Overview of neuroinflammation

Neuroinflammation is a complex and dynamic process that plays a crucial role in both neuroprotection and neurodegeneration. It is primarily mediated by glial cells, including microglia and astrocytes, in response to various stimuli such as infection, injury, or neurodegenerative diseases (Figure 1) [1]. While acute neuroinflammation serves as a protective mechanism by clearing pathogens and damaged cells, chronic neuroinflammation contributes to neuronal dysfunction and cell death, leading to the progression of neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). The sustained release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) not only promotes gliosis but also initiates a cascade of harmful events by enhancing oxidative stress and disrupting neurotransmitter balance [2, 3]. This disruption can impair synaptic signaling and plasticity, further compromising neuronal communication. Additionally, activation of toll-like receptors (TLRs) and nuclear factor kappa B (NF-κB) signaling pathways amplifies inflammatory responses, creating a pathological loop that perpetuates neuronal damage. This self-reinforcing cycle contributes to neuronal death through mechanisms such as excitotoxicity, mitochondrial dysfunction, and impaired autophagy. Understanding the molecular underpinnings of neuroinflammation is essential for identifying novel therapeutic targets and developing effective interventions to mitigate its deleterious effects on brain function [4, 5]. Emerging strategies include the use of anti-inflammatory agents like minocycline, immune modulators targeting microglial activation, and neuroprotective compounds such as cannabinoids [6] and Nrf2 activators, which show promise in preclinical and early clinical studies [7, 8].

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Figure 1. 

Generalized mechanism of induced neuroinflammation. CNS: central nervous system; TNF-α: tumor necrosis factor-alpha; IL-1β: interleukin-1 beta; IL-6: interleukin-6

Role of neurotransmitter receptors in brain homeostasis

Neurotransmitter receptors play a fundamental role in maintaining brain homeostasis by modulating synaptic transmission, neuronal excitability, and neuroplasticity [9]. These receptors, classified into ionotropic and metabotropic types, respond to key neurotransmitters such as glutamate, dopamine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine [10]. Excitatory neurotransmitters like glutamate activate N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are crucial for synaptic plasticity and cognitive functions. Conversely, inhibitory neurotransmitters like GABA bind to GABA_A and GABA_B receptors to regulate neuronal excitability and prevent excitotoxicity [11].

Neuroinflammation disrupts neurotransmitter receptor signaling, leading to synaptic dysfunction and neuronal loss. Pro-inflammatory cytokines can alter receptor expression, desensitize synaptic responses, and impair receptor trafficking [12]. For instance, increased levels of TNF-α have been shown to enhance AMPA receptor expression, exacerbating excitotoxicity in neurodegenerative conditions [13]. Similarly, dopaminergic dysfunction due to neuroinflammation is a key pathological feature in PD, where microglial activation and cytokine release lead to the progressive loss of dopaminergic neurons in the substantia nigra [14]. The interaction between inflammatory mediators and neurotransmitter receptors underscores the need to explore their crosstalk in the context of neurodegenerative diseases [15].

Importance of heteroreceptor complexes

Heteroreceptor complexes are emerging as critical modulators of brain function, serving as integrators of multiple signaling pathways by facilitating receptor crosstalk [16]. These complexes are formed through the physical and functional interaction of different neurotransmitter receptors, altering their pharmacological and signaling properties. Notable examples include dopamine-glutamate receptor complexes (D2-NMDA, D1-NMDA), adenosine-dopamine (A2A-D2) [17], and serotonin-dopamine (5-HT2A-D2) receptor interactions [18, 19]. By modulating neurotransmission, synaptic plasticity, and neuroinflammatory responses, heteroreceptor complexes contribute to brain homeostasis and neuroprotection [20].

In the context of neuroinflammation, heteroreceptor complexes play a dual role by either exacerbating or mitigating inflammatory responses depending on their configuration and signaling dynamics. However, it is important to note that the existence and stability of these heteromers under pathological conditions remain an active area of investigation. In some disease states, receptor expression may be downregulated or altered, potentially preventing heteromer formation [21]. Further studies using post-mortem tissues, disease models, and advanced imaging techniques are needed to confirm whether these complexes are maintained or disrupted in patients with neuroinflammatory disorders. For instance, the A2A-D2 receptor complex is known to regulate dopaminergic neurotransmission, and its dysfunction has been implicated in neuroinflammatory processes observed in PD [22]. Conversely, activation of A2A receptors within these complexes can also suppress microglial activation and inhibit pro-inflammatory cytokine release, thereby exerting anti-inflammatory effects in certain neurodegenerative conditions. Similarly, alterations in the balance between excitatory and inhibitory receptor complexes contribute to synaptic dysfunction in neurodegenerative diseases [23]. Targeting heteroreceptor complexes offers a promising therapeutic avenue, as modulating their interactions can restore receptor function and attenuate neuroinflammatory damage [24]. Recent studies suggest that allosteric modulators and biased agonists can selectively influence heteroreceptor complex activity, paving the way for precision medicine approaches in neurodegenerative and psychiatric disorders [25]. For instance, several A2A receptor antagonists and 5-HT2A inverse agonists are currently being evaluated in preclinical and early-phase clinical trials for their potential to modulate neuroinflammatory pathways and improve cognitive or motor symptoms in PD and schizophrenia models.

Understanding the interplay between neuroinflammation and heteroreceptor complexes provides a new dimension in neuropharmacology and disease management [26]. Given their intricate role in regulating neurotransmission and neuroinflammation, further research into heteroreceptor complexes could unlock novel therapeutic strategies aimed at mitigating chronic neuroinflammatory conditions and improving neurodegenerative disease outcomes [27, 28].

AD

AD is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque accumulation, tau protein hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. The role of heteroreceptor complexes in AD pathology is increasingly recognized, particularly in relation to neurotransmitter dysregulation and inflammatory responses [54]. Dopamine-glutamate heteroreceptor complexes, such as the D1-NMDA and D2-NMDA receptor interactions, are crucial for synaptic plasticity and cognitive function. In AD, these complexes are disrupted due to excessive glutamate excitotoxicity and reduced dopamine signaling, leading to impaired synaptic transmission and neuronal loss. The dysregulation of the D1-NMDA receptor complex exacerbates synaptic weakening, further contributing to cognitive deficits in AD patients [55].

Adenosine-dopamine heteroreceptor complexes, particularly the A2A-D2 complex, also play a significant role in AD-associated neuroinflammation. The overactivation of A2A receptors in response to chronic neuroinflammatory stimuli inhibits D2 receptor signaling, leading to impaired cognitive and motor functions [56]. The involvement of these receptor interactions in neuroinflammation suggests that targeting A2A receptors could be a potential therapeutic approach to modulate neuroinflammatory cascades and improve neurotransmitter balance in AD patients. Additionally, serotonin-dopamine heteroreceptor complexes (5-HT2A-D2) contribute to AD pathology by altering neurotransmitter homeostasis and inflammatory responses. Dysregulated 5-HT2A receptor activity is associated with increased tau aggregation and neuroinflammatory processes, making these heteroreceptor interactions a promising target for AD interventions [57].

PD

PD is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra and chronic neuroinflammation. The dysregulation of heteroreceptor complexes, particularly those involving dopamine and adenosine receptors, is a key contributor to PD pathophysiology. The A2A-D2 heteroreceptor complex is critically involved in the regulation of motor control, as A2A receptor overactivation suppresses dopamine D2 receptor function, leading to motor deficits [58]. In PD, excessive adenosine A2A receptor activity enhances neuroinflammatory signaling through microglial activation and pro-inflammatory cytokine release, exacerbating neuronal loss and motor impairments. Pharmacological blockade of A2A receptors has been explored as a therapeutic approach to restore D2 receptor function and reduce neuroinflammation [59].

Dopamine-glutamate heteroreceptor complexes, such as D1-NMDA and D2-NMDA interactions, are also disrupted in PD, contributing to cognitive impairments and excitotoxic damage. The loss of dopaminergic input in PD alters NMDA receptor activity, leading to excessive calcium influx and oxidative stress, further promoting neurodegeneration. Additionally, serotonin-dopamine heteroreceptor complexes (5-HT2A-D2) play a role in PD-related non-motor symptoms, including depression and cognitive decline [60]. The dysregulation of these receptor interactions contributes to altered neurotransmitter signaling and inflammation, making them potential targets for adjunctive therapies in PD treatment. The modulation of heteroreceptor complexes offers a promising strategy to mitigate neuroinflammation and neurodegeneration in PD patients [61].

MS

MS is a chronic autoimmune-mediated neuroinflammatory disorder characterized by demyelination, axonal damage, and neurodegeneration. The role of heteroreceptor complexes in MS pathology is gaining attention, particularly regarding neurotransmitter dysregulation and immune system interactions. Glutamate-dopamine heteroreceptor complexes, such as D1-NMDA and D2-NMDA interactions, are implicated in MS-related excitotoxicity and neuroinflammation [62]. The excessive activation of NMDA receptors due to dysregulated glutamate signaling contributes to oligodendrocyte damage and demyelination, leading to disease progression [63].

Adenosine-dopamine heteroreceptor complexes (A2A-D2) are also involved in MS-related neuroinflammation. A2A receptor activation promotes microglial activation and pro-inflammatory cytokine release, exacerbating neuroimmune responses. The inhibition of A2A receptors has been proposed as a potential therapeutic approach to modulate neuroinflammatory pathways and protect against demyelination in MS patients [64]. Additionally, serotonin-dopamine heteroreceptor interactions (5-HT2A-D2) are linked to mood disturbances and cognitive impairments observed in MS. The dysregulation of these receptor complexes affects neurotransmitter balance, leading to increased neuroinflammatory responses and exacerbation of psychiatric symptoms. Targeting heteroreceptor complexes to modulate neurotransmitter and immune interactions presents a novel approach for mitigating neuroinflammation and neurodegeneration in MS patients [65].

Depression, schizophrenia, and psychiatric disorders

Neuroinflammation plays a significant role in psychiatric disorders, including depression and schizophrenia, where heteroreceptor complexes are key regulators of neurotransmitter interactions. In depression, serotonin-dopamine heteroreceptor complexes (5-HT2A-D2) are crucial for mood regulation and cognitive function. The dysregulation of 5-HT2A receptor activity in response to chronic stress and neuroinflammation contributes to altered dopamine signaling, leading to depressive symptoms [66]. The interaction between serotonin and dopamine receptors modulates neuroinflammatory responses, and abnormalities in these complexes are linked to increased levels of pro-inflammatory cytokines, oxidative stress, and neuronal dysfunction. Pharmacological agents targeting these receptor interactions, such as serotonin-dopamine modulators, have shown promise in alleviating depressive symptoms by restoring neurotransmitter balance and reducing inflammation [67].

In schizophrenia, dopamine-glutamate heteroreceptor complexes, such as D2-NMDA interactions, play a crucial role in synaptic plasticity and cognitive function. The dysfunction of these complexes contributes to altered glutamate signaling, leading to excitotoxic damage and neuroinflammatory processes [68]. The dysregulation of dopamine-serotonin interactions (5-HT2A-D2) is also implicated in schizophrenia-related cognitive deficits and psychotic symptoms. Increased serotonin receptor activity negatively affects dopamine transmission, contributing to impaired cognitive processing and neuroinflammatory responses. Antipsychotic medications targeting these heteroreceptor interactions aim to restore neurotransmitter homeostasis and reduce neuroinflammation, providing therapeutic benefits in schizophrenia treatment [69].

Heteroreceptor complexes also play a role in bipolar disorder and anxiety-related conditions, where neurotransmitter imbalance and neuroinflammatory mechanisms contribute to disease pathology. The modulation of glutamate-dopamine and serotonin-dopamine receptor interactions influences mood regulation, synaptic plasticity, and inflammatory pathways. Emerging research suggests that targeting heteroreceptor complexes could provide novel therapeutic strategies for psychiatric disorders by reducing neuroinflammation and restoring neurotransmitter function [70]. Understanding the role of these receptor interactions in psychiatric conditions is essential for developing precision medicine approaches that address the underlying neurobiological mechanisms of mental health disorders [71].

Impact on neuroimmune response

Neuroinflammation is a complex physiological process involving interactions between neurons, glial cells, and immune signaling pathways. Heteroreceptor complexes play a crucial role in modulating neuroimmune responses by regulating synaptic transmission, neurotransmitter release, and inflammatory signaling cascades [72]. These receptor complexes, consisting of two or more different neurotransmitter receptors physically interacting, influence intracellular signaling pathways that mediate neuroinflammation. Disruptions in heteroreceptor crosstalk can lead to aberrant immune activation, contributing to chronic neuroinflammatory states that underlie various neurological disorders [73].

In conditions such as AD, PD, and MS, heteroreceptor complexes act as regulators of neuroimmune interactions. Dysregulated heteroreceptor complexes, particularly those involving dopamine (D2), adenosine (A2A), serotonin (5-HT2A), and glutamate (NMDA) receptors, contribute to altered immune responses [74]. These interactions affect the release of pro-inflammatory cytokines, reactive oxygen species, and neurotoxic mediators, leading to neuronal dysfunction and neurodegeneration. Thus, understanding the role of heteroreceptor complexes in neuroimmune signaling provides valuable insights into novel therapeutic approaches targeting neuroinflammatory pathways [75].

Role of microglia and astrocytes

Microglia and astrocytes are the primary immune cells of the CNS, playing an integral role in maintaining homeostasis and responding to neuroinflammatory stimuli. Heteroreceptor complexes modulate the activation state of these glial cells, influencing their capacity to regulate synaptic function and neuroinflammatory responses [76]. In pathological conditions, dysregulated receptor crosstalk between neurons and glial cells exacerbates inflammation, leading to progressive neuronal damage [77].

Microglial activation is influenced by heteroreceptor interactions involving purinergic (P2X7), dopamine (D2), and adenosine (A2A) receptors. Under normal physiological conditions, these complexes maintain microglial homeostasis by balancing pro-inflammatory and anti-inflammatory responses [78]. However, in neurodegenerative diseases, excessive activation of A2A receptors, for instance, leads to heightened microglial reactivity, promoting the release of TNF-α and IL-1β, which contribute to neurotoxicity. Similarly, dopamine-glutamate heteroreceptor complexes influence astrocytic function, modulating glutamate uptake and preventing excitotoxicity. When disrupted, these interactions impair astrocytic glutamate clearance, exacerbating neuroinflammatory damage [79].

Astrocytes, in particular, contribute to neuroinflammation by releasing pro-inflammatory cytokines and modulating blood-brain barrier integrity. The crosstalk between serotonin (5-HT2A) and glutamate receptors in astrocytes regulates inflammatory responses, influencing cytokine production and gliosis [80]. The involvement of heteroreceptor complexes in glial function highlights their significance in shaping neuroimmune responses and presents potential targets for mitigating neuroinflammation-associated neurodegeneration [81].

Cross-talk with cytokines and inflammatory markers

Heteroreceptor complexes influence the expression and release of cytokines and other inflammatory markers, serving as mediators of neuroinflammation [82]. These receptor complexes modulate intracellular signaling pathways that regulate the balance between pro-inflammatory and anti-inflammatory cytokine production. Dysregulation of these interactions leads to excessive inflammation, a hallmark of neurodegenerative and psychiatric disorders [83].

The activation of heteroreceptor complexes, such as A2A-D2 and 5-HT2A-D2, alters immune responses by modulating the activity of NF-κB, MAPKs, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways [84]. These intracellular signaling cascades govern the production of cytokines such as IL-6, TNF-α, and IL-1β. Excessive cytokine release in response to dysregulated receptor crosstalk contributes to chronic neuroinflammation, exacerbating neuronal damage and synaptic dysfunction [85].

Furthermore, heteroreceptor complexes interact with chemokines and other inflammatory mediators that regulate immune cell infiltration into the CNS. In MS, for example, heteroreceptor interactions influence the migration of peripheral immune cells across the blood-brain barrier, contributing to neuroinflammatory demyelination [86]. Similarly, in psychiatric disorders such as depression and schizophrenia, heteroreceptor dysregulation leads to altered cytokine profiles, influencing neurotransmitter function and exacerbating disease pathology [87].

Drug development

Heteroreceptor complexes represent a promising target for drug development, particularly in the treatment of neuroinflammatory and neurodegenerative disorders. These complexes, formed by interactions between different neurotransmitter receptors, play a crucial role in modulating synaptic transmission, neuroimmune responses, and inflammatory signaling pathways [88]. Given their influence on neuronal homeostasis and immune activation, pharmacological interventions aimed at restoring the balance of heteroreceptor signaling may provide novel therapeutic avenues for conditions such as AD, PD, MS, and psychiatric disorders [89].

One of the key advantages of targeting heteroreceptor complexes is the ability to fine-tune neurotransmitter systems with greater specificity than traditional single-receptor-targeting drugs. For instance, the dopamine-glutamate heteroreceptor complexes, including D2-NMDA interactions, are involved in cognitive and motor functions. Dysregulation of these complexes contributes to excitotoxicity and neurodegeneration, making them potential targets for drugs that modulate both dopamine and glutamate signaling simultaneously [90]. Similarly, the adenosine-dopamine heteroreceptor complex (A2A-D2) has been implicated in PD, where excessive adenosine A2A receptor activity inhibits dopamine D2 receptor function, exacerbating motor impairments and neuroinflammation. Drugs that selectively modulate A2A receptor activity, such as istradefylline, have demonstrated therapeutic potential in alleviating symptoms of PD by restoring dopaminergic signaling and reducing neuroinflammation [91].

Another promising approach is the modulation of serotonin-dopamine heteroreceptor complexes (5-HT2A-D2), which play a role in psychiatric disorders such as schizophrenia and depression. Atypical antipsychotics, such as clozapine and risperidone, target these receptor interactions, leading to improved treatment efficacy compared to traditional dopamine-based antipsychotics. By refining drug design to selectively target heteroreceptor complexes, researchers can develop more effective and less side-effect-prone treatments for neuropsychiatric and neurodegenerative conditions [92].

Role of allosteric regulators and biased agonism

The emergence of allosteric modulators and biased agonists has revolutionized the field of receptor pharmacology, offering new strategies to manipulate heteroreceptor complex function. Unlike traditional orthosteric ligands, which directly activate or inhibit receptors, allosteric modulators bind to distinct sites on the receptor complex to enhance or diminish receptor responses in a highly selective manner. This specificity reduces off-target effects and allows for more precise control over receptor signaling pathways [93].

Positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) have shown potential in fine-tuning heteroreceptor activity in neuroinflammatory disorders. For example, PAMs targeting metabotropic glutamate receptors (mGluRs) have been explored as potential treatments for neurodegenerative diseases by modulating glutamate-dopamine receptor interactions and reducing excitotoxicity. Similarly, A2A receptor antagonists, acting as NAMs, have demonstrated efficacy in preclinical and clinical models of PD by preventing excessive adenosine-mediated inhibition of D2 receptor activity [94].

Biased agonism, or ligand-directed signaling, is another promising approach for targeting heteroreceptor complexes. This concept involves designing drugs that preferentially activate specific signaling pathways while avoiding pathways associated with adverse effects. For example, dopamine D2 receptor-biased agonists have been developed to selectively engage beneficial G-protein signaling while minimizing β-arrestin-mediated side effects, which are linked to dyskinesia and cognitive dysfunction [95]. Such approaches could enhance the therapeutic index of drugs targeting heteroreceptor complexes in neuroinflammatory and neuropsychiatric disorders [96].

In addition to small-molecule modulators, peptide-based therapeutics and monoclonal antibodies are being investigated as potential modulators of heteroreceptor function. These biologics offer high specificity and can be engineered to disrupt or stabilize receptor-receptor interactions, providing novel therapeutic strategies for neuroinflammatory diseases [97].

Clinical trials and future directions

The clinical translation of heteroreceptor complex-targeting drugs is still in its early stages, but several promising candidates are being explored in clinical trials. Adenosine A2A receptor antagonists, such as istradefylline, have already been approved for the treatment of PD, providing proof of concept that targeting heteroreceptor interactions can yield therapeutic benefits [98]. Additionally, serotonin-dopamine receptor modulators, including pimavanserin, have been developed for the treatment of PD psychosis and are being investigated for other neuropsychiatric disorders [99].

Several ongoing clinical trials are evaluating allosteric modulators targeting heteroreceptor interactions in neuroinflammatory conditions. For example, mGluR5 allosteric modulators are being tested for their ability to modulate glutamate-dopamine receptor interactions in schizophrenia and depression. Similarly, biased agonists targeting dopamine and serotonin receptors are being explored for their potential to improve therapeutic outcomes in psychiatric and neurodegenerative diseases while reducing side effects [100].

Future research in this area will focus on refining our understanding of heteroreceptor complex dynamics and identifying novel targets for therapeutic intervention. Advances in Boolean analysis, structural biology, cryo-electron microscopy, and computational modeling are providing new insights into receptor-receptor interactions, enabling the rational design of drugs with enhanced specificity and efficacy [101, 102]. Additionally, the development of gene editing technologies and RNA-based therapies holds promise for modulating heteroreceptor function at the genetic and epigenetic levels [103].

Personalized medicine approaches will also play a key role in the future of heteroreceptor-targeted therapies. By utilizing biomarkers and neuroimaging techniques, clinicians can identify patient-specific alterations in heteroreceptor signaling and tailor treatments accordingly [104]. This precision medicine approach has the potential to improve treatment outcomes for patients with neuroinflammatory and neurodegenerative disorders [105].