Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking

Abstract

Psychiatric disorders characterized by uncontrolled reward seeking, such as substance use disorders (SUDs), alcohol use disorder (AUD) and some eating disorders, impose a significant burden on individuals and society. Despite their high prevalence and substantial morbidity and mortality rates, treatment options for these disorders remain limited. Over the past two decades, there has been a gradual accumulation of evidence pointing to the sigma-1 receptor (S1R) system as a promising target for therapeutic interventions designed to treat these disorders. S1R is a chaperone protein that resides in the endoplasmic reticulum, but under certain conditions translocates to the plasma membrane. In the brain, S1Rs are expressed in several regions important for reward, and following translocation, they physically associate with several reward-related GPCRs, including dopamine receptors 1 and 2 (D1R and D2R). Psychostimulants, alcohol, as well as palatable foods, all alter expression of S1R in regions important for motivated behavior, and S1R antagonists generally decrease behavioral responses to these rewards. Recent advances in structural modeling have permitted the development of highly-selective S1R antagonists with favorable pharmacokinetic profiles, thus providing a therapeutic avenue for S1R-based medications. Here, we provide an up-to-date overview of work linking S1R with motivated behavior for drugs of abuse and food, as well as evidence supporting the clinical utility of S1R antagonists to reduce their excessive consumption. We also highlight potential challenges associated with targeting the S1R system, including the need for a more comprehensive understanding of the underlying neurobiology and careful consideration of the pharmacological properties of S1R-based drugs.

Introduction

Psychiatric illnesses characterized by uncontrolled reward seeking impose a significant burden on both the individual and society. Primary among these illnesses are substance use disorders (SUD), alcohol use disorder (AUD), as well as eating disorders that are characterized by food overconsumption, including binge eating disorder (BED) and bulimia nervosa (BN). These disorders (SUD, AUD, BED and BN) are each associated with high rates of morbidity and mortality, and treatment outcomes are poor, in part due to limited approved pharmacotherapies available for their clinical management. This paucity largely reflects an incomplete understanding of the mechanistic underpinning of these diseases, especially with respect to the neural systems that underlie uncontrolled drug and food seeking. Over the past ~20 years, there has been a gradual accumulation of evidence linking the sigma-1 receptor (S1R) system with disordered reward seeking in preclinical models of SUD, AUD and binge eating. The past 5 years, in particular, has witnessed the solving of the crystal structures of S1R, as well as a greater understanding of the mechanisms through which S1R signaling mediates reward seeking, thus prompting renewed interest in the development of selective S1R-based therapies for potential clincal application.

Here, we seek to provide a comprehensive and timely overview of the extant literature linking S1R signaling to drug and food behaviors. First, we describe efforts to characterize the S1R and how these have informed the development of compounds designed to modulate signaling at the S1R for therapeutic purposes. Next, we describe evidence linking S1R signaling to both drug and food behaviors, with an emphasis on those studies examining the utility of S1R modulators for reducing ‘addiction’ relevant outcomes. Finally, we consider potential shortcomings of targeting the S1R for the treatment of addictive disorders and highlight key unanswered questions that must be addressed before such compounds can be considered for clinical use. To this end, our goal herein is to stimulate efforts to further explore the S1R as a target for SUDs, AUD, BED, and related disorders. Although we focus on S1R, we note that significant recent advances have also been made in determining the structure of the sigma 2 receptor (S2R) [1], and that there is some evidence linking S2R to reward [2,3].

Phenotypic overlap of SUDs, AUD, and eating disorders

Significant recent attention has been given to the overlap in the behavioral symptoms of SUDs, AUD and binge eating, which is a core component of BED and BN, and is reliabily associated with overweight and obesity [4]. Proponents of this view highlight similarities in the diagnostic criteria for SUDs, AUD and binge eating episodes in BED and BN, as outlined in the Diagnostic and Statistical Manual for Mental Disorders (DSM5), including consumption of larger amounts than intended, frequent and intense cravings and continued use despite negative (health and otherwise) consequences [5,6]. Moreover, both SUDs, AUD and BED share a range of non-diagnostic phenomena, including comorbidity of mood disorders and sleep dysregulation [7]. Likewise, human and animal studies have identified several common brain regions and networks that underlie food and drug craving [8], and there is a high lifetime incidence of SUDs and AUD in persons with eating disorders [9]. These observations have led some to suggest that compulsive overeating, as in BED and BN, may reflect the ‘addictive’ properties of foods, particularly those with high fat and sugar contents that are now widely available in Western societies (e.g. cookies, cakes etc.) [6]. Although ‘Food Addiction’ has not been recognized by the DSM as a disorder separate from BED or BN, there has been widespread adoption of the Yale Food Addiction Scale (YFAS) since its development in 2009 as a means of measuring and ‘diagnosing’ addictive eating [5]. The majority of obese individuals meet the criteria for ‘food addiction’, as defined by the YFAS, and ‘addictive eating’ is observed at an increased rate among individuals with a current eating disorder diagnosis, including BED and BN [10,11]. Importantly, the notion of ‘food addiction’ as a diagnostic construct remains highly controversial and is sometimes criticized for its oversimplification of a complex behavioral phenomena [12]. Despite this, discussion of the similarities in the behavioral manifestation of SUDs, AUD and food overconsumption has highlighted the possibility that these disorders might share a common neurobiology [13,14].

To this end, there has been significant recent interest in whether compounds that are effective at reducing drug seeking might also exhibit some therapeutic benefit for BED and related disorders, and vice versa. By way of example, compounds that block the brain’s orexin neuropeptide system have been comprehensively shown in preclinical studies to be effective at reducing the seeking and motivated consumption of drugs of abuse (cocaine, opioids, alcohol) as well as highly palatable foods (reviewed in [15–18]). Despite this, clinical studies testing the utility of orexin receptor antagonists to treat SUDs and AUD are extremely limited at this time [19,20], and a recent Phase II trial of a selective orexin 1 receptor antagonist failed to find meaningful changes in binge eating outcomes associated with drug treatment [21]. Similarly, glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as highly effective treatments for promoting weight loss, however they are not currently approved for the management of binge eating [22,23]. Although there is an emerging literature to indicate that GLP-1 agonists might have some efficacy for treating SUDs and AUD, this possibility requires further investigation before a label extension for these compounds can be considered [24]. Similarly, although the ghrelin [25,26] and cannabinoid [27,28] systems have been explored in the context of both feeding and drug taking, compounds targeting these systems have so far failed to progress to clinical use for SUDs, AUD, BED or BN.

Interestingly, a parallel line of inquiry over the past 20 years has identified an alternative receptor system, the S1R, as playing a similarly common role in mediating motivated reward seeking, with mounting evidence indicating that this system might hold promise for reducing both drug and food overconsumption [29]. Several S1R-based compounds are currently at various stages of clinical development for different indications, potentially opening the door for the use of these drugs managing SUDs, AUD and binge eating. However, such an approach requires careful consideration of the pharmacology of the S1R system, as well as the results of behavioral and toxicological studies examining S1R-based drugs in preclinical models of these disorders.

Overview of the sigma 1 receptor system

The sigma receptors have remained somewhat enigmatic despite being the subject of intense research by pharmacologists and bio-chemists since their discovery over 40 years ago. The first description of sigma receptors was in 1976, when studies of opioid compounds in dogs led to the proposal of three distinct opioid receptor subtypes; mu (u), kappa (k) and sigma (σ) [30]. Subsequent work using radioligand binding approaches revealed that the sigma receptor does not bind classical opioid ligands such as naloxone [31] but rather has high affinity for benzomorphans, indicating that sigma receptor binding is distinct from other opioid receptors. In light of these data, the sigma-opioid receptor was re-named to sigma receptor [32]. The development of a specific radioligand with high affinity and specificity for sigma-1 receptor (S1R) in 1993 enabled the identification of two distinct sigma receptor bindings sites, the first being S1R (which largely corresponds to the classical σ receptor first described by Su and Tam), and the second being sigma 2 receptor (S2R), which does not bind benzomorphans but instead has high affinity for haloperidol and ditolylguanidine (DTG). The identification of endogenous ligands for either S1R or S2R remained elusive for many years. Some steroids, including progesterone, and the hallucinogen N,N-dimethyltryptamine (DMT) were shown to have actions at the S1R, although at non-physiological levels [33]. A recent study showed that the intracellular messenger choline binds S1R and mimics S1R agonists, pointing to its role as a potential endogenous modulator of the σ system [34]. Importantly, both S1R and SR2 have been cloned [35–37] and their crystal structures determined [1,38] which has allowed for a structural investigation into their function (for more details, see Recent Advances in the Development of S1R antagonists, below). The S1R does not share homology with any other mammalian protein, but is 90% identical and 95% similar across species [39].

It is now broadly accepted that S1Rs act as ligand-operated chaperone proteins that reside at the mitochondria associated membrane (MAM) of the endoplasmic reticulum (ER; for an overview, see Fig. 1). At rest, S1Rs form a complex with another chaperone protein, BiP (immunoglobulin heavy chain-binding protein), which plays a critical role in maintaining proper protein synthesis and degradation of misfolded proteasomal proteins [40]. Activation of the S1R by a ligand or depletion of ER calcium concentrations (ER stress) induces S1Rs to dissociate from BiP and interact with other proteins in the ER to regulate Ca²⁺ signaling and thus support cell survival and cellular stress responses. More critical to the topic at hand, however, is evidence that the S1R may translocate from the ER membrane to the nuclear and plasma membranes. Following translocation, S1Rs interact with various ion channels (K⁺, Na⁺ channels) and ion channel receptors (NMDARs; GluN1, Glun2a,b subunits). Coimmunoprecipitation studies also indicate that S1Rs physically associate with GPCRs, including several known to play critical roles in reward and motivated behavior, including the mu opioid receptor, corticotropin-releasing factor (CRF) receptor, dopamine receptors 1 and 2 (D1R and D2R), cannabinoid receptor 1 (CB1) and the orexin receptor (Ox1R) [41]. S1Rs also modulate the activity of stimulated dopamine neuronal activity via actions at the dopamine transporter [42]. S1Rs are ubiquitous and found in multiple organs, including heart, gastrointestinal tract, liver, testes and ovaries, as well as the central nervous system [43]. In the brain, S1R distribution is widespread, making them an attractive candidate for therapeutics for a broad range of psychiatric and neurological illnesses. Notable in the context of this article, S1R expression is particularly dense in regions known to be important in feeding and reward, including arcuate and paraventricular regions of hypothalamus, hippocampus, amygdala and septum, and more moderate expression in accumbens and locus coeruleus [44]. This pattern of expression, along with the aforementioned evidence indicating that S1R interacts with several reward-related receptor proteins, has prompted significant interest in the potential involvement of S1Rs in behavioral outcomes associated with excessive reward function, as in addiction and overeating [29].

Fig. 1.

Overview of the sigma-1 receptor system. A. Under baseline conditions, sigma-1 receptors (S1Rs) are predominantly localized in the endoplasmic reticulum (ER) membrane. S1Rs form complexes with binding immunoglobulin proteins (BiP’s; also known as GRP78), serving as chaperones to assist in protein folding and ER homeostasis. This interaction helps maintain ER function and regulate calcium signaling through inositol 1,4,5-trisphosphate receptors (IP3R’s). B. ER stress refers to the disruption of ER homeostasis, typically resulting from the accumulation of misfolded or unfolded proteins in the ER lumen. Under normal conditions, S1Rs bind to BiP, preventing its association with inositol-requiring enzyme 1 alpha (IRE1-alpha), an ER stress sensor protein. However, during ER stress, the accumulation of misfolded proteins leads to the dissociation of BiP from S1Rs, enabling BiP to bind to and activate IRE1-alpha. This activation results in the formation of IRE1-alpha dimers, leading to the splicing of XBP1 mRNA. The spliced XBP1 mRNA is then translated into an active transcription factor called XBP1s (X-box binding protein 1 s). XBP1s translocates to the nucleus and induces the expression of genes involved in the unfolded protein response (UPR) to alleviate ER stress, restore ER homeostasis, and enhance protein folding capacity. C. During ER stress, S1Rs undergo translocation from the ER to the mitochondria-associated endoplasmic reticulum membranes (MAM). Once localized at the MAM, S1Rs interact with IP3Rs and voltage-dependent anion channels (VDACs) to form a complex. This S1R-IP3R-VDAC complex plays a role in calcium signaling and modulation of ER-mitochondria communication, which is crucial for cellular homeostasis, response to stress, cell survival, and apoptosis. D. ER stress can also cause S1Rs to undergo translocation from the ER to various cellular compartments, including the plasma membrane. Once trans-located to the plasma membrane, S1Rs can interact with both excitatory and inhibitory synapses, including dopaminergic, orexinergic, serotonergic, opioidergic, and cannabinoid synapses. By interacting with these synapses, S1Rs are thought to modulate neurotransmitter release and signaling, contributing to the regulation of neuronal activity and various physiological processes. Notably however, these interactions are not as well-characterized in the literature compared to the S1R-IP3R-VDAC complex, and require further study (especially in the case of orexin transmission). Glu: Glutamate. DA: Dopamine. OxA: Orexin A. OxB: Orexin B; 5-HT: Serotonin; CBD: cannabanoids; GABA: gamma-aminobutyric acids.

Recent advances in the development of S1R antagonists

The chemical structures of commonly utilized S1R antagonists are presented in Fig. 2. As sigma receptors were initially and mistakenly identified as members of the opioid receptor family, binding to these receptors were considered off-targeted and undesired. For example, haloperidol (Fig. 2), a butyrophenone-based antipsychotic, has been shown to exhibit potent binding affinity for S1R (Ki = 2.3 nM) and be commonly used as a reference S1R antagonist for more than 20 years. However, haloperidol preferentially binds to dopamine receptors both in vitro and in vivo with sub-nano molar binding affinity for D2R and D3R [45,46]. NE-100, BD-1047, and BD-1063 are early selective S1R antagonists with potent binding affinity (Ki < 10 nM), and have been widely used as research probes [47,48]. Since the re-identification of S1R as a distinct receptor from opioid receptors in the mid of 1990s, and because of additional evidence linking S1R signaling with several disease states, there has been increased recent interest in the development of potent and selective S1R antagonists as potential therapeutic agents. PD-144418 exhibited very potent S1R binding (Ki = 0.08 nM) [49] and has been used to obtain the first X-ray crystal structures of human S1R [38]. Numerous S1R antagonists have been developed with various chemical structures, including pyrrolidine-ones, substituted piperazines, benzothiazole-ones, spirocyclics, di-substituted pyrazoles and triazoles (Fig. 2) [50–56].

Fig. 2.

Structures and binding affinities of representative S1R antagonists commonly utilized to examine the role of S1R signaling in reward behaviors. Subscripts (h, r, and gp) before S1R indicate different species: human, rat, and guinea pig.

MR309 (S1RA/E-52862), a potent and selective S1R antagonist (Ki =17 nM), has been the first of its kind to advance to Phase 2 clinical trials and showed promising proof-of-concept results in peripheral neuropathy of different etiologies (e.g., chemotherapy-induced neuropathy) as well as in the potentiation of opioid analgesia without inducing adverse effects associated with opioid use such as tolerance [54,57]. However, further clinical development of S1RA was dis-continued due to poor oral bioavailability and low efficacy [58]. The radio-tracer [¹⁸F]FTC-146, the most potent S1R antagonist thus far with a binding affinity (Ki) of 0.0025 nM (Fig. 2), has been studied in phase I clinical trials as a diagnostic agent for positron emission tomography/magnetic resonance imaging (PET/MRI) to identify sites of nerve damage in patients with chronic neuropathic pain [52,59]. Unfortunately however, its non-radiolabeled analog CM304 demonstrated an undesirable pharmacokinetics profile with a short elimination half-life (115 min) and moderate clearance (Cl = 33 mL/min/kg), which prevented this compound from advancing into clinical development, despite its efficacy in multiple preclinical models of pain [60].

The structural design and optimization of S1R antagonists with improved oral bioavailability, metabolic stability, and efficacy would address an urgent need for new treatments for the management of several conditions, includng those addressed in this article (SUDs, AUD and eating disorders). Our laboratory has discovered di-substituted 1,2,4 triazoles as potent and selective S1R antagonists (Fig. 2). The early lead Compound 10 (we named it PW507) showed an improved oral bioavailability of 28% (vs 15% for MR309) in rats, and is currently under preclinical development for the management of disorders characterized by uncontrolled reward seeking [46].

S1R as a modulator of the rewarding properties of drugs of abuse and palatable food

Expression of S1R in reward-related regions of the brain, as well as its physical association with canonical reward-related GPCRs (e.g. D1R, D2R), has driven interest in the potential involvement of S1R as a potential important mediator of drug and food behaviors. A considerable body of evidence now implicates the S1R as a key system governing behavioral and physiological reactivity to psychostimulants (cocaine, methamphetamine) and alcohol; below we summarize this evidence, including work that highlights S1R involvement in the development of ‘addiction’ to these drugs. We note that significant work has been dedicated to examining how the S1R system also modulates reactivity to opioids, including morphine; although some work has examined the implications for opioid addiction behaviors, most of it has focused on analgesia outcomes, and thus is not a focus here. As noted above, many of the same reward systems that mediate drug outcomes have been implicated in feeding. Thus, here we also provide a summary of emerging data implicating S1R in binge-like eating behaviors. Across both drugs and food, these data generally point to the S1R as a potential target for new medications to treat SUDs, AUD and overeating. However, as we draw attention to below, there remains many important, unanswered questions that should be the focus of future studies in this therapeutic area.

Psychostimulants

Cocaine and methamphetamine both bind S1R [55,61,62], pointing to S1R as a site through which these drugs might produce some of their physiological and reinforcing effects. Consistent with this, acute and repeated cocaine injections in mice increase S1R expression in several brain regions, including the cortex, olfactory bulb, hippocampus, striatum, and hypothalamus [63–65]. Interestingly, these studies found no cocaine-induced changes in S1R expression in cerebellum, perhaps indicating that their upregulation occurs specifically within reward-related regions. Changes in S1R levels following cocaine are blocked by pretreatment with S1R antagonists BD1063 and BD1047 [63–65] and S1R antagonists also partially block changes in gene expression observed following cocaine administration [66]. Similar to cocaine, methamphetamine increases S1R expression in specific regions, including ventral tegmental area (VTA) substantia nigra and olfactory bulb; no changes are observed in olfactory tubercle, amygdala, red nucleus and locus coeruleus [67,68]. Methamphetamine exposure is also associated with an increase in the ERK1 gene which is critical for S1R transcription [68]. S1R ligands are also effective modulators of cocaine and amphetamine outcomes. For example, pretreatment with the S1R antagonists BD1008, BD1060, and BD1067 mitigate cocaine-induced convulsions, hyperlocomotion, and toxicity [69]. Similarly, the S1R antagonists BMY 14,802, AZ66 and SN79 reduce methamphetamine-induced biting behavior and hyperthermia [55,70, 71]. Finally, administration of the non-selective sigma receptor agonist (+)SKF-10,047 induces psychotomimetic effects in dogs [30].

With respect to psychostimulant reward behaviors, S1R antagonists block locomotor reactivity and behavioral sensitization to both cocaine and methamphetamine [55,61,64,72,73], and these effects are recapitulated by genetic downregulation of S1R [61]. In animals trained to exhibit a conditioned place preference for cocaine (CPP), S1R agonists reinstate extinguished CPP, whereas the S1R antagonists NE-100 and BD1047 block the expression of CPP induced by a priming injection of cocaine [65]. This same study reported that BD1047 blocked reinstatement of an extinguished CPP for cocaine elicited by phencyclidine, nicotine and morphine (but not ethanol), indicating S1R might play a general role in mediating the reinforcing properties of several drugs of abuse [65]. Co-administration of S1R antagonist BD1063 with cocaine blocked the acquisition of CPP without affecting overall motor activity, indicating that these effects are unlikely due to non-specific soporific effects [2,]. Finally, CPP for methamphetamine is blocked by the antidepressant fluoxetine, which is a S1R agonist, and this effect is abrogated by co-administration of the S1R antagonist NE-100, further indicating an important role for S1R signaling in this type of psychostimulant reward behavior [74].

In line with experiments using non-contingent injections of cocaine or methamphetamine, the S1R system is an important mediator of operant responding for these drugs. Consistent with evidence that cocaine acts directly at S1R, rats trained to lever press for cocaine infusions exhibit stable lever responding when cocaine is substituted for a S1R agonist [75]. This appears to be dependent on prior drug experience, as other S1R agonists, PRE-084 and pentazocine, maintained responding only in rats with a history of cocaine (but not food) self-administration [76]. It is surprising, therefore, that the S1R antagonist BD1047 had no effect on low-effort responding for cocaine in rats [77]. However, this same study found that BD1047 is effective at reducing reinstatement of cocaine- (but not food-) seeking elicited by drug-associated discriminative stimuli, highlighting S1R antagonists as potential therapeutics designed to reduced drug relapse.

Although the mechanisms through which S1R mediates psychostimulant reward remains largely uncharacterized, recent work points to important functional interactions between S1R and the dopamine system. S1Rs are expressed in dopaminergic regions, including ventral tegmental area (VTA), substantia nigra and striatum [67,78,79], and S1Rs are expressed on dopamine neurons themselves [80]. One study reported that VTA dopamine neurons increase their basal firing activity when exposed to the S1R agonist (+)SKF-10,047 [81]; a subsequent study using the more selective agonist SA4503 failed to reproduce the increase in firing activity, but did report an increase in the number of spontaneously active VTA neurons [82], leaving the precise effects of S1R signaling on midbrain dopamine signaling somewhat unclear. Despite this, administration of the selective S1R agonist SA4503 increases DA levels in cortex [83]; this effect appears to be regionally-specific, as DA release in striatum appears to be mediated by S2R signaling, and largely unrelated to S1R signaling [76,84]. In animal models of Parkinson’s disease, S1R signaling has been shown to be both neuroprotective [80] and facilitate DA neurodegeneration [85], pointing to a complicated relationship between these two systems.

Several studies indicate that S1R interacts with the dopamine system to regulate reward behaviors. For example, CPP induced by treatment with a selective dopamine reuptake inhibitor is blocked by S1R antagonists [86]. S1R agonists shift the conformation of the dopamine transporter (DAT) towards an outward-facing conformation, which facilitates cocaine binding and enhances cocaine self-administration potency [85]. Consistent with this, co-administration of DAT inhibitors and sigma receptor antagonists attenuates cocaine and methamphetamine self-administration [87,88]. Other studies indicate that cocaine self-administration increases the number of dopamine receptor 2 (D2R)-S1R clusters in nucleus accumbens shell, and acute treatment with the monoamine stabilizer OSU-6162, which has high affinity for S1R, increases the density of D2R-S1R in the same region [89]. Cocaine-induced reorganization of D2R-S1R complexes may in turn contribute to the formation of adenosine 2A receptor (A2AR)-D2R-S1R heterocomplexes; this is interesting as A2AR agonists have anti-cocaine properties. However, a recent study reported that combined treatment with S1R and A2AR failed to inhibit cocaine self-adminstration [90], highlighting the need for further work to understand these interactions and their role in psychostimulant outcomes and behaviors. [75,91].

Alcohol

S1R expression levels appear to be linked to alcohol exposure and vulnerability. Genetically selected Sardinian alcohol-preferring rats have higher baseline S1R protein levels in nucleus accumbens compared to outbred Wistar rats, which is normalized by chronic, voluntary alcohol drinking [92]. Moreover, human alcohol use disorder patients exhibit polymorphisms in the 5′-upstream region of the S1R gene [93]. Similar to psychostimulants, the S1R appears to generally mediate the reinforcing effects of alcohol. For example, S1R KO mice exhibit higher homecage alcohol intake and lower sensitivity to the stimulant effects of ethanol [94], and pretreatment with the S1R antagonist BD-1047 decreased alcohol-induced locomotor activity [95,96]. Acute treatment with S1R antagonists NE-100 and BD-1063 reduced homecage intake of low (10%) and high (20–28%) concentrations of ethanol [96, 97] and prevented escalation of intake after 7d abstinence [97], while repeated administration of NE-100 over 7d reduces 24h homecage alcohol intake over the treatment period [97]. Similar effects are observed with daily (14d) treatment with BD-1063, which attenuates acquisition of homecage alcohol drinking without affecting total fluid or caloric intake, indicating a specific reduction in alcohol intake [92]. Finally, S1RA and BD-1063 both reduce binge-like alcohol intake in adolescent rats and have a persistent effect on ethanol intake in a two-bottle choice post-test, indicating that modulating the S1R with these compounds alters plasticity associated with ethanol drinking [98].

Also similar to psychostimulants, signaling at S1R appears to be important for alcohol seeking behaviors. For example, central injections of BD-1047 blocked the acquistion, expression and reinstatement of ethanol-induced CPP [95,99], whereas S1R agonists facilitated the acqusition of ethanol CPP and reinstate the expression of CPP following extinction [95]. These findings largely align with data from self-administration studies, which show that pretreatment with S1R antagonists are effective at reducing low-effort lever responding for ethanol [97] and break points for ethanol on a progressive ratio (PR) schedule [100]. Moreover, S1Rs antagonists block ethanol seeking in rats trained under a second-order schedule of reinforcement [92] and abrogate reinstatement of seeking elicited by discriminative stimuli following extinction training [101]. Importantly, these studies have generally reported that at doses that reduce alcohol responding, S1R antagonists do not affect responding for water or palatable solutions [96,97,100,101], indicating specificity and potential translational utility.

Finally, a recent study reported that the involvement of S1R in alcohol may extend beyond its reinforcing properties to mediating sequelae associated with chronic intake. Quadir and colleagues reported that mice given 36d of continuous homecage access to ethanol exhibit hyperalgesia, as indicated by increased thermal pain sensitivity, during acute (24 h) withdrawal. Acute treatment with BD-1063 reversed this effect without affecting thermal sensitivity in ethanol naïve mice or general locomotor activity in either group. These findings align with evidence that S1R signaling modulates neuropathic pain, including by interacting with opioid receptors to restrain their function [102]. Given that hyperalgesic states are thought to promote ongoing alcohol use in alcohol use disorder, these data indicate that the therapeutic effects of S1R antagonists for treating this condition might be multifaceted.

Palatable food

As discussed above, there has been significant recent interest in the phenotypic overlap between substance use disorders and conditions associated with overeating, including binge eating. Clinically, binge eating is defined by the consumption of large amounts of food in a short amount of time and a subjective sense of loss of control. This can be modeled in laboratory animals (typically rodents) via several related procedures that involve providing access to palatable foods for restricted periods (for review, see [14]). As with drugs of abuse, binge-like consumption of palatable foods alters S1R gene expression and protein levels in brain regions involved in reward [103], indicating a role for this system in mediating excessive food intake. Notable also is that S1R knockout mice maintained on a high fat diet have lower fat mass compared to wildtype controls, but do not differ in metabolism, indicating that S1R is important for diet-induced adiposity [104].

Several studies now indicate that S1R antagonists generally suppress binge-like intake of palatable foods. In rats given cycling home cage access to chow (2d) and high-sucrose palatable food (1d), the S1R antagonist BD-1063 prevented escalation of palatable food intake across successive cycles [105]. Similarly, in rats trained to lever press for sucrose pellets for 1 h/d, a procedure that promotes an escalation of intake that recapitulates the ‘loss of control’ over food intake observed in BED, BD-1063 abrograted sucrose consumption [103]. This study also reported that BD-1063 reduced time spent and the amount of food eaten in an aversive environment, considered a proxy of ‘compulsive’ food seeking. Interestingly, a separate study showed that in rats trained to respond for saccharin or sucrose pellets on a schedule of reinforcement that did not promote binge-like intake, repeated pretreatment with an S1R agonist increased intake of both foods [100]. In a different procedure where rats undergo repeated cycles of food restriction followed by brief access to a sweetened fat mixture, S1R antagonists blocked overeating induced by stress [106,107]. Finally, acute treatment of BD-1063 and BD1047 reduced discriminative stimulus-driven reinstatement of sweetened-condensed milk seeking and a highly palatable glucose/saccaharin mix, respectively [77,101]. Thus, across several paradigms that promote binge-like intake or seeking of palatable foods, S1R antagonists reliably reduce both outcomes.

One key question with any therapeutic designed to reduce ‘problematic’ food intake is its effect on homeostatic feeding. In this respect, data on S1R antagonists are mixed. For example, one study reported that several S1R antagonists, including BD-1063 and NE-100, decreased rates of food-maintained responding at doses that had no effect on cocaine self-administration [88]. Despite this, several other studies have reported limited/no effect of S1R antagonists on food intake. In three separate studies, BD-1063 had no effect on regular chow or water intake at doses that suppressed palatable food [103,105] and alcohol intake [96]. Notably, the doses of BD-1063 used in these studies was similar to those previously shown to affect cocaine and methamphetamine outcomes [61,63,64,72], indicating a potential dosing window in which this compound might impair drug and palatable food motivation without affecting homeostatic food intake. Similarly, studies using the S1R antagonist NE-100 indicate that this compound has no effect on food or water intake at doses that reduce ethanol intake [97]. Moreover, S1R antagonists impaired motivated responding for sucrose in sated, but not food-deprived rats [108,109], and did not affect free-feeding of sucrose [109], indicating a selective interference with hedonic feeding. One challenge in interpreting these data is the fact that very few studies have tested feeding outcomes in animals treated with a clinically relevant dosing regimen (i.e., repeated daily dosing); these studies will be necessary for evaluating any potential off-target effects on homeostatic feeding outcomes.

Considerations regarding the therapeutic development of S1R antagonists for motivational disorders

As outlined above, data from preclinical studies generally indicate that S1R modulators might hold therapeutic utility for the management of psychiatric conditions associated with excessive drug and food intake, including SUD, AUD and binge eating disorder. The development of S1R modulators, including antagonists, for clinical use has been fraught, not least due to difficulities in designing compounds with suitable bioavailability following oral dosing, although several new compounds, including our PW507 compound, appear to be more favorable in this regard. Despite this, several other important considerations exist relating to the potential therapeutic use of S1R antagonists. First, S1Rs are expressed in peripheral tissues, including heart, gastrointestinal tract, and liver [110], and their signaling has been shown to promote positive health outcomes in a slew of conditions, including chronic heart failure [111] and coronavirus disease 2019 (COVID-19; [112]). Compounds with high brain-to-plasma ratios may have preferable toxicity and tolerability profiles in this regard. Alternatively, it may be possible to combine a S1R modulator with a second, peripherally-restricted compound that serves to counteract any off-target effects resulting from binding in the periphery, as has been done recently with other systems [113]. Next, within the brain, signaling at S1R is important for a range of psychiatric (mood, anxiety, memory) and non-psychiatric (synaptogenesis, motor) outcomes. Notably, S1R antagonism can promote depression-like outcomes, and the S1R agonist properties of several compounds has been linked to their antidepressant effects [114]. Indeed, a combination drug containing dextromethorphan, which acts as a S1R agonist, recently gained FDA approved for the treatment of major depressive disorder following successful clinical trial outcomes [115]. It would thus seem important that any treatment approach involving chronic S1R antagonism examine the implicatons for mood and related outcomes. Relatedly, it will be important to determine the precise brain loci where S1R signaling mediates reward; it is likely that these circuits are distinct from those that mediate other psychiatric outcomes. Finally, although there are some examples of studies examining behavioral outcomes in both male and female animals, potential sex-dependent effects of S1R antagonists remain to be fully characterized. This is important, as S1R is activated by 17b-estradiol and testosterone, which bind at different sites and can exert opposing pharmacological effects [116,117] and sex-dependent effects of S1R antagonists on other health-related outcomes have been reported in rats [117].

Conclusions

In conclusion, there has been a gradual accumulation of evidence implicating the S1R system in the regulation of behaviors relating to drugs of abuse and palatable foods. As such, there is interest in S1R modulators as potential novel treatments for SUDs, AUD and eating disorders characterized by uncontrolled eating, including BED. Recent advances in our understanding of the S1R, including identification of the crystal structures of the S1R, has paved the way for the development of selective S1R antagonists and thereby potential therapeutics. However, further research is needed to address key questions and potential limitations before these compounds can be considered for clinical use. Nevertheless, the growing interest in S1R-based therapies holds promise for improving treatment outcomes and addressing the significant burden imposed by these disorders on individuals and society. Continued exploration of the S1R system as a target for SUDs, AUD and binge eating disorder, and related disorders is warranted to advance the development of more effective treatments for these conditions.