Cocaine use disorder: A look at metabotropic glutamate receptors and glutamate transporters
Ewa Niedzielska-Andres 1, Lucyna Pomierny-Chamioło 2, Michał Andres 3, Maria Walczak 4, Lori A Knackstedt 5, Małgorzata Filip 6, Edmund Przegaliński 6
Abstract
Glutamate transmission is an important mediator of the development of substance use disorders, particularly with regard to relapse. The present review summarizes the changes in glutamate levels in the reward system (the prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, and ventral tegmental area) observed in preclinical studies at different stages of cocaine exposure and withdrawal as well as after reinstatement of cocaine-seeking behavior. We also summarize changes in the glutamate transporters xCT and GLT-1 and metabotropic glutamate receptors mGlu2/3, mGlu1, and mGlu5 based on preclinical and clinical studies with an emphasis on their role in cocaine-seeking. Glutamate transporters, such as GLT-1 and xc-, play a key role in maintaining glutamate homeostasis. In preclinical models, agents reversing cocaine-induced decreases in GLT-1 and xc- in the nucleus accumbens attenuate relapse. Very recent studies indicate that other mechanisms of action, such as reversing the mGlu2 receptor downregulation, contribute to these compounds’ anti-relapse efficacy. In preclinical models, antagonism of mGlu5 receptors and stimulation of mGlu2/3 autoreceptors decrease relapse. Therefore, analysis of the above glutamatergic adaptations seems to be crucial because, so far, there are no prognostic biomarkers that can forecast relapse vulnerability in clinical practice, which would be helpful in alleviating or suppressing this phenomenon. Moreover, these receptor sites can be molecular targets for the development of effective medication for cocaine use disorder.
Keywords: Cocaine addiction; Cocaine use disorder; GLT-1; Glutamate; mGluR1; mGluR2/3; mGluR5; xCT; xc-.
1. Introduction
1.1. Substance use disorder
Abuse of psychoactive substances is a chronic disease of the central nervous system (CNS). The behavioral hallmarks of substance use disorders (SUDs) are an overwhelming motivation to seek and use psychoactive substances and compulsive, uncontrollable drug administration in spite of known, negative consequences (Castilla-Ortega et al., 2016; Kostowski, 2006).
An initial decision to take the drug is voluntary, but repeated drug use can lead to drug-induced neuroadaptations that distort selfcontrol and decrease the ability to resist the desire to obtain drugs (Kalivas & Volkow, 2005). The nature of SUDs does not lie in the number and frequency of drug use episodes but in difficulties in controlling compulsive behaviors (Belin & Deroche-Gamonet, 2012).
Another important component of SUDs is related to the development of an association between the effects of addictive drugs and the stimuli that usually accompany their use. These stimuli can include contextual cues such as the sound of a song heard during earlier drug use or discrete cues like a pipe for crack smoking or razor blades applied to cut cocaine into lines. The association between drug effects and stimuli paired with drug use triggers learned reactions that induce drug-craving and -seeking behavior in response to cue presentation. Prolonged drug use perpetuates these reactions that become habits. Under normal circumstances, habit formation is an adaptive learning process that is useful in performing complex tasks in an automatic way, like driving. However, in relation to SUDs, habit formation is a pathological process and leads to habitual drug-seeking and drug-use. The habit formation is accompanied by neurobiological changes that can be permanent, and hence, SUD is a disease characterized by relapses. Importantly, people with SUD show increased risk of relapse to drug use even after many years of withdrawal (Castilla-Ortega et al., 2016).
1.2. Cocaine
Cocaine belongs to the psychostimulant class of drugs. According to the last World Drug Report, cocaine remains one of the most popular abused drugs, and it was estimated that approximately 18 million people worldwide were cocaine past-year users in 2017 (World Drug Report: Stimulants, 2019). The largest cocaine-using populations were identified in North America, South America, Oceania, and Western, Central, and Southern Europe (World Drug Report: Stimulants, 2019). A recent analysis (urban wastewater) has indicated that cocaine consumption is presently rising (World Drug Report: Stimulants, 2019). It has been estimated that 2-3 million young Europeans aged 15–34 years consumed cocaine at least once a year (EMCDDA, 2017). The estimated cocaine market is worth 5.7 billion Euro per year on average (World Drug Report, 2017).
1.3. Glutamate and drug-seeking
Cocaine directly binds to dopamine, noradrenaline, and serotonin transporters, blocking transport and increasing concentrations of these neurotransmitters in the synapse. While exaggerated dopaminergic transmission is most significant early in the course of drug use and mediates the rewarding effect of psychoactive substances and associative learning, glutamatergic transmission is an important mediator of drug-seeking after a period of withdrawal and is particularly important in mediating relapse (Kalivas, 2009; Kalivas & Duffy, 1998; Spencer & Kalivas, 2017). In this aspect, great significance is attached to the glutamatergic system because of its involvement in sensitization to drug effects, habit formation, neuroplasticity, and reinforcement learning (Kalivas, 2009).
1.4. Organization of the glutamatergic system
Glutamate is the main excitatory neurotransmitter, responsible for almost 70-90% of synaptic transmission in the CNS (PomiernyChamioło et al., 2014). Glutamate is synthesized in presynaptic nerve endings from glucose in the Krebs cycle or from glutamine. Glutamine is synthesized in glial cells, and the reaction of its formation is catalyzed by glutaminase. It is then released into the extrasynaptic space and transported to nerve terminals. In presynaptic neuronal terminals, glutamine is transformed to glutamate by mitochondrial glutaminase (Schmidt & Pierce, 2010), and glutamate is transported to synaptic vesicles. After depolarization of presynaptic endings, glutamate is released to intersynaptic space, where it passively diffuses and binds to pre-, post-, and peri-synaptic glutamate receptors (Schmidt & Pierce, 2010) that belong to ionotropic or metabotropic receptors. Subsequently, glutamate is removed by excitatory amino acid transporters 1-5 (termed EAATs 1-5 in humans) (Had-Aissouni, 2012). The most prevalent glutamate transporter in the CNS is EAAT2, which in the rodent is termed “GLT-1” (Haugeto et al., 1996; Lehre, Levy, Ottersen, Storm-Mathisen, & Danbolt, 1995). Glutamate transported into glial cells is released again to extrasynaptic space by cystine-glutamate antiporter (xc-) (Baker et al., 2002). A portion of glutamate removed from the extrasynaptic compartment by GLT-1 is then packaged into vesicles for release by astrocytes (Höltje et al., 2008; Xu et al., 2007), while the remaining portion is converted to glutamine. An increase in intra-glial glutamate concentrations promotes the formation of glutamatecontaining vesicles, which then fuse to the glial membrane and exocytose glutamate (Höltje et al., 2008; Xu et al., 2007).
The present review summarizes the changes in glutamate levels in structures of the reward system such as the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (DSTR), hippocampus (HIP), and ventral tegmental area (VTA) that have been observed in preclinical studies at different stages of cocaine experience. Moreover, the changes in expression of the glutamate transporters xCT and GLT-1 and metabotropic glutamate receptors mGluR2/3, mGluR1, and mGluR5 were compared at different stages of cocaine exposure and withdrawal in preclinical and clinical studies. The results of such studies can contribute to the identification of targets for potential medications to reduce cocaine-seeking. Consideration of the levels of the above-mentioned proteins is also crucial because so far, there are no prognostic biomarkers that can forecast relapse vulnerability in clinical practice and thus be helpful in alleviating or suppressing this phenomenon.
1.5. The effect of cocaine experience on extracellular glutamate levels in the structures of the reward system
A number of studies have measured extracellular glutamate levels after cocaine experience using microdialysis and, more recently, amperometric methods (Siemsen et al., 2020). Glutamate levels can also be assessed using PET ligands for the mGluR5 receptor and magnetic resonance (MR) spectroscopy. In this review, we describe changes in glutamate levels and the expression of glutamate transporters and receptors during drug administration and after a period of withdrawal. Many preclinical studies utilize the intravenous drug self-administration paradigm, where a response (e.g. lever press or nose poke) results in the delivery of intravenous cocaine. Following a self-administration period, some studies then utilize extinction procedures, wherein the association between drug-paired cues (usually stimulus light and/or tone) and drug delivery is weakened by cue presentation without those events happening (Myers & Carlezon Jr, 2010). Here, the term withdrawal refers to a period of forced drug abstinence without extinction training. In practice, forced abstinence implies removing the access to the drug as well as the place where the animal obtained drug infusion/injection by placing it, for example, in the home cage.
1.5.1. Prefrontal cortex
Human studies with magnetic resonance imaging (MRI) or positron emission tomography (PET) demonstrated that the PFC is involved in different aspects of drug use, including drug craving in which it is activated and cocaine withdrawal when its activity drops (Bell, Milne, & Lyons, 1994; Volkow, Mullani, Gould, Adler, & Krajewski, 1988; Wilson, Sayette, & Fiez, 2004). The PFC is also activated during acute intoxication (Howell et al., 2002). Few studies investigate glutamate release in the PFC at different stages of cocaine experience. Glutamate levels in the PFC diminish during cocaine self-administration (measured on day 7 and 14 of cocaine self-administration using MR spectroscopy), normalize after 7 days of withdrawal, and remain at the pre-cocaine level on day 14 of withdrawal (de Laat et al., 2018). Using no-net-flux microdialysis, (Baker et al., 2003a) showed that after 3-week withdrawal from non-contingent cocaine, extracellular glutamate levels remained unchanged in the PFC (Baker et al., 2003a).
Using conventional microdialysis techniques, Williams and Steketee (2004) noted elevated glutamate release in the mPFC after cocaine challenge at 1 and 7 days of cocaine withdrawal but only in animals exhibiting locomotor sensitization (Williams & Steketee, 2004). This change was not seen after 21 days of withdrawal, even in sensitized animals. After intravenous cocaine self-administration withdrawal, cued cocaine-seeking was accompanied by increased extracellular glutamate levels in the vmPFC after 30 days of abstinence but not 3 days. Lever pressing during the test of cued cocaine-seeking positively correlated with vmPFC glutamate levels (Shin et al., 2016). The same relationship was not observed in rats that had self-administered sucrose pellets or pressed the lever for cues only. No differences in baseline glutamate (prior to the relapse test) were found between the 3- and 30-day abstinence conditions; however, no cocaine-naïve control group was used. The same authors later determined that after 30 (but not 3) days of withdrawal from cocaine, reducing glutamate release with an mGluR2/3 agonist administered into the dmPFC reduces cued cocaineseeking (Shin et al., 2018). The same treatment into the vmPFC has no effect on cocaine-seeking. Enhancing glutamate levels in the vmPFC with the GLT-1 blocker TBOA does not increase cocaine-seeking, but instead inhibits it. Injection of TBOA into the dmPFC had no effect on behavior.
Taken together, these findings reveal that after withdrawal from both contingent and non-contingent cocaine, basal glutamate levels in the mPFC are unchanged. However, both cocaine itself and cocainepaired cues have the potential to induce glutamate release in the PFC. Such increase is relevant to cocaine-seeking because pharmacological inhibition of glutamate release prevents cued cocaine-seeking. It is not clear at this time whether this increase in glutamate is synaptic (derived from action potentials). A summary of changes in glutamate release in the PFC in different phases of cocaine experience is presented in Table 1.
1.5.2. Nucleus accumbens
The NAc contains glutamate terminals from neurons of the PFC, HIP, AMY,andTh(Brog,Salyapongse,Deutch,&Zahm,1993).TheVTAalsoreleasesdopamineand glutamate into the NAc (Hnasko, Hjelmstad, Fields, &Edwards, 2012). Inpreclinical studies, changes inNAc glutamate levels were examined at different stages following cocaine administration/ self-administration: 1) immediately after single/repeated cocaine doses (without withdrawal), 2) during cocaine withdrawal, and 3) during relapse to cocaine administration (Table 2).
A single non-contingent injection of a high dose of cocaine (15-30 mg/kg i.p.) produces a rise in extracellular glutamate in the NAc of drug-naïve rodents (Reid, Hsu, & Berger, 1997; Smith, Mo, Guo, Kunko, & Robinson, 1995). These doses of cocaine are higher than that required for reward. The noncontingent acute administration of cocaine dose (10 mg/kg intraperitoneally (i.p.); 1-4 mg/kg intravenously (i.v.) ) sufficient for manifestation of the rewarding effect is not accompanied by a rise in extracellular glutamate (Miguens et al., 2008; Suto, Ecke, You, & Wise, 2010; Zhang, Loonam, Noailles, & Angulo, 2001). While the above assessments of glutamate were accomplished with microdialysis and HPLC procedures, voltammetric assessment of glutamate levels finds that a single administration of 1 mg/kg i.v. cocaine elevates extracellular glutamate in the NAc (Wakabayashi & Kiyatkin, 2012). Voltammetry may be more sensitive to glutamate changes, which explains the discrepancy in results.
Repeated cocaine administration usage has been found to have different effects on accumbens glutamate levels depending on whether the cocaine was administered in a contingent or non-contingent manner (Suto et al., 2010). In rats with a history of 10-20 days of i.v. cocaine self-administration, extracellular glutamate is elevated in the NAc core and shell during cocaine self-administration sessions (Suto et al., 2010). Interestingly, passive i.v. cocaine (yoke) delivery decreases extracellular glutamate throughout a four-hour session (Suto et al., 2010). These differences indicate that motivation to take the drug (in self-administering animals) or its lack (yoked procedure) diversely modulates cocaine-induced extracellular glutamate level in the NAc.
During a single extinction session (24-48 hours following the last cocaine session) in which a discriminative stimulus (odor) previously associated with cocaine was present, extracellular glutamate levels increase in the NAc core and shell (Suto et al., 2010). The increase in glutamate levels during the extinction session is more pronounced early in the session and decreases over the four-hour session in contrast with a self-administration session, when glutamate level remains increased (Suto et al., 2010). Presentation of the odor cue that indicated that cocaine was not available resulted in decreased glutamate relative to baseline (Suto et al., 2010). When a cocaine-primed reinstatement test was conducted 24 h after the last cocaine self-administration session, NAc core glutamate levels increased relative to baseline. Thus, even after short periods of withdrawal, glutamate increases in the NAc during a relapse test.
Extinction of 5, 10, or 14-21 days (without relapse test) reduced the level of extracellular glutamate in the NAc (Miguens et al., 2008; Trantham-Davidson, LaLumiere, Reissner, Kalivas, & Knackstedt, 2012; Wydra et al., 2013).
During the reinstatement of cocaine-seeking, extracellular glutamate level is increased in the NAc (Hotsenpiller, Giorgetti, & Wolf, 2001; LaCrosse, Hill, & Knackstedt, 2016; Lutgen et al., 2014; McFarland, Lapish, & Kalivas, 2003; Miguens et al., 2008; Pierce, Bell, Duffy, & Kalivas, 1996; Reid & Berger, 1996; Siemsen et al., 2020; A. Smith et al., 2017; Trantham-Davidson et al., 2012; Zhang et al., 2001). This effect is observed across multiple stimuli inducing relapse and after a range of withdrawal times. For example, an increase in extracellular glutamate level is observed in the NAc when cocaineprimed reinstatement testing occurs 1, 21, or 60 days after the end of cocaine self-administration and to a similar degree in rats afforded brief (2 h) and extended (6 h) access to cocaine self-administration (Lutgen et al., 2014). While most studies assessing NAc glutamate release during a relapse test have used cocaine-primed reinstatement (e.g. McFarland et al., 2003), cue-primed and cocaine+cue-primed reinstatement are also accompanied by increased extracellular glutamate level in the NAc (Smith et al., 2017; Stennett, Frankowski, Peris, & Knackstedt, 2017). Glutamate release in the NAc core also accompanies cocaine-seeking after abstinence without extinction procedures, when it is prompted both by re-exposure to the cocaine-taking context only after 21 days of abstinence (LaCrosse et al., 2016) and when prompted by both context and cues (Bechard et al., 2020). McFarland et al. (2003) found that during cocaine-primed reinstatement, this glutamate release was TTX-dependent and required activation of the dmPFC (McFarland et al., 2003).
Followingaperiodofabstinencefromcocaine(24hrs–21days),basal extracellularglutamatelevelshaveconsistentlybeenfoundtobereduced in the NAc (Baker et al., 2003a; Lutgen et al., 2014; Pierce et al., 1996; Trantham-Davidson et al., 2012; Wydra et al., 2013). Basal glutamate referstoglutamatelevelsassessedoutsideofthedrug-takingenvironment, in the absence of cocaine itself or cocaine-associated cues. The source of suchNAcbasalglutamateissystemxc-,thecystine-glutamateexchanger, the activity of which is also decreased following noncontingent and selfadministered cocaine (Baker et al., 2003a; Trantham-Davidson et al., 2012).
Taken together, glutamate levels in the NAc are consistently found to be reduced following both short and long abstinence/extinction periods and increase when reinstatement of cocaine-seeking is primed by cocaine itself, cocaine-associated cues and context, and the combination of these stimuli. The increases in glutamate during reinstatement tests occur after both abstinence and extinction procedures. As basal glutamate in the NAc primarily arises from system xc-, the decreased basal glutamate levels are extrasynaptic, both physically outside of the synapse (from astrocytes) and derived from nonsynaptic (e.g. non-TTX dependent) sources. Conversely, the glutamate released during a reinstatement test is synaptic, as it is TTX dependent. Finally, while rats that self-administer cocaine in extended access paradigms display greater cocaine-primed reinstatement than those self-administering in limited access (2 h/day) sessions, the glutamate release during reinstatement is no different between groups, and the change is not found at basal, nonsynaptic glutamate levels (Lutgen et al., 2014).
1.5.3. Dorsal striatum
Evidence for cocaine-induced changes in glutamatergic transmission in the DSTR is considerably less than for the neighboring NAc. Acute intraperitoneal (i.p.) injection of cocaine 10 mg/kg or 20 mg/kg does not increase extracellular glutamate levels in the DSTR (Lee et al., 2008; Shin et al., 2007; Zhang et al., 2001). However, after repeated noncontingent or self-administered cocaine, increased glutamate is observed in the DSTR. When assessed under chloral hydrate anesthesia using glutamate biosensors, repeated noncontingent cocaine administrations increased glutamate levels for at least the first 30 minutes post-injection on each of 9 days of repeated cocaine (Lee et al., 2008). Zhang et al., 2001 found that after 7 days of repeated cocaine, on a challenge injection administered after 4 days of abstinence, glutamate levels increased and were accompanied by locomotor sensitization. Similarly, 24 h following the last of 10 cocaine self-administration sessions, a non-contingent cocaine injection increased glutamate levels but had no effect in cocaine-naïve rats (Gabriele, Pacchioni, & See, 2012). After the same regimen of cocaine self-administration, glutamate levels only increased during an extinction session on Day 1 of abstinence. After 14 days of abstinence, when rats underwent a single extinction session (context-primed relapse test), no increase in glutamate efflux was observed (Gabriele et al., 2012). Based on the above data, it can be concluded that an increase in extracellular glutamate level in the DSTR occurs after short withdrawal from repeated passive and self-administered cocaine, but not during a context-primed relapse test. A summary of changes in the glutamate level in the DSTR in different phases of cocaine experience is presented in Table 1.
1.5.4. Hippocampus
The HIP is a structure engaged in memory and emotional processes. It is built mostly of excitatory glutamatergic neurons and inhibitory GABAergic interneurons, and the latter compose ca. 10% of its structure (Castilla-Ortega et al., 2016). Four anatomical substructures can be distinguished in the HIP: CA1, CA2, and CA3 areas and dentate gyrus. The HIP contains glutamate terminals from the PFC and AMY while the HIP sends glutamatergic projections to the NAc and septum. The HIP, via its connections, mediates the impact of emotion and motivation on memory and learning processes. Studies on the glutamate level at different stages of cocaine experience in the HIP are lacking. At present, only one study investigated glutamate release in the HIP and found that a high dose of cocaine (75 mg/kg) induced seizures and a surge of glutamate in the HIP (Gobira et al., 2015).
1.5.5. Ventral tegmental area
Studies on the significance of the glutamatergic system in cocaine experience were also conducted in the VTA. The VTA receives projections from the PFC and AMY (Castilla-Ortega et al., 2016). Both acute and chronic cocaine administration (i.p.) elevates extracellular dopamine level in the VTA (Kalivas & Duffy, 1995, 1998; Zhang et al., 2001). A similar effect is observed after regular self-administration of cocaine (You, Wang, Zitzman, Azari, & Wise, 2007). This effect is a result of enhancement of dopamine D1 receptor-dependent signaling and is silenced by functional blockade of these receptors by local administration of D1 antagonists (Kalivas, 2009; Kalivas & Duffy, 1995, 1998). Interestingly, as in the case of dopamine, glutamate release also increases in the VTA after presentation of cocaine-associated cues (Wise, 2009; You et al., 2007). This release is TTX-dependent and is thus synaptic in origin (You et al., 2007).
In conclusion, cocaine use causes changes in extracellular glutamate level/glutamate release in different structures of the reward system at various stages of cocaine experience. Increased glutamate concentrations during reinstatement have been demonstrated to be synaptic in origin in the NAc and VTA. Conversely, the decrease in basal glutamate observed in the NAc after abstinence from cocaine is due to decreased extra-synaptic glutamate export via system xc-. Considering the fact that glutamate interacts inter alia with metabotropic receptors like mGluR1 or mGluR5 and its level is regulated by the transporters GLT-1 and xc- and mGlu2/3 receptor, these components can play an important role in the development of cocaine use disorder.
2. Glutamate transporters
To date, five types of excitatory amino acid transporters (EAAT) were identified: EAAT1/GLAST (gene: SLC1A3), EAAT2/GLT1 (gene: SLC1A2), EAAT3/EAAC1 (gene: SLC1A1), EAAT4 (gene: SLC1A6), and EAAT5 (gene: SLC1A7). These are sodium ion Na+ -dependent highaffinity glutamate transporters, characterized by distinct anatomical and cellular locations (Beart & O’Shea, 2007). They transport one molecule of glutamate with three cations of Na+ and one H+ against the concentration gradient while removing one K+ molecule (Grewer et al., 2008).
2.1. GLT-1
The transporter EAAT2 (rodent GLT-1) plays a key role in maintaining glutamate homeostasis or the balance between glutamate release and reuptake. This transporter is one of the most abundant proteins in the CNS and is found throughout the brain (Takahashi, Foster, & Lin, 2015). GLT-1 is responsible for ca. 90% uptake of extracellular glutamate (Sari, Smith, Ali, & Rebec, 2009; Takahashi et al., 2015), and as such, it protects cells against excitotoxicity and excessive receptor stimulation (Takahashi et al., 2015). In both laboratory animals and humans, it is localized mostly in the cell membrane of astrocytes and to a lesser extent in the cell membrane of neurons (Chen et al., 2004; Furness et al., 2008; Holmseth et al., 2009; Takahashi et al., 2015) This transporter acts to remove glutamate from extracellular space to astrocytes where it can be metabolized inter alia to glutamine which is indispensable for the proper function of neurons or glutathione which is an important component of the antioxidant protective system. There are at least three isoforms of GLT-1 differing in C-terminal sequence: GLT-1a, GLT-1b, and GLT-1c (Holmseth et al., 2009; Peacey, Miller, Dunlop, & Rattray, 2009). These isoforms also differ in the distribution in the brain; for instance, the HIP contains 90% of GLT-1a, 6% of GLT-1b, and 1% of GLT-1c (Holmseth et al., 2009).
2.1.1. GLT-1 and cocaine-seeking
2.1.1.1. Preclinical studies. Preclinical studies report that following 2-3 weeks of extinction of standard (2 h/day) cocaine self-administration, GLT-1 is decreased in the NAc (Sepulveda-Orengo et al., 2018) and specifically in the NAc core (Knackstedt, Melendez, & Kalivas, 2010, ); Reissner et al., 2014, 2015; LaCrosse et al., 2017). Decreased GLT-1 expression in the NAc core is also present in female rats after extinction from 2 h/day cocaine self-administration (Bechard, Hamor, Schwendt, & Knackstedt, 2018). Fischer-Smith, Houston, and Rebec (2012) showed that GLT-1 protein in the NAc core was downregulated both after short (1 day) and long (40-45 days) abstinence from limited (2 h/day) or extended (6 h/day) access to cocaine self-administration. In this study, GLT-1 reduction was also observed in the NAc shell (except after 1 day abstinence from limited access); however, it was weaker than in the NAc core (Fischer-Smith et al., 2012). As the decreases in the NAc core GLT-1 expression correlate with enhanced cue-induced cocaineseeking, these results suggest the involvement of GLT-1 in relapse to cocaine-seeking (Spencer & Kalivas, 2017). The reinstatement (Hammad, Alasmari, Althobaiti, & Sari, 2017) and persistence (Niedzielska-Andres, Mizera, Sadakierska-Chudy, Pomierny-Chamioło, & Filip, 2019) of cocaine-induced place preference is also accompanied by reduced GLT-1 expression both in the NAc core and shell. The changes in GLT-1 expression in the rat brain are presented in Table 3.
The molecular mechanism of the cocaine-induced GLT-1 reduction in the NAc has not been fully explained. Following short access (2 h/ day) cocaine self-administration, GLT-1a and GLT-1b mRNA is not decreased in the NA core (Kim, Sepulveda-Orengo, Healey, Williams, & Reissner, 2018; LaCrosse et al., 2017). However, extended access to self-administration (6 h/day) and prolonged withdrawal (45 days) led to a drop in mRNA for GLT-1a isoform in the NAc and basolateral amygdala (BLA) and in mRNA for GLT-1b isoform in the prelimbic cortex. It was also revealed that the decreases in GLT-1 mRNA were accompanied by hypermethylation of GLT-1 gene in the NAc, which suggests an epigenetic mechanism of these changes (Kim et al., 2018).
GLT-1 level has also been determined in the PFC. No changes in GLT1 level in the PFC (Knackstedt, Melendez, & Kalivas, 2010; ) or dmPFC (Reissner et al., 2014, 2015) have been found after 12-21 days of extinction of cocaine self-administration. Reinstatement to conditioned-place preference decreased GLT-1 level in the dmPFC (Hammad et al., 2017).
Several studies documented that compounds that restore GLT-1 activity and expression suppress the reinstatement of cocaine-seeking triggered by cue presentation, cocaine challenge, or exposure to the cocaine-associated environment. The following compounds showed such ability: propentoxyphylline (Reissner et al., 2014), Nacetylcysteine (Knackstedt, Melendez, & Kalivas, 2010, ), beta-lactam antibiotics like ampicillin (Hammad et al., 2017), and ceftriaxone (Knackstedt, Melendez, & Kalivas, 2010; ; LaCrosse et al., 2017; Sari et al., 2009). Additionally, it was shown that ceftriaxone can restore the co-localization of astrocytes and neurons to levels of cocaine-naïve controls (Scofield et al., 2016). In the study by Scofield et al. (2016), cocaine decreases co-localization of neurons and astrocytes and decreases astrocyte size in the NAc. These cocaine-induced effects may potentially weaken the removal of glutamate from the synaptic cleft to astrocytes in the NAc during reinstatement to cocaine-seeking. Thus, apart from GLT-1 expression/activity restoring ability, ceftriaxone may also prevent relapse due to the ability to restore the co-localization of neurons and astrocytes, which is important for keeping the glutamate homeostasis. Clavulanic acid, a beta-lactamase inhibitor with beta-lactam ring, has also been shown to enhance GLT-1 expression in the NAc and decrease the reinforcing efficacy of cocaine in mice (Kim et al., 2016). However, Bechard, Hamor, Wu, Schwendt, and Knackstedt (2019) showed no anti-relapse activity of orally-administered clavulanic acid (Bechard et al., 2019). Recently, GLT-1 upregulation in the NAc was shown to be necessary for the anti-relapse action of N-acetylcysteine and ceftriaxone (LaCrosse et al., 2017; Reissner et al., 2015). However, Logan, LaCrosse, and Knackstedt (2018) showed that adeno-associated virus (AAV)-mediated overexpression of GLT-1a alone in the NAc is not sufficient to attenuate cue- and cocaine-primed reinstatement (Logan et al., 2018). The possible reason for that failure may be the fact that AAV-mediated overexpression of GLT-1a alone did not fully attenuate the glutamate efflux to the baseline levels during the reinstatement test (C. Logan et al., 2018). Thus, while GLT-1 downregulation likely mediates some aspects of cocaine-seeking after extinction/withdrawal, it is not solely responsible for increasing glutamate efflux that accompanies reinstated drug-seeking. The authors propose, among other hypotheses, that the transporters may not be positioned sufficiently close to the synapse to perform glutamate uptake efficiently.
2.1.1.2. Clinical studies. Clinical studies on changes in GLT-1 expression in humans are lacking. Available data indicate that N-acetylcysteine administration to cocaine users during the abstinence period could suppress cocaine-craving and -seeking behavior in response to cocaine cues (https://clinicaltrials.gov, study no. NCT00136825) (LaRowe et al., 2007). N-acetylcysteine restores homeostasis of the glutamatergic system by elevating xc- and GLT-1 expression and activity. Therefore, it can be surmised that recovery of the disturbed GLT-1 and xc- activity has crucial therapeutic implications. However, it should be underlined that this trial was conducted only in 15 patients. A similar study in 14 patients found that N-acetylcysteine attenuates cocaine-cue bias and the reinforcing effects of acutely administered intranasal cocaine (Levi Bolin et al., 2017). The next study, in a larger group (n=111), confirmed that N-acetylcysteine (2400 mg) reduces cocaine craving and increases the time to relapse in individuals who already achieved abstinence from cocaine (LaRowe et al., 2013). On the other hand, N-acetylcysteine was not able to diminish cocaine use in individuals with active cocaine use disorder, which was evidenced by positive benzoylecgonine (a cocaine metabolite) urine samples in this group of patients. Thus, N-acetylcysteine cannot serve as a drug to induce abstinence in active cocaine users, but rather as a drug to alleviate craving during abstinence (LaRowe et al., 2013). The next randomized trial with N-acetylcysteine (NCT02626494) finished in 2017, but the results have not been published yet. The authors aimed to investigate for the first time the changes in glutamate concentration in the NAc in people with CUD. Moreover, the possible anti-relapse effect of N-acetylcysteine administration and influence on homeostasis in the glutamatergic system was established.
As in animal studies, clavulanic acid also began to be tested in humans. The first clinical trials investigated the safety of clavulanic acid administration in combination with cocaine (clinical trial no. NCT02563769). The study finished in 2018; however, the results have not been published yet. A second trial started in March 2019 and aims to verify, using magnetic resonance (MRI) scans, whether and how clavulanic acid affects glutamate level in the human brain (clinical trial no. NCT03986762). Both trials are the introduction to possible future research aiming to investigate the effects of clavulanic acid in treating CUD.
Taken together, preclinical studies indicate the importance of diminished GLT-1 function/expression in the reinstatement to cocaine-seeking. The reduced level/activity of GLT-1 may decrease the removal of synaptically released extracellular glutamate, thereby enhancing the amount of glutamate binding to the postsynaptic receptors during reinstatement (Logan et al., 2018). Therapeutic upregulation of GLT-1 is expected to reverse those changes and inhibit relapse to cocaine-seeking. Several substances, like N-acetylcysteine or ceftriaxone, have been shown to enhance GLT-1 expression/function and suppress the relapse to cocaine-seeking (Knackstedt, Melendez, & Kalivas, 2010; ; LaCrosse et al., 2017; Sari et al., 2009). However, the latest results revealed that overexpression of GLT-1a alone does not suppress relapse to cocaine-seeking behavior and does not fully normalize glutamate level in the NAc during reinstatement testing (C. Logan et al., 2018). Therefore, other processes, along with GLT-1 upregulation, are probably responsible for the antirelapse effects of substances like N-acetylcysteine or ceftriaxone (Knackstedt, Melendez, & Kalivas, 2010; LaCrosse et al., 2017; Sari et al., 2009). Very recent studies showed that the antagonism of mGlu2/3 in the NAc core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement (Logan et al., 2020). This result suggests that ceftriaxone’s effects depend on mGlu2/3 function and possibly mGluR2 expression. However, future work will test this mGluR2-hypothesis.
2.2. System xc
As already mentioned, the transporter GLT-1 removes glutamate from the synaptic space and transports it into astrocytes while glutamate transport from astrocytes to the extracellular space is carried out by another transporter, namely system x−c . System x−c is a sodiumindependent antiporter which, under physiological conditions, transports cystine into the cell while glutamate is exported. This is done at the stoichiometric ratio of 1:1, down the concentration gradient. Cystine is reduced in the cell to cysteine, which is of key significance for glutathione synthesis (Massie et al., 2016). System x−c is built of two subunits: heavy chain 4F2hc (gene SLC3A2) and light chain xCT (gene SLC7A11). The chain 4F2hc is probably responsible for transporter anchoring in the membrane while the chain xCT plays a catalytic role and is indispensable for antiporter functioning (Lewerenz et al., 2013). System x−c is the main source of extracellular glutamate in many brain structures of rodents (Massie et al., 2016; Williams & Featherstone, 2014), such as in the NAc core as much as 60% of extracellular glutamate is a consequence of its activity (Baker, Xi, Shen, Swanson, & Kalivas, 2002). Glutamate released by x−c regulates synaptic transmission through the activation of pre- and post-synaptic metabotropic receptors localized near the synaptic cleft. Furthermore, glutamate transported by this antiporter can activate extrasynaptic N-methyl-D-aspartate receptors (NMDA) and can thus activate excitotoxicity (Hardingham & Bading, 2010). It was also shown that the mentioned antiporter was able to reduce expression of postsynaptic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPA) (selectively activated by α-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid) in the HIP (Williams & Featherstone, 2014) and NA core (LaCrosse et al., 2017) and could thus modulate glutamatergic transmission.
System x−c is localized mostly in the glial cell membrane and to a lesser extent in the neuronal cell membrane (Massie et al., 2016). Results of in vitro studies indicated that its expression is present in the following order of magnitude: neurons
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