G Protein-Coupled Receptors in Addiction Neurobiology: Mechanisms, Therapeutic Targets, and Advances in Pharmacotherapy

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Data may be preliminary. 7 April 2025 V1 Latest version Share on G Protein-Coupled Receptors in Addiction Neurobiology: Mechanisms, Therapeutic Targets, and Advances in Pharmacotherapy Authors : Mohammad Khan , Mohammed Alanazi , Ibrahim Alsulaihim , Asma S. Alonazi , Fawaz Alasmari , and Khaled Alhosaini [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174402936.68512104/v1 769 views 247 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract G protein-coupled receptors (GPCRs) are central regulators of neurotransmission and neuroplasticity, influencing the pharmacodynamics of psychoactive substances. As key nodes in signal transduction, they modulate second messenger systems, ion channel activity, and synaptic communication. Despite extensive research on GPCRs as therapeutic targets, their specific role in addiction-related neuroadaptations remains insufficiently understood. This review systematically examines how core GPCR subtypes; dopamine, opioid, cannabinoid, and metabotropic glutamate receptors mediate the reinforcing properties of addictive drugs. It highlights the dual roles of GPCR-dependent and independent pathways in altering reward circuitry and driving compulsive drug-seeking. The review also explores recent innovations in structure-based drug design, including biased agonism, allosteric modulators, and GPCR conformational dynamics, for next-generation addiction therapies. By integrating molecular pharmacology with addiction neuroscience, this review identifies translational challenges and opportunities, underscoring the value of GPCR-targeted pharmacotherapies. Ultimately, it advocates for interdisciplinary strategies to bridge preclinical findings with effective clinical interventions for substance use disorders. Title: G Protein-Coupled Receptors in Addiction Neurobiology: Mechanisms, Therapeutic Targets, and Advances in Pharmacotherapy Mohammad R. Khan 1 , Mohammed M. Alanazi 1 , Ibrahim N. Alsulaihim 2 , Asma S. Alonazi 1 , Fawaz F. Alasmari 1 , Khaled A. Alhosaini 1 * Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Saudi Arabia 2 Ph.D. Student, Department of Pharmacology and Toxicology, Pharmacy College, King Saud University, Saudi Arabia *To whom correspondence should be addressed: Khaled Alhosaini, [email protected] College of Pharmacy, King Saud University P.O. Box 2475, Riyadh 11451, Saudi Arabia Running title: G-Protein coupled Receptor and Drug Addiction. Keywords: GPCR, Drug Addiction, Dopamine, Cannabinoid receptor-1, mGlu2 Abstract G protein-coupled receptors (GPCRs) are central regulators of neurotransmission and neuroplasticity, influencing the pharmacodynamics of psychoactive substances. As key nodes in signal transduction, they modulate second messenger systems, ion channel activity, and synaptic communication. Despite extensive research on GPCRs as therapeutic targets, their specific role in addiction-related neuroadaptations remains insufficiently understood. This review systematically examines how core GPCR subtypes; dopamine, opioid, cannabinoid, and metabotropic glutamate receptors mediate the reinforcing properties of addictive drugs. It highlights the dual roles of GPCR-dependent and independent pathways in altering reward circuitry and driving compulsive drug-seeking. The review also explores recent innovations in structure-based drug design, including biased agonism, allosteric modulators, and GPCR conformational dynamics, for next-generation addiction therapies. By integrating molecular pharmacology with addiction neuroscience, this review identifies translational challenges and opportunities, underscoring the value of GPCR-targeted pharmacotherapies. Ultimately, it advocates for interdisciplinary strategies to bridge preclinical findings with effective clinical interventions for substance use disorders. Introduction G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain (7TM) receptors, represent one of the largest and most diverse families of membrane proteins. These receptors mediate a wide array of physiological functions, including neurotransmission, hormone regulation, and sensory perception, by interacting with heterotrimeric G proteins to transduce extracellular signals into intracellular responses (Rosenbaum et al., 2009). GPCRs regulate cellular functions by influencing second messengers such as cyclic adenosine monophosphate (cAMP), modulating calcium signaling, controlling ion channels, altering neurotransmitter release, and affecting gene expression (Latek et al., 2012). The functional significance of GPCRs in cellular signaling has made them prominent drug targets, with over one-third of all approved pharmaceuticals acting on these receptors. GPCRs are broadly classified based on their interaction with G protein alpha subunits. Notably, Gαi/o-coupled GPCRs play a critical role in modulating neurotransmitter release by inhibiting adenylyl cyclase, reducing cAMP levels, and regulating ion channel activity. These receptors interact with voltage-gated calcium channels, G protein-activated inward-rectifying potassium (GIRK) channels, and vesicular release machinery, ultimately influencing synaptic transmission (Seino and Shibasaki, 2005; Kretz et al., 1986; Ikeda, 1996). Recent structural studies have provided deeper insights into receptor-specific activation mechanisms, paving the way for targeted pharmacological interventions. Psychoactive substances profoundly impact GPCR signaling, often through both G protein-dependent and independent pathways. These substances interact with multiple molecular targets in a phenomenon known as polypharmacology, significantly altering central nervous system (CNS) function (Zhu and Reith, 2008). Cocaine and amphetamines, for instance, disrupt dopamine transporters, prolonging dopamine GPCR signaling and leading to enhanced dopaminergic transmission. Opioids such as fentanyl and morphine (Zhuang et al., 2022), cannabinoids like tetrahydrocannabinol (THC) (Felder and Glass, 1998), and psychedelics such as lysergic acid diethylamide (LSD) and psilocybin (Nichols, 2016) all exert their effects through GPCR activation. These substances not only engage classical G protein signaling pathways but also interact with GPCR kinases and β-arrestins, leading to receptor desensitization, internalization, and downregulation (Wingler and Lefkowitz, 2020; Luttrell et al., 2018). Understanding these mechanisms is crucial in addressing the widespread issue of drug addiction. Drug addiction is a multifaceted neurobehavioral disorder characterized by compulsive drug-seeking behavior, the inability to regulate drug intake, and the development of withdrawal symptoms upon cessation (Koob and Volkow, 2016). Several neurobiological factors contribute to addiction, including primary (unconditioned) and secondary (conditioned) rewards, reinforcement learning, sensitization processes, withdrawal symptoms, and relapse triggers. Contextual conditioning plays a particularly important role, as environmental cues associated with drug use can become potent relapse triggers, making addiction one of the most difficult conditions to treat (Cornish and Kalivas, 2000). The consequences of addiction extend beyond individual health, severely impacting employment, family relationships, and overall societal well-being. Despite decades of research, available pharmacological treatments remain insufficient, necessitating the exploration of novel therapeutic strategies (Koob et al., 2009; Leggio et al., 2010). Preclinical models of substance use disorder, such as passive drug exposure, conditioned place preference (CPP), and operant drug self-administration, have provided invaluable insights into the complex interactions between GPCRs and addictive substances. Several key findings have emerged from these studies. First, GPCRs, particularly dopamine (DA) receptors, are central to the neurochemical and behavioral effects of addictive substances. Second, modulating presynaptic GPCRs can either enhance or suppress the rewarding and stimulant properties of drugs. Third, chronic exposure to substances such as alcohol, cocaine, and nicotine induces lasting neuroadaptive changes in presynaptic GPCRs, especially those involved in glutamate release. These neuroadaptations contribute to compulsive drug-seeking behaviors, tolerance, and heightened vulnerability to relapse. Recent studies have demonstrated that targeting presynaptic GPCRs pharmacologically can attenuate drug-seeking and drug-taking behaviors in both rodent and primate models, underscoring their therapeutic potential (Belin-Rauscent et al., 2016; Scofield et al., 2016). Psychoactive substances encompass a broad range of therapeutic and illicit drugs that influence CNS function. These include illegal substances such as cocaine, heroin, methamphetamine, and LSD, as well as legal drugs such as alcohol and nicotine. Additionally, prescription medications, including amphetamines and opioids, have been widely misused. The opioid epidemic, fueled by the overprescription of medications such as oxycodone (OxyContin), has emerged as a significant public health crisis, leading to widespread addiction and overdose fatalities (Miech et al., 2023). A common feature among these substances is their psychoactive nature, which induces states of euphoria and intoxication, often resulting in severe dependence and addiction. The adverse effects of drug misuse include cognitive impairments, behavioral abnormalities, and life-threatening consequences such as opioid-induced respiratory depression (Spencer et al., 2022). Addressing these challenges requires a deeper understanding of GPCR-mediated drug interactions and the development of targeted therapies to mitigate addiction-related harm. This review provides a comprehensive analysis of the role of GPCRs in addiction neurobiology, focusing on their interactions with major classes of psychoactive substances. We examine how opioids, cannabinoids, and psychedelics influence GPCR signaling at the molecular level, leading to neurochemical and behavioral alterations associated with substance use disorders. Additionally, we explore recent advancements in GPCR-targeted drug development, including biased agonism, allosteric modulation, and structure-based drug design, which offer promising avenues for the development of safer and more effective addiction treatments. Furthermore, we highlight the therapeutic potential of modulating presynaptic GPCRs to regulate neurotransmitter release and reverse drug-induced neuroadaptations (Belin-Rauscent et al., 2016; Scofield et al., 2016). The structure of this review follows a logical progression, beginning with an overview of GPCR signaling and its critical role in neurotransmission. Next, we explore the molecular mechanisms by which different classes of drugs interact with GPCRs, with a focus on dopamine, opioid, cannabinoid, and metabotropic glutamate receptors. We then discuss recent advances in GPCR pharmacology and their therapeutic implications, emphasizing novel receptor-targeting strategies. By integrating insights from molecular and behavioral neuroscience, this review aims to bridge the gap between preclinical research and clinical applications, contributing to the development of more effective treatments for substance use disorders. Ultimately, leveraging the latest discoveries in GPCR biology will facilitate the design of precision-targeted pharmacotherapies, addressing the urgent need for improved addiction treatments and reducing the societal burden of substance abuse. The Role of GPCRs in Signal Transduction: From Structural Dynamics to Therapeutic Targets GPCRs represent the largest superfamily of cell surface membrane receptors, encoded by roughly 1000 genes. They share a conserved structure of seven-transmembrane (7TM) helices, which are interconnected by three intracellular and three extracellular loops (Rosenbaum et al., 2009; Eichel & von Katritch, 2012; Zastrow, 2018). These proteins are highly dynamic in their conformation and play crucial roles in signal transduction, responding to a variety of extracellular signals such as photons, ions, lipids, neurotransmitters, hormones, peptides, and odorants (Nussinov, 2016; Latorraca et al., 2017; Dunn et al., 2019; Zarzycka et al., 2019; Mannes et al., 2022). The signaling mechanism of GPCRs is allosteric due to the distinct topography between the extracellular binding sites and the intracellular signaling sites, separated by approximately 40 Å (Canals et al., 2012; Flock et al., 2015; Dawaliby et al., 2016; Dokholyan, 2016; Hilger et al., 2018). Upon activation by external stimuli, GPCRs primarily utilize heterotrimeric G-proteins and arrestins as transducers, leading to the production of second messengers and the initiation of downstream signaling pathways, which result in diverse signaling profiles within cells (Hilger, D., et al. 2018). This signaling diversity is crucial for the functional versatility of GPCRs and plays a fundamental role in regulating physiological processes such as sensory perception, neurotransmission, and endocrine functions (Hauser, A. S. et al. 2017; Sriram, K. & Insel, P. A. 2018). However, mutations and truncations in GPCRs can disrupt their functionality by modifying constitutive activity, affecting membrane expression, and altering posttranslational behaviors (Schöneberg, T. & Liebscher, I. 2021). The focus on GPCRs for approved drugs has led to a surge in modulators at the clinical trial or preclinical stages (Yang, D. H. et al. 2021; Casadó, V. & Casadó-Anguera, V. 2023). Orthosteric ligands, in particular, influence GPCR activity and signaling by competitively blocking the binding of endogenous ligands (Mohr, K. et al 2010). Nonetheless, the high sequence conservation of orthosteric sites often results in poor subtype selectivity, which leads to unavoidable side effects (Goupil, E., et al. 2012). To address this issue, targeting allosteric sites alone or in combination with orthosteric sites offers a promising alternative or complementary strategy (Wootten, D., et al. 2013; Smith, R. D., et al. 2017; Lu, S. Y., et al. 2019; Wang, Y. et al. 2020; Zhang, M. et al. 2023). Allosteric modulators are noted for their high selectivity towards specific subtypes and minimal side effects. Advancing structural insights into receptor-ligand interactions are facilitating fragment-to-lead optimization in structure-based drug design (SBDD). Additionally, understanding allosteric sites aids in creating bitopic ligands, which bind to both allosteric and orthosteric sites on a receptor. These bitopic ligands offer significant benefits, including increased affinity and selectivity, compared to ligands that target only one site. Furthermore, uncovering the mechanisms of GPCR allosteric modulation offers a promising approach for developing biased ligands, such as those based on G protein or β-arrestin pathways (Slosky, L. M., et al. 2021). Complexities of GPCR Activation: Transducers, Second Messengers, and Therapeutic Implications Despite the considerable diversity in GPCRs and their activating stimuli, these receptors mainly orchestrate unique downstream signaling pathways via two types of transducers: heterotrimeric G proteins and arrestins. Human G proteins are categorized into four main families (Gs, Gi/o, Gq/11, and G12/13), with over half of the GPCRs being capable of activating multiple G proteins, each demonstrating distinct efficacy and kinetic properties (Hauser, A. S. et al., 2022; Inoue, A. et al., 2019). The promiscuous coupling creates unique signaling profiles within the cell, adding to the complexity of GPCR signaling. In its GDP-bound state, the Gαβγ heterotrimer is inactive. Agonist binding induces an active GPCR conformation, initiating signaling cascades that recruit and activate G-proteins. The activated GPCR promotes the exchange of GDP for GTP on the Gα subunit, leading to the dissociation of Gα from the Gβγ dimer. Given the high cellular GTP concentration, Gα quickly binds GTP at the nucleotide-binding site. Both Gα-GTP and Gβγ can then modulate effector proteins. Depending on the G protein type, Gα-GTP may activate or inhibit enzymes like adenylyl cyclase (AC), phospholipase C (PLC), or ion channels. Similarly, Gβγ can influence various signaling pathways and interact with target proteins. The activation of effector proteins by Gα-GTP or Gβγ produces second messengers such as cyclic AMP (cAMP). The cellular response ends when the Gα subunit hydrolyzes GTP to GDP, allowing it to reassociate with Gβγ and inactivate the G protein. Finally, the Gα subunit completes the G-protein activation cycle by reuniting with Gβγ ( Fig-1 ). Figure-1: GPCR Effector Pathways: Crosstalk of downstream pathway of Gs, Gq, Gi and Arrestin To avoid sustained signaling, activated GPCRs can be phosphorylated at their C-terminal regions by G-protein coupled receptor kinases (GRKs). This process of multi-site phosphorylation influences the binding affinity of β-arrestin, which in turn leads to receptor desensitization due to steric hindrance. Subsequent steps include clathrin-mediated endocytosis and receptor ubiquitination (Leftowitz, R. J. & Shenoy, S. K. 2005; Ranjan, R. et al. 2017; Hilger, D., et al. 2018). Additionally, the receptor-arrestin complex acts as a scaffold for over 20 different kinases, such as mitogen-activated protein (MAP) kinases, ERK1/2, p38 kinases, and c-Jun N-terminal kinases, thereby initiating a G-protein independent signaling pathway (Chen, Q. Y. & Tesmer, J. J. G. 2022). Without agonists, GPCRs can exhibit varying degrees of inherent activity. Ligands interacting with a single GPCR show a broad range of efficacy in either activating or deactivating the receptor. Based on receptor activity and drug efficacy, GPCR ligands are classified into agonists, partial agonists, antagonists, and inverse agonists. These differences in ligand efficacy play a crucial role in their therapeutic effects. Neurobiological Mechanisms of Drug Addiction: Stages, Neural Circuits, and Behavioral Implications The challenges posed by drug abuse and addiction are significant, affecting both society and public health. This makes the study of the neurobiology underlying drug effects and addiction an essential field of research. Drug addiction is a chronic and relapsing condition characterized by compulsive drug-seeking behavior, an inability to regulate consumption, and adverse emotional states when substances are unavailable. This condition encompasses three stages, each associated with disruptions in specific neural circuits: the intoxication phase, governed by modifications in the basal ganglia; the withdrawal phase, shaped by changes in the extended amygdala; and the anticipation phase, associated with alterations in the prefrontal cortex (PFC) (Koob and Volkow, 2016). Koob and Volkow (2016) highlight neuroadaptations across 18 different subsystems, notably the mesocorticolimbic dopamine system, corticotropin-releasing factor (CRF) within the central amygdala, and corticostriatal glutamate pathways. During the binge/intoxication phase, individuals show heightened impulsivity and a compulsion to use drugs regardless of negative outcomes. This phase is characterized by the excessive activation of the mesocorticolimbic dopamine reward pathway, which enhances the pleasurable effects of drug use. Impairments in incentive salience arise, where drug-related cues become excessively rewarding and trigger dopamine (DA) release, driving the motivation to take the drug even as tolerance develops. The withdrawal/affect stage begins with opponent-process responses following binge episodes, characterized by changes that reduce motivation for non-drug rewards and impair emotional regulation. Within-system adaptations include decreased dopaminergic signaling in the nucleus accumbens (NAcc) and dorsal striatum, raising reward thresholds and contributing to a lack of motivation. Between-system changes affect neurochemical systems not primarily involved in drug rewards, such as stress-related increases in corticotropin-releasing factor (CRF) release in the amygdala and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. These changes lead to withdrawal symptoms like increased anxiety, irritability, malaise, and dysphoria during both acute and prolonged abstinence (Koob and Volkow, 2016). The anticipation stage involves the risk of relapse, where executive control over cravings and impulsivity, mediated by the prefrontal cortex (PFC), is crucial for maintaining abstinence. This stage is marked by disrupted signaling between the PFC and brain regions responsible for decision-making, self-regulation, inhibitory control, and working memory, potentially involving altered GABAergic and glutamatergic activity. Behaviorally, this results in heightened attention to drug-related cues, reduced responsiveness to non-drug cues, and an impaired ability to inhibit maladaptive behavior (Koob and Volkow, 2016). Role of GPCRs in the Opioid Receptor’s Analgesic and Addictive functions Opioid receptors play a key role in mediating both the pain-relieving (analgesic) and addictive, potentially fatal consequences of opioid medications, including morphine and fentanyl. Morphine and its related compounds, such as oxycodone and hydrocodone, are frequently utilized for managing pain in cases of musculoskeletal back pain. (Haris et al., 2019). Synthetic opioids, such as fentanyl and its derivatives, are often used to induce sedation during intubation (Ferguson et al., 2022) or to treat cancer-related chronic pain (Plante and Van Itallie, 2010). Paulozzi et al ., 2011; has reported that, the over-prescription of opioid medications for chronic pain are believed to have initiated the opioid epidemic. Beyond their analgesic properties, opioids produce euphoric effects that contribute to their chronic use. Prolonged use can lead to drug tolerance and addiction, resulting in opioid use disorder (OUD). OUD involves cravings that push individuals toward stronger opioids such as fentanyl, which is about 100 times more powerful than morphine (Buresh et al., 2022). The euphoric sensations produced by opioids result from their influence on dopaminergic activity in the mesolimbic system, which also relates to the withdrawal symptoms experienced after long-term use is stopped (Kosten and George, 2002). The most serious effect of opioids is respiratory depression, which is the primary cause of opioid-related deaths (Baertsch et al., 2021). Addiction treatment through opioid-based mechanisms utilizes various approaches. Buprenorphine, a partial agonist, activates the μ-opioid receptor (MOR) with a ceiling effect, reducing the likelihood of misuse. Antagonists like naloxone and naltrexone block MOR activity, effectively reversing opioid overdose and preventing relapse. Oliceridine (TRV130), a novel MOR agonist, selectively activates G protein signaling while limiting β-arrestin pathway involvement. This selective activation is designed to provide effective pain relief while minimizing common opioid-related side effects such as respiratory depression, constipation, and sedation (Urits et al., 2019). Naloxone (NARCAN), an antagonist of the μ-opioid receptor (MOR), is frequently administered to counteract acute opioid overdoses. Unfortunately, its efficacy diminishes when dealing with stronger opioids such as fentanyl (Hill et al., 2020). Besides MOR, other opioid GPCRs encompass δ- and κ-opioid receptors (Manglik, 2020). Opioids generally function as agonists of MOR, triggering inhibitory Gi/o proteins that decrease cellular cAMP levels and stimulate G protein–inward rectifying potassium channels, leading to neuronal hyperpolarization and decreased excitability. Opioids achieve their pain-relieving effects through two main mechanisms: first, by inhibiting peripheral pain signals in nerves, such as C-fibers or neuron clusters like the dorsal root ganglion in the spine. Second, by blocking the perception of pain and its emotional aspects in the central nervous system (CNS), which is mediated by inhibiting GABAergic interneurons in the periaqueductal gray, the brain’s primary pain control center (Basbaum et al., 2009; Hahm et al., 2011; Che and Roth, 2021). Continuous activation of MOR and the persistent suppression of cellular cAMP levels via Gi/o protein can result in a compensatory increase in adenylyl cyclase activity. This upregulation elevates the expression of cAMP-response element-binding protein along with other G protein-associated adaptations. Consequently, this process desensitizes opioid signals, necessitating higher doses of opioids to maintain the same degree of cellular inhibition, thus contributing to tolerance. Interestingly, numerous preclinical studies suggest that β-arrestin significantly influences opioid analgesia, respiratory depression, and addiction (Schmid and Bohn, 2009). Nevertheless, substantial uncertainty persists regarding the exact signaling pathways and mechanisms by which opioids cause differential signaling or biased agonism (Kliewer et al., 2020), complicating the development of safer opioids or new treatments for opioid use disorder (OUD) (Zhu and Reith, 2008). Role of GPCRs in Cannabis and the Endocannabinoid System Cannabis, commonly referred to as marijuana, is a psychoactive substance obtained from the Cannabis sativa plant (Gaoni & Mechoulam, 1964). It produces a complex range of perceptual sensations, encompassing both pleasurable and dysphoric effects. Beyond its recreational use, cannabis has several therapeutic applications, including treatment for nausea during chemotherapy, chronic pain (Tramer et al., 2001), anxiety and immunological disorders (Mackie, 2006; Petrie et al., 2021), and epilepsy (Morano et al., 2020 and Von Wrede et al.,2021) The cannabinoid receptors CB1 and CB2, which are activated by lipids, are responsible for the majority of cannabis’s physiological effects. Naturally, these receptors are triggered by specific lipids known as endocannabinoids (endogenous cannabinoids), mainly anandamide and 2-arachidonoylglycerol. The endocannabinoid system regulates cognitive processes, appetite, and mood through central CB1 receptors, and it influences various immune system activities via CB2 activation (Zou & Kumar, 2018). Like opioid receptors, CB1 and CB2 also interact with the Gi/o family of G proteins. Within the central nervous system (CNS), CB1 is mainly located in presynaptic terminals. When activated, it decreases neuronal excitability and inhibits neurotransmission (Manzanares et al., 2006). This inhibition affects downstream elements, including voltage-gated calcium channels, unspecified parts of the vesicle fusion machinery, and possibly some potassium channels (Chevaleyre et al., 2006). The analgesic effects of cannabis are partly due to the inhibition of pain signals at both the spinal and supraspinal levels, including areas like the dorsal horn and the periaqueductal gray (Manzanares et al., 2006). Despite its therapeutic benefits, cannabis can significantly alter perception and coordination, and in extreme cases, cause hallucinations (Skolnick & Crystal, 2020). These negative effects present significant safety issues when considered for use as either a medication or a recreational drug. Additionally, several orphan GPCRs, such as GPR3, GPR6, GPR12, GPR18, and GPR55, have been provisionally associated with cannabinoid pharmacology, specifically cannabidiol (CBD) (Morales & Reggio, 2017). However, the potency and efficacy of these compounds at these less-studied targets remain a topic of debate. Interestingly, GPR55 has been suggested as a potential third cannabinoid receptor since it is activated by tetrahydrocannabinol (THC) and the endogenous cannabinoid receptor agonist, like anandamide. (Lauckner et al., 2008; Calvillo-Robledo et al., 2022). Despite this, GPR55 also responds strongly to lysophosphatidylinositol, leading to debates about its designation as a specialized cannabinoid receptor. Future research is expected to substantially alter the present comprehension of how cannabinoids function and their physiological effects. Involvement of GPCRs and Dopamine Receptor in Drug Addiction Dopamine (DA) is the core neurotransmitter molecule that uniquely activates GPCRs in the mammalian brain, resulting in various modulatory neurophysiological and neurochemical effects. The DA receptors are categorized into five subtypes (D1–5). The D1 and D5 receptors generally couple with Gs/olf G proteins, while the D2, D3, and D4 receptors associate with Gi/o proteins (Beaulieu and Gainetdinov, 2011). Dopamine receptors are found on both the presynaptic and postsynaptic components of central nervous system neurons. In neurons like striatal medium spiny projection neurons (MSNs), DA receptors mediate postsynaptic effects. Many drugs of abuse directly target dopaminergic transmission, while nearly all abused substances affect it indirectly (Volkow and Morales, 2015). Stimulants such as cocaine, amphetamines, and methylphenidate impact the central nervous system by interacting with the dopamine transporter (DAT), which is primarily responsible for clearing dopamine from the extracellular space. Cocaine and methylphenidate inhibit the function of DAT, thereby preventing the reuptake of extracellular dopamine thereby prolonging its presence and increasing its extracellular spread following vesicular release. The reduced activity or synaptic transmission of GABAergic neurons, leads to the disinhibition of midbrain dopaminergic neurons. This mechanism likely contributes to the dopamine-enhancing effects of substances such as benzodiazepines, cannabinoids, and opiates (opium, morphine and heroin) (Johnson and North, 1992; Szabo et al., 2002; Lupica and Riegel, 2005; Tan et al., 2010), and also influences the effects of nicotine (Pidoplichko et al., 2004). For example, cannabinoids activate Gi/o-coupled GPCRs on GABAergic presynaptic terminals synapsing onto midbrain dopaminergic neurons (Szabo et al., 2002; Lupica and Riegel, 2005). When these GPCRs are activated, they inhibit the release of GABA, thereby diminishing the suppression of DA neurons and facilitating increased DA release. The primary effect of other abused drugs on dopaminergic transmission takes place in specific regions such as the striatum and frontal cortex, where they increase extracellular DA levels (Di Chiara and Imperato, 1988; Benwell and Balfour, 1997; Mathews et al., 2006). Early studies indicated that these effects were particularly significant in the ventral striatum, influencing elements of drug use and relapse (Di Chiara and Imperato, 1988). Nonetheless, the dorsal striatum also plays a vital role in the development of goal-directed and habitual drug-seeking behaviors (Gremel and Lovinger, 2016). Dopamine Transmission and GPCRs: Insights into D1-like and D2-like Receptor Function Dopamine (DA) transmission is facilitated by metabotropic G protein-coupled receptors (GPCRs). The five cloned DA receptors are categorized into two main groups based on their structural and pharmacological characteristics include: (a) D1-like receptors (comprising D1 and D5), which elevate cAMP production, and (b) D2-like receptors (including D2, D3, and D4), which reduce intracellular cAMP levels. The contrasting regulation of cAMP by D1-like and D2-like receptors, and their resulting impact on downstream signal pathways, rely on their interaction with distinct G proteins. D1-like receptors are some of the most abundantly expressed dopamine receptors in the brain, predominantly found in the forebrain. In contrast to the D2-like family, these receptors possess a highly conserved sequence (Tritsch and Sabatini, 2012). When dopamine binds to D1-like receptors, it enhances adenylyl cyclase activity, resulting in increased cAMP levels. This pathway activates protein kinase A (PKA), which phosphorylates various substrates and induces the expression of immediate early genes, contributing to the overall response mediated by D1R (Beaulieu and Gainetdinov, 2011) ( Fig-2 ). Figure-2 : Presynaptic G protein-coupled receptors (GPCRs) neurotransmitter modulation mechanisms: Presynaptic Gi/o-coupled GPCRs (e.g., mGlu2, CB1, and D2) reduce neurotransmitter release by inhibiting calcium influx, modulating vesicle release machinery, and potentially activating potassium channels to hyperpolarize or shunt the presynaptic terminal. These receptors also decrease cAMP and PKA activity, contributing to long-term release regulation. In contrast, presynaptic D1 receptors (Gs/Golf-coupled) enhance release through PKA activation. Additional pathways may also influence neurotransmitter release. DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) is one of the primary PKA substrates activated by dopamine, playing a crucial role in dopaminoceptive neurons (Svenningsson et al., 2004). It influences neuronal excitability and glutamatergic signaling by modulating Protein Phosphatase-1 (PP-1). The activation of the cAMP/PKA/DARPP-32 signaling pathway leads to an increased opening of L-type Ca2+ channels, thereby enhancing the excitability of medium spiny neurons (MSNs) (Vergara et al., 2003). Activation of D2 receptors (D2R) leads to several modulatory effects. These receptors are associated with Gi/o proteins, and their activation suppresses cAMP signaling, leading to a decrease in the phosphorylation of downstream proteins such as DARPP-32, which are targets of PKA. Moreover, the activation of D2 receptors (D2R) through the Gβγ subunits inhibits L-type Ca2+ channels and activates G-protein-coupled inwardly rectifying potassium (GIRK) channels, which results in lower neuronal excitability and a reduction in dopamine synthesis and release (Kebabian and Greengard, 1971). Additionally, D2Rs are found presynaptically on excitatory inputs, where they modulate glutamate release, and on cholinergic interneurons (ChaT) in the striatum, where they help diminish acetylcholine release (Surmeier et al., 2007). Interestingly, dopamine (DA) shows a lower affinity for D1 receptors (D1Rs) compared to D2 receptors (D2Rs), resulting in distinct impacts on the direct and indirect pathways during tonic or phasic DA release. Phasic DA release is thought to primarily activate D1Rs, enhancing limbic inputs, whereas tonic DA release bidirectionally stimulates D2Rs associated with prefrontal cortex (PFC) inputs (Floresco et al., 2003; Goto and Grace, 2005; Goto et al., 2007). Notably, variations in DA levels significantly influence the functions of brain regions that receive DA inputs. Changes in DA modulation of excitatory inputs to these regions are crucial in the pathophysiology of numerous neurological disorders (Goto et al., 2007). Role of GPCRs and Group II Metabotropic Glutamate Receptors in drug addiction Glutamate functions as the main rapid excitatory neurotransmitter within the central nervous system (CNS). It influences neurophysiological processes via ionotropic and metabotropic receptors. The metabotropic glutamate receptors (mGluRs) belong to the class C group of G protein-coupled receptors (GPCRs) and consist of eight subtypes. These subtypes are categorized into three subgroups based on their sequence similarity, G protein-coupling characteristics, and ligand-binding properties (Niswender and Conn, 2010). Group I mGluRs, specifically mGlu1 and mGlu5, are linked with Gq family G proteins and are mainly found postsynaptically. In contrast, Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6, mGlu7, and mGlu8) mGluRs associate with Gi/o family G proteins, often acting as presynaptic auto- and heteroreceptors. Group II mGluRs are notably prevalent in brain areas associated with drug-related behaviors. Although postsynaptic functions of Group II mGluRs have been observed, their primary role is recognized as inhibiting presynaptic neurotransmitter release at glutamatergic synapses (Otani et al., 2002; Walker et al., 2015; Jin et al., 2016) ( Fig-2 ). Activation of Group II mGluRs leads to a reduction in glutamate release across several crucial brain regions. These regions include the medial prefrontal cortex (mPFC) (Otani et al., 1999, 2002; Huang and Hsu, 2008; Walker et al., 2015), dorsal striatum (Lovinger and McCool, 1995; Kahn et al., 2001), nucleus accumbens (NAc) (Manzoni et al., 1997; Robbe et al., 2002a, b), central amygdala (Neugebauer et al., 2000), and bed nucleus of the stria terminalis (BNST) (Grueter and Winder, 2005). Various mechanisms are involved in the suppression of neurotransmitter release by Group II mGluRs. These include the inhibition of voltage-gated calcium channels (Anwyl, 1999; Robbe et al., 2002a; Kupferschmidt and Lovinger, 2015), disruption of vesicle fusion and release processes (Kupchik et al., 2008, 2011), and the activation of presynaptic potassium channels (Anwyl, 1999). Given that Group II mGluRs regulate glutamate release in critical brain circuits associated with addiction, a decrease in the expression and/or functionality of these receptors following drug use could lead to abnormal glutamate transmission. Dopamine and Glutamate Receptors cross talk in drug Addiction Dopamine (DA) is essential for regulating long-term synaptic strength changes. In the striatum, a well-known type of synaptic plasticity is long-term depression (LTD). This plasticity, present in both the dorsal and ventral striatum, necessitates simultaneous activation of mGluR5 and voltage-gated calcium channels and involves endocannabinoids (eCB) release. The eCBs exert a retrograde effect on CB1 receptors, thereby reducing the likelihood of glutamate release (Robbe et al., 2002a; Kreitzer and Malenka, 2005). It is intriguing that this type of LTD relies on the activation of D2 receptors (D2Rs). Nonetheless, there is debate regarding whether this LTD is solely present at glutamatergic inputs to medium spiny neurons (MSNs) in the indirect pathway of the dorsal striatum. While eCB-LTD was initially identified in D2R-expressing MSNs within the dorsal striatum (Kreitzer and Malenka, 2007), it has also been detected in both D1R and D2R striatal neurons of the direct and indirect pathways in BAC transgenic mice (Wang et al., 2006). One potential reason for the occurrence of this type of LTD at MSN synapses lacking D2Rs could be that, in both cell types, the induction of D2R-dependent LTD is indirectly mediated through the activation of D2Rs in cholinergic interneurons (Wang et al., 2006). Drug-induced synaptic plasticity at glutamatergic synapses within the mesocorticolimbic system is strongly linked to addictive behaviors (Luscher and Bellone, 2008). The dopamine (DA) neurons in the ventral tegmental area (VTA) act as a central hub where addictive substances can modify brain circuits (Brown et al., 2010). This plasticity has been noted in excitatory inputs to DA neurons in the VTA as soon as 24 hours after a single dose of addictive drugs (Ungless et al., 2001; Bellone and Lüscher, 2006; Mameli et al., 2007; Yuan et al., 2013). Remarkably, this plasticity is triggered by the activation of D1/D5 receptors (D1/D5Rs) and NMDA receptors (NMDARs) (Ungless et al., 2001; Argilli et al., 2008). It is manifested through the insertion of GluN3A-containing NMDARs (Yuan et al., 2013) and GluA2-lacking AMPA receptors (AMPARs) (Bellone and Lüscher, 2006). Moreover, the redistribution of glutamatergic receptors in the VTA triggered by cocaine relies on the drug’s interaction with the dopamine transporter (DAT). The activity of dopamine neurons alone can induce drug-evoked synaptic plasticity at glutamatergic synapses (Brown et al., 2010). D1 receptor signaling in the VTA is essential for these changes, indicating that the integration of dopaminergic and glutamatergic signaling within the VTA alters the circuitry at the synaptic level. Targeting Group II mGlu Receptors: Advancements and Challenges in Drug Discovery for Addiction Treatment Given the substantial evidence from preclinical studies demonstrating that activating Group II mGlu receptors can diminish the craving for and consumption of various drugs of abuse, both academic institutions and pharmaceutical companies have initiated drug discovery programs to develop ligands for clinical trials aimed at treating human drug use disorders. However, traditional methods for developing drugs that target these receptors have faced numerous challenges. For instance, attempts to create ligands for the orthosteric (glutamate) binding site of mGlu receptors frequently produce amino acid analogs with inadequate pharmacokinetic properties for human use (Conn et al., 2014). In drug discovery programs, a key objective is to attain high selectivity for a particular receptor subtype. This is important for several reasons, such as creating preclinical tools that validate specific targets for various disorders and minimizing the risk of adverse effects from off-target interactions. Nevertheless, the glutamate binding site is highly conserved among mGlu receptor subtypes, making it difficult to develop highly selective ligands for this site. Recently, research has increasingly focused on allosteric modulators. These compounds attach to a different site on the receptor than the orthosteric binding site and can either amplify or suppress the activity of the natural agonist. This approach has shown promise in overcoming the challenges associated with targeting the conserved orthosteric site and achieving greater receptor subtype selectivity. Positive allosteric modulators (PAMs) amplify the actions of endogenous agonists via several mechanisms. These include raising the receptor’s affinity for its natural ligand and enhancing the efficiency of receptor coupling to downstream effectors such as G proteins. As a result, PAMs of mGlu receptors can boost both the potency of glutamate and the maximal efficacy of receptor activation, even with low receptor expression. Given that allosteric binding sites exhibit less conservation across GPCR families, numerous drug discovery efforts have effectively created subtype-selective ligands (Conn et al., 2014). This success has enabled the preclinical assessment of specific mGlu receptor subtypes for addressing drug use disorders. The creation of several highly selective PAMs for mGlu2, which have properties conducive to in vivo testing, has highlighted mGlu2 as the principal group II mGlu receptor subtype that could be explored as a therapeutic approach to mitigate drug taking and seeking behaviors across different drug categories. For instance, the mGlu2 PAM BINA, along with other innovative mGlu2-selective PAMs, has demonstrated a reduction in cocaine self-administration in rats (Jin et al., 2010; Dhanya et al., 2011, 2014). In a similar vein, the newly developed mGlu2-selective PAM AZD8529 has been observed to slightly decrease alcohol self-administration in rats (Augier et al., 2016) and to lessen nicotine self-administration in both rats and squirrel monkeys (Justinova et al., 2015; Li et al., 2016). The mGlu2 receptor has been identified as a potential therapeutic target for preventing relapse. Positive allosteric modulators (PAMs) of mGlu2 have been demonstrated to inhibit cue-induced reinstatement of substance seeking behaviors in various studies. Specifically, these PAMs have been shown to block the reinstatement of cocaine (Jin et al., 2010), methamphetamine (Caprioli et al., 2015), nicotine (Li et al., 2016), and alcohol (Augier et al., 2016) seeking in rat models. Additionally, they inhibit cue- and priming-induced reinstatement of nicotine seeking in squirrel monkeys (Justinova et al., 2015). However, it is notable that AZD8529, an mGlu2 PAM, did not prevent stress-induced reinstatement of alcohol seeking, suggesting that the effectiveness of mGlu2 PAMs in preventing drug-seeking behaviors may be contingent on the nature of the inducing stimulus (Augier et al., 2016). A frequent issue with using traditional agonists for treating CNS disorders is their continuous activation of the receptor, which may result in desensitization, internalization, and ultimately tolerance to the drug’s effects. Liechti et al. (2007) conducted a study that examined the impact of the mGlu2/3 agonist LY379268 on nicotine self-administration. Initially, the study observed a significant reduction in self-administration, but after 14 days of treatment, the rats progressively reverted to their previous nicotine intake levels, indicating that they had developed tolerance to LY379268’s effects. PAMs enhance the response to synaptic or endogenous glutamate without directly activating the receptor when the endogenous agonist is absent. This characteristic makes them more likely to preserve normal spatial and temporal activation patterns of receptors, thereby decreasing the risk of developing tolerance. Recent research on the mGlu2 PAM AZD8529 has shown that repeated dosing of this compound consistently reduced nicotine self-administration in both rats (Li et al., 2016) and squirrel monkeys (Justinova et al., 2015). These findings strongly suggest that PAMs might have a significant advantage over agonists when it comes to tolerance. In contrast, the research conducted by Li et al. (2016) discovered that AZD8418, another mGlu2-selective PAM, exhibited a reduced ability to decrease nicotine self-administration in rats due to tolerance development. These results underscore the variability in the in vivo behavior of different PAMs targeting the same receptor, emphasizing the need for careful consideration in study design when assessing their therapeutic potential. Interestingly, such divergent outcomes might reveal important insights into the pharmacological characteristics required to sustain the suppression of drug consumption. This could present an opportunity to refine and optimize medications for clinical application, considering these specific profiles. One possible downside of therapeutic strategies that depend on pharmacological enhancement of presynaptic receptor function is the potential impairment of presynaptic GPCR function after prolonged drug use. Various studies indicate that the observed reduction in auto- or heteroreceptor activity may stem from decreased receptor expression. In these instances, pharmacologically activating the residual receptor population may not be adequate to reestablish the regulation of neurotransmitter release. Meinhardt et al. (2013) proposed this concept, noting a reduction in mGlu2 mRNA levels in the prefrontal cortex of rodents dependent on alcohol. Their research demonstrated that restoring mGlu2 expression via lentivirus in the infralimbic PFC-NAc pathway successfully inhibited cue-induced relapse into alcohol-seeking behavior. However, the study did not address the effectiveness of pharmacological methods in replicating this restoration. Despite the challenge, a wealth of research has shown that both agonists and PAMs of mGlu2 effectively reduce drug taking and seeking behaviors. This evidence reinforces the idea that, even with mGlu2 function changes due to prolonged drug use, pharmacological treatments can still effectively address drug-related behaviors. Although the reduced expression of receptors presents a challenge, the potential of pharmacological agents that target mGlu2 to alter drug-seeking behavior remains encouraging. Recent advancements in the development of clinically effective drugs targeting mGlu2 offer a promising opportunity to test the hypothesis that enhancing mGlu2 function can reduce drug seeking and taking behaviors in humans. Two mGlu2 PAMs, AZD8529 (AstraZeneca) and JNJ-40411813 (Janssen Pharmaceuticals, Inc., in partnership with Addex Therapeutics Ltd.), have undergone evaluation in small clinical trials (Salih et al., 2015). So far, there have been no significant safety or tolerability issues reported. In a small study, researchers evaluated JNJ-40411813’s effectiveness in reducing cigarette cravings and smoking among male smokers. The results indicated a trend toward decreased craving, although there was no notable reduction in the number of cigarettes smoked (Salih et al., 2015). Interestingly, clinical trials involving N-acetylcysteine (NAC) have demonstrated a moderate capacity to encourage abstinence from cocaine, cannabis, and nicotine (McClure et al., 2014). This offers further, though indirect, evidence supporting the notion that enhancing mGlu2 activity might diminish drug-seeking behavior in humans. Additional clinical trials are needed to thoroughly explore how drugs targeting mGlu2 can prevent relapse and reduce the use of various substances, thereby identifying specific human addictive behaviors most likely affected by mGlu2 activation. Developing Safer Opioid Medications: Targeting μ-opioid receptor with G Protein-Biased Ligands Opioid receptors, including μ-opioid receptor (MOR), are essential in influencing the physiological impacts of opioids such as morphine and fentanyl. Thus, they are vital targets for developing drugs to address opioid use disorder (OUD) and related side effects. NARCAN, for instance, works by competing for these receptors and is a key treatment for quickly reversing opioid overdoses. Conversely, methadone, a synthetic MOR partial agonist, and buprenorphine, a morphinan partial agonist often combined with naloxone in Suboxone, are employed to manage cravings and ease withdrawal symptoms. Despite having fewer side effects, both methadone and buprenorphine still carry a risk of abuse akin to that of fentanyl and other opioids (Whelan & Remski, 2012). MOR and other opioid receptors are pivotal in mediating the physiological effects of opioids like morphine and fentanyl, making them prime targets for developing treatments aimed at alleviating opioid use disorder (OUD) and its associated side effects. NARCAN, which competes for binding at these receptors, is crucial for swiftly reversing acute opioid overdoses. Conversely, the synthetic MOR partial agonist methadone and the morphinan partial agonist buprenorphine (sold with naloxone as Suboxone) are used to alleviate cravings and manage withdrawal symptoms. Nonetheless, despite having milder side effects, methadone and buprenorphine still possess abuse potential similar to that of fentanyl and other opioids (Whelan & Remski, 2012). This highlights the necessity for more effective medications to treat opioid addiction and manage withdrawal symptoms (van Dorp, Yassen, & Dahan, 2007). Recently, there has been a substantial focus on developing new opioid-based analgesics with fewer side effects (Che et al., 2021; Pasternak & Pan, 2013). Numerous studies and drug development initiatives are aimed at creating novel MOR-targeting drugs that engage specific signaling pathways. Research using mouse knockout models has indicated that the analgesic effects of opioids are mainly linked to G protein signaling, while β-arrestin-mediated signaling might be responsible for tolerance, addiction, and the dangerous side effects of these drugs (Bohn et al., 1999, 2000; Schmid et al., 2017). As a result, significant efforts are being made to develop G protein-biased ligands that do not activate β-arrestin (Schmid et al., 2017). One notable compound, PZM21, was identified through a computational ligand discovery campaign utilizing MOR structural data. PZM21 exhibits lower MOR β -arrestin recruitment in vitro and shows enhanced safety profiles in preclinical animal studies, particularly in reducing respiratory depression (Manglik et al., 2016). Likewise, SR-17018 and TRV130 are MOR-selective ligands that bias towards G protein signaling, significantly reducing β-arrestin recruitment. This characteristic leads to lower dependence and respiratory depression in rodent models. (Schmid et al., 2017; Soergel et al., 2014). TRV130, now marketed as Oliceridine, has entered the market but still shows significant respiratory side effects observed in clinical trials, typically prescribed solely for managing moderate to severe acute pain (Singla et al., 2019; Viscusi et al., 2019). Subsequent research has shown that removing β-arrestin-mediated activities does not inherently reduce opioid side effects, indicating that G protein signaling plays a considerable role in these adverse effects (Kliewer et al., 2019, 2020; Bachmutsky et al., 2021). These results suggest that the broader therapeutic ranges of new opioid compounds are attributed to their low intrinsic efficacy rather than a bias towards G protein (Gillis et al., 2020a; Gillis et al., 2020b). Conclusion This review underscores the central role of G protein-coupled receptors (GPCRs) in mediating diverse physiological and pathological processes, highlighting their potential as therapeutic targets for treating various disorders, including addiction, pain, and neurological diseases. Advances in understanding GPCR signaling mechanisms, including biased signaling, allosteric modulation, and receptor-specific pathways, have paved the way for the development of more precise and effective therapies. For addiction, targeting dopamine and glutamate signaling pathways offers insights into neural mechanisms underlying substance use disorders, with promising therapeutic strategies focusing on Group II metabotropic glutamate receptors (mGlu2) and dopamine receptor subtypes. Similarly, innovations in opioid receptor targeting, including G protein-biased ligands, aim to optimize pain relief while minimizing the risks of tolerance, addiction, and respiratory depression. 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Keywords addiction behavioural pharmacology biochemical pharmacology cannabinoid dopamine glutamate opioids psychedelics psychopharmacology Authors Affiliations Mohammad Khan King Saud University View all articles by this author Mohammed Alanazi King Saud University View all articles by this author Ibrahim Alsulaihim King Saud University View all articles by this author Asma S. Alonazi King Saud University View all articles by this author Fawaz Alasmari King Saud University View all articles by this author Khaled Alhosaini [email protected] King Saud University View all articles by this author Metrics & Citations Metrics Article Usage 769 views 247 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Mohammad Khan, Mohammed Alanazi, Ibrahim Alsulaihim, et al. G Protein-Coupled Receptors in Addiction Neurobiology: Mechanisms, Therapeutic Targets, and Advances in Pharmacotherapy. Authorea . 07 April 2025. 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