Cocaine use disorder: A look at metabotropic glutamate receptors and glutamate transporters

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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.

Introduction

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 self-control 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).

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).

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).

Glutamate is the main excitatory neurotransmitter, responsible for almost 70-90% of synaptic transmission in the CNS (Pomierny-Chamioło 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 glutamate-containing 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.

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.

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 cocaine-seeking (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 cocaine-paired 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.

The NAc contains glutamate terminals from neurons of the PFC, HIP, AMY, and Th (Brog, Salyapongse, Deutch, & Zahm, 1993). The VTA also releases dopamine and glutamate into the NAc (Hnasko, Hjelmstad, Fields, & Edwards, 2012). In preclinical studies, changes in NAc 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 cocaine-primed 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).

Following a period of abstinence from cocaine (24 hrs – 21 days), basal extracellular glutamate levels have consistently been found to be reduced 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 refers to glutamate levels assessed outside of the drug-taking environment, in the absence of cocaine itself or cocaine-associated cues. The source of such NAc basal glutamate is system xc-, the cystine-glutamate exchanger, the activity of which is also decreased following noncontingent and self-administered 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).

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.

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).

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 and Duffy, 1995, Kalivas and Duffy, 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 and Duffy, 1995, Kalivas and Duffy, 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.

Section snippets

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 high-affinity 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

Metabotropic glutamate receptors

Metabotropic glutamate receptors (mGluRs) are a family of transmembrane receptors coupled via G-proteins with second messengers. They are receptors with the longest amino acid sequence (872-912 amino acids) of all types of metabotropic receptors in the human body. When stimulated, mGluRs interact with ion channels located nearby. In addition, through the activation of intracellular signals, they trigger functional changes in the cytoplasm, gene expression, and protein synthesis. These processes

Concluding remarks

Disturbances in glutamate homeostasis induced by cocaine use underlie long-term relapse vulnerability. This conclusion is supported by the findings that compounds which restore glutamate homeostasis reduce the risk of relapse in preclinical models and reduce cocaine-cue reactivity in humans. The very recent studies indicate that other mechanisms of action, such as reversing mGlu2 receptor surface expression downregulation by ceftriaxone, contribute to these compounds' anti-relapse efficacy.

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by the National Science Centre (Poland) grant no UMO-2013/11/N/NZ7/01617 and the statutory funds of Jagiellonian University Medical College (Cracow, Poland) and of the Maj Institute of Pharmacology, Polish Academy of Sciences (Cracow, Poland).

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