmacokinetics, and potential long-term effects are worth consider- above suggesting a role of σRs in the regulation of dopamine homeosta- ing these two drugs of abuse as distinct addiction targets. This is briefly sis, predicted early on a potential role of σRs in basal locomotion as well discussed in the Conclusions section. as METH-stimulated locomotor activity. Although (+)SKF-10,047,

as well as pentazocine, promote hyperactivity, more selective σ1R 5.1. Regulation of sigma-1 receptor expression ligands do not induce locomotion when administered alone. When investigating the effects of METH-induced (3 mg/kg) acute locomotor

The upregulation of σ1R expression after METH administration activity in σ1R knockout mice, no difference was observed between was first demonstrated in 1993 in rats exposed to 4 mg/kg of METH the knockout and wild-type mice (Fontanilla et al., 2009). The lack of 3 for 10 days. Increased binding of [ H](+)-pentazocine was observed effect of selective σ1R ligands alone as well as METH-stimulated loco- in the SN, frontal cortex, and cerebellum, suggesting a upregulation of motor activity being unaffected in σ1R knockout mice suggests that σ1Rs in response to METH (Itzhak, 1993). In 2004, Stefanski et al. inves- the σ1R is not required to regulate motor activity at baseline or in re- tigated the effect of both self-administration and passive administration sponse to METH. In 1992, Ujike et al. showed that while the nonselective of METH on σ1R levels in the brain (Stefanski et al., 2004). An increase in σ1/2R antagonist BMY 14802 had no effect on acute METH-induced σ1R protein levels, as measured via Western blot, was found in the mid- (2 mg/kg) locomotor activity, it blocked locomotor sensitization after brain of rats self-administering METH 5-days-per-week for 5 weeks but repeated METH exposure (Ujike, Kanzaki, Okumura, Akiyama, & not in rats that passively received the same amount of METH over the Otsuki, 1992). Similarly, the selective σ1R ligand MS-377 also attenuated same period (Stefanski et al., 2004). In 2009, Hayashi et al. similarly in- the development of METH-induced (2 mg/kg) locomotor sensitization; vestigated the effect of METH administration on σ1R levels, as well as however, it was not distinguished whether MS-377 acted as a σ1Rago- other chaperone proteins, in the brain of rats either self-administered nist or antagonist in this study (Takahashi, Miwa, & Horikomi, 2000). METH or passively received the drug. They found via Western blot In the same report that determined the affinity of METH for the σRs, that ER chaperone proteins σ1R, BiP, and calreticulin were all signifi- treatment with σ1R antagonists BD1063 and BD1047 as well as admin- cantly elevated in the VTA and SN of rats under both treatment istration of an antisense oligodeoxynucleotide against the σ1Rinto paradigms (Hayashi et al., 2010). This is consistent with studies the ventricles of rats attenuated acute METH-induced locomotor reporting ER chaperone protein upregulation by METH due to ER stress activity at METH doses between 0.1 and 3 mg/kg (Nguyen et al.,

(Jayanthi, Deng, Noailles, Ladenheim, & Cadet, 2004). The differences 2005). The nonselective σ1/2R antagonist AC927 also decreased acute between the Stefanski study where σ1R levels were only upregulated locomotor activity induced by 0.5 and 1 mg/kg METH in a separate in the midbrain of self-administering rats compared to the Hayashi study (Matsumoto et al., 2008). Both intraperitoneal injection and study where the σ1R was upregulated in the VTA and SN of both rats oral administration of the σ1/2R ligand AZ66, which putatively acts self-administering and passively receiving METH was attributed to as an σ1/2R antagonist, dose-dependently decreased METH-induced the detection of proteins in the VTA and SN as opposed to the entire (1 mg/kg) acute locomotor activity as well as METH-induced locomotor midbrain. Because a global upregulation of σ1R levels in many different sensitization (Seminerio et al., 2012). It is currently unclear why some brain regions was not observed, this upregulation appears to selectively σR antagonists attenuate acute locomotor activity and some are only ef- occur in dopaminergic structures. Currently, the functional consequence fective on locomotor sensitization; nevertheless, these ﬁndings suggest of the upregulation of σ1R levels in response to METH is unknown. speciﬁc σR antagonists may have different effects. σ1R upregulation may be a contributing factor to the development of In addition to σR antagonists and knockdown, the effect of σ1R METH addiction, or conversely could act as a compensatory mechanism agonists on METH-induced locomotion is investigated. Administration to counteract the untoward effects of METH. of the selective σ1R agonist SA4503 dose dependently affected METH- induced (0.5 mg/kg) locomotor activity with lower doses enhancing 5.2. Interactions with the sigma-1 receptor hyperactivity and higher doses inhibiting it (Rodvelt, Oelrichs, et al., 2011). More recently, Miller, Park, Lever, & Lever, 2016 investigated

In addition to METH-induced increases in σ1R levels in the ro- the effect of different N-phenylpropyl-N′-substituted piperazine li- dent VTA and SN, METH interacts with the σ1R at physiologically gands, including SA4503, on METH-induced hyperactivity (Miller

et al., 2016). All ligands tested had high affinity for the σ1Randno pentazocine reduced CPP to morphine, cocaine, and METH (Mori et al., appreciable affinity for DAT. They found that higher doses of the com- 2014). This study supports the ability of the σ1R agonist SA4503 to at- pounds attenuated METH-induced (0.5 mg/kg) locomotor activity, tenuate the rewarding effects of drugs of abuse in general and highlights whereas lower doses potentiated it (Miller et al., 2016). Utilizing a the phenomenon that not all σ1R agonists produce the same outcomes. different selective σ1R agonist, our laboratory recently revealed that Similar to SA4503, the σ1R agonist PRE-084 also reduced the acquisition 8 mg/kg PRE-084 attenuates acute METH-stimulated (2 mg/kg) loco- of METH-induced CPP in rodents (Sambo et al., 2017). Considering motor activity. Interestingly, 30 mg/kg of the σ1R antagonist BD1063, fluoxetine, SA4503, and PRE-084 are all more selective for the σ1R but not 10 mg/kg, also significantly reduced METH-induced locomotor compared to the σ2R and no studies have shown effects of σ2R ligands, activity. When analyzing locomotion during the pretreatment period, this suggests that agonist activity at the σ1R is effective for reducing we found that 30 mg/kg BD1063 alone decreased locomotion, an effect METH-induced CPP. The effect of pretreatment with σ1R ligands on that appears to be acute as no difference was detected after a subse- METH self-administration has not been reported, although Hiranita quent 1 h of saline treatment. This effect of 30 mg/kg of BD1063 on loco- et al. showed that rats first trained to self-administer METH, but not motor activity alone suggests this dose of the antagonist may have some heroin or ketamine, subsequently self-administered the σ1R agonists sedative effects (Sambo et al., 2017). Collectively, these reports indicate PRE-084 and (+)-pentazocine. The effect of PRE-084 was blocked that the type and dose of σ1R ligand used may present varying results by treatment with σ1R antagonist BD1008 but not the dopamine recep- but support the potential ability of σ1R ligands to reduce the hyperac- tor antagonist (+)-butaclamol or opioid antagonist (−)-naltrexone tive effects of METH, both acutely and after sensitization. A comprehen- (Hiranita, Soto, et al., 2013), suggesting that neither dopaminergic sive study using multiple σR ligands at different doses would potentially nor opioid mechanisms were involved. A recent report from our labora- provide a clearer picture of how σRligandsinfluence METH-stimulated tory showed that PRE-084 treatment reduced the ability of METH to locomotion. potentiate brain reward function as measured by intracranial self- stimulation (ICSS) (Sambo et al., 2017). It was previously shown that 5.4. Stereotypic behavior like other drugs of abuse, METH reduces the stimulation threshold for ICSS in rats (Harris et al., 2015). Our study showed that PRE-084 Another behavioral consequence of METH exposure is the induction pretreatment decreased the ability of METH to reduce the ICSS thresh- of repetitive and compulsive behaviors called stereotypies (Canales & old, with no effect of PRE-084 by itself (Sambo et al., 2017). Although Graybiel, 2000). In rodents, this includes repetitive grooming, sniffing, reinforcing behavior has been less examined compared to locomotor biting, licking, head-bobbing, and circling (Kitanaka et al., 2009). An activity, few studies similarly support a lack of effect of σ1Rligands early study by Ujike et al. showed that treatment with 3 mg/kg of alone, with no reports showing aversive or rewarding effects of the the σ1/2R agonist (+)-3-PPP acutely decreased rearing, locomotion, σ1R drugs. The effect of σ1R antagonist on reinforcing behaviors seems sniffing, and head movement but potentiated these behaviors when to be under-investigated. Furthermore, the effect of σ1R on more higher doses were utilized. In rats that received repeated 4 mg/kg protracted addictive processes such as drug extinction and reinstate- METH treatment followed by 5 to 8 days of abstinence, (+)-3-PPP en- ment, to our knowledge, has not been examined. hanced sensitization to locomotor behavior but decreased sensitization to rearing, sniffing, and head movement (Ujike, Okumura, Zushi, 5.6. Toxicity

Akiyama, & Otsuki, 1992). Similar to this study, the σ1/2R antagonist BMY 14802 also had no effect on acute stereotypic behavior but An important consequence of METH use is resultant dopaminergic decreased stereotypy sensitization (Akiyama, Kanzaki, Tsuchida, & neurodegeneration that is at least in part due to direct neurotoxic Ujike, 1994). While MS-377 did not affect acute METH-induced ste- actions of METH on DA neurons (Bowyer et al., 1994; Broening, Pu, & reotypic behavior in rats, pretreatment signiﬁcantly attenuated the be- Vorhees, 1997; Hotchkiss & Gibb, 1980). Hyperthermia and excitotoxic havioral sensitization of stereotypic behavior in rats receiving METH NMDA receptor activation have been identiﬁed as critical mechanistic for 10 days (Takahashi et al., 2000). Investigating the effect of different components of METH-induced neurotoxicity (Bowyer et al., 1994;

σR ligands with dual afﬁnity as well as selective afﬁnity for σ1Randσ2R, Sonsalla, Nicklas, & Heikkila, 1989). As described above, the METH- Kitanaka et al. found that different σR ligands differentially affected mediated dopaminergic insult is hypothesized to increase the risk the pattern and the type of stereotypies expressed but produced no for PD in individuals with a history of METH, but not cocaine, abuse change in the overall frequency of METH-induced stereotypy behavior (Callaghan et al., 2012).

(Kitanaka et al., 2009). While many of these studies only reported ef- σ1Rs have been investigated extensively in the context of METH- fects on stereotypy sensitization and not acute stereotypic behavior, induced DA neurotoxicity due to their described neuroprotective poten- several of the METH locomotor studies showed acute effects of σ1R tial and ability to modulate METH's behavioral responses (Nguyen et al., ligands, this suggesting the potential involvement of different mecha- 2005). One of the ﬁrst compounds examined for neuroprotection nisms across different METH-induced behaviors. against METH-induced neurotoxicity in vitro and in vivo was the σ1/2R antagonist AC927 (Matsumoto et al., 2008). Pretreatment with AC927 5.5. Reinforcing behavior prior to METH (1 mg/kg) exposure not only blocked the METH- induced increases in locomotor activity but similarly blocked METH- In addition to the acute behavioral effects of psychomotor activation induced (5 mg/kg) decreases in DA levels and dopaminergic immu- and stereotypy behavior, the role of σ1Rinanimalmodelsofaddictive- noreactivity as well as METH-induced hyperthermia (Matsumoto like behavior has also been investigated. While the σ1R agonist SA4503 et al., 2008). These results were replicated in further studies, and the did not substitute for METH at any dose tested, pretreatment with protective effects of AC927 were shown to extend to the serotonergic

SA4503 augmented drug discrimination for METH such that lower system (Seminerio et al., 2011). Similarly, the high-affinity σ1/2R dose of METH elicited responding compared to animals pretreated antagonist CM156 was also shown to be protective against METH with saline (Rodvelt, Oelrichs, et al., 2011). In contrast, in 2013 Rahmadi toxicity (Kaushal et al., 2011; Kaushal, Seminerio, Robson, McCurdy, et al. found that the antidepressant and σ1R agonist fluoxetine decreases & Matsumoto, 2013). Additional mechanistic insight revealed that the rewarding effects of METH as measured by conditioned place prefer- inhibition of σ1R with BD1047 prevented NMDA receptor induced ence (CPP). The effect of fluoxetine was blocked by the σ1R antagonist neurotoxicity in the hippocampi of mice injected with METH (Smith, NE-100, suggesting the role of σ1Rs in attenuating METH-induced Butler, & Prendergast, 2010). Furthermore, AC927 pretreatment atten- reinforcing behaviors (Rahmadi et al., 2013). Similar to this study, uated the generation of reactive oxygen species triggered by METH in in 2014 Mori et al. reported that the σ1R agonist SA4503 but not (+)- differentiated NG108-15 cells (Seminerio et al., 2011). The mechanisms

σR antagonist BD1008 attenuated METH self-administration with no to activate σ1Rs, making in vitro mechanistic studies difficult to com- effect on self-administration of heroin or ketamine (Hiranita et al., pare to functions measured in in vivo studies. As σ1R agonism is canon- 2014). These studies suggest that σR antagonists capable of DAT block- ically defined as the dissociation of σ1R from BiP, studies showing ade may be a viable target for METH addiction, and further support the whether σ1R ligands can dissociate σ1R from BiP in vivo would better idea that σRs may be involved in the clinical efficacy of commonly allow researchers to understand the nature of these ligands and whether prescribed drugs with dual affinity for σRs and other targets (such as the doses used reach physiological levels that replicate in vitro cellular haloperidol and fluoxetine). findings. Importantly, the focus of this review was to summarize studies

regarding the effects of σ1R ligands on METH addiction, although σ1R li- 5.8. Potential mechanisms gands have been investigated against other drugs of abuse. In particular,

several studies have examined the effects of different σ1R ligands in To date, there is no clear mechanistic evidence as to how the different models of cocaine addiction. It should be noted that while

σ1R modulates METH-mediated behavioral responses, although σ1R- METH and cocaine are both psychostimulants with similar behavioral regulation of the dopaminergic system remains a potential candidate. proﬁles, as a DAT substrate and not a DAT blocker, METH acts via differ-

In addition to investigating the effects of σ1R on basal dopamine release, ent cellular mechanisms including promoting DAT-mediated reverse σ1R ligands have also been examined for their effects on METH- transport of DA, increasing the firing activity of DA neurons, stimulating stimulated dopamine release. A 2011 study by Rodvelt et al. revealed DAT internalization, and increasing intracellular calcium levels, all of that while the σ1R antagonists BD1047 and BD1063 did not alter which are blocked by cocaine. These molecular differences should METH-induced [3H]DA overflow in preloaded rat striatal slices, higher be considered as these different mechanisms may require different 3 doses of the σ1R agonist SA4503 attenuated evoked [ H]DA release by pharmacological treatment strategies. For example, it was recently METH but not nicotine (Rodvelt, Oelrichs, et al., 2011). Recently, our lab- shown that a single infusion of AMPH reversed cocaine-induced deficits oratory similarly revealed both in vitro in DAT-expressing HEK cells as in DAT function (Ferris et al., 2015). This highlights the importance in well in vivo in the mouse striatum using amperometry that the σ1R considering these classes of drugs separately as AMPHs can potentially agonist PRE-084 also attenuated METH-stimulated dopamine release, attenuate the effects of cocaine, and vice versa. Although studies show while the σ1R antagonist BD1063 had no effect (Sambo et al., 2017). similar effectiveness for some σR ligands across different drugs of In both studies, neither the σ1R agonists nor antagonists affected dopa- abuse (Hiranita, Soto, et al., 2013; Mori et al., 2014), it is important to mine release at baseline, consistent with reports described above that li- not necessarily generalize the effectiveness of σR drugs, or other drugs gands selective for the σ1R, but not the σ2R, do not influence dopamine for that matter, across different addictive drugs. release alone. Although the actions of σ1R-targeting ligands remain complex, the The molecular mechanisms by which σ1R agonists attenuate METH- potential therapeutic potential for σ1R drugs is promising. One attrac- mediated dopamine neurotransmission is poorly understood. σ1R inter- tive feature of selective σ1R ligands is the lack of baseline activity, sug- actions with the D2R and DAT regulating the actions of these proteins gesting minimal off-target effects. This may seem contradictory given could in turn regulate METH-stimulated dopamine release. Although the wide distribution of σ1Rs as well as the large number of proteins the σ1R/D2R interaction has not been investigated in the context and pathways it has been shown to modulate, but importantly the σ1R of METH, our laboratory showed that METH treatment alone had no seems to selectively elicit responses under stimulated or pathological effect on the interaction between σ1R and DAT as measured by Foster conditions. This, in theory, would suggest that in cells at physiological Resonance Energy Transfer; however, METH exposure after treatment homeostasis, ligand activation or inhibition of σ1Rs would not provoke with the σ1R agonist PRE-084 potentiated the σ1R/DAT interaction. a response. Along these lines, many selective σ1R ligands also do not This suggests that σ1R agonism alone does not affect its interaction show rewarding effects on their own, which is an important feature with DAT but the presence of METH produces the cellular environment when considering pharmacotherapies for the treatment of drug abuse. for the σ1R to then association with DAT. In this study, we also revealed Several clinically used drugs have appreciable affinity for the σ1R, in- that σ1R activation by the σ1R agonist PRE-084 decreased the METH- cluding the antipsychotic haloperidol and the antidepressants fluoxe- stimulated increase in intracellular calcium, which is a crucial cellular tine and sertraline, supporting the efficacy of σ1R-targeting drugs for event for METH-stimulated dopamine efflux (Sambo et al., 2017). the treatment of psychiatric disorders. Selective σ1R ligands have been Interactions with DAT or regulation of intracellular calcium represent investigated in clinical trials for the treatment of neuropathic pain potential mechanisms by which the σ1R may reduce METH-stimulated (Abadias, Escriche, Vaque, Sust, & Encina, 2013; Collina et al., 2013), dopamine release, which would in turn reduce METH-mediated behav- neurodegenerative disease (Collina et al., 2013), anxiety (Moller, Volz, ioral responses. Further investigation is required to properly link these Reimann, & Stoll, 2001), depression (Moller, Volz, & Stoll, 2003; Volz, effects. Moller, Reimann, & Stoll, 2000), and schizophrenia (Frieboes et al.,

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