Long-lasting adaptive changes in mGlu8 receptor expression and function within certain limbic structures, observed in animal models of brain disorders, may contribute to glutamatergic transmission remodeling. This remodeling is crucial for understanding the pathogenesis and symptoms of these illnesses. The current understanding of mGlu8 receptor biology and its possible contribution to several prevalent psychiatric and neurological disorders is reviewed in this summary.
Intracellular ligand-regulated transcription factors, namely estrogen receptors, were initially identified as those causing genomic changes upon ligand engagement. Nonetheless, rapid estrogen receptor signaling commenced outside the nucleus, but the mechanisms governing this activity were not completely known. Modern research suggests that traditional receptors, specifically estrogen receptor alpha and estrogen receptor beta, are capable of translocation and activity at the cell surface membrane. The signaling cascades emanating from membrane-bound estrogen receptors (mERs) swiftly modify cellular excitability and gene expression, especially via CREB phosphorylation. Neuronal mER action often employs glutamate-independent transactivation of metabotropic glutamate receptors (mGlu), yielding diverse signaling outcomes. WS6 IκB modulator Research has shown that interactions between mERs and mGlu are crucial for a variety of female functions, including the driving force behind motivated behaviors. Observational evidence points to estradiol-dependent mER activation of mGlu receptors as a key mechanism driving a considerable portion of the neuroplasticity and motivated behaviors, both positive and negative, induced by estradiol. This review delves into estrogen receptor signaling, encompassing classical nuclear receptors and membrane-bound receptors, alongside estradiol's interactions with mGlu receptors. Female motivated behaviors will be the subject of this examination, focusing on the effects of these receptor interactions and signaling cascades. We will analyze the adaptive example of reproduction and the maladaptive example of addiction.
Marked discrepancies in the presentation and rate of occurrence of a number of psychiatric ailments are noteworthy when considering sex differences. Compared to men, women experience a higher incidence of major depressive disorder, and women developing alcohol use disorder frequently reach drinking milestones more quickly. Women often demonstrate a more favorable response to selective serotonin reuptake inhibitors in psychiatric treatments, in contrast to men, who frequently experience better outcomes with tricyclic antidepressants. While sex is a clearly established biological factor influencing incidence, presentation, and therapeutic response, it has unfortunately been understudied in preclinical and clinical research endeavors. Throughout the central nervous system, metabotropic glutamate (mGlu) receptors are broadly distributed G-protein coupled receptors, an emerging family of druggable targets for psychiatric diseases. Glutamate's neuromodulatory influence, conveyed through mGlu receptors, manifests in various ways, including synaptic plasticity, neuronal excitability, and gene transcription. We present a summary of current preclinical and clinical evidence concerning sex disparities in mGlu receptor function within this chapter. Starting with the primary sex differences in mGlu receptor expression and operation, we subsequently elucidate how gonadal hormones, notably estradiol, govern mGlu receptor signaling. Thereafter, we expound upon sex-differentiated mechanisms whereby mGlu receptors affect synaptic plasticity and behavior in typical circumstances and in models relevant to disease. Lastly, we analyze human research results, highlighting critical areas needing further study. The collected findings of this review underscore the disparity in mGlu receptor function and expression across sexes. A more complete understanding of sex differences in mGlu receptor function's contribution to psychiatric conditions is imperative for the development of treatments that work universally well.
In the last two decades, the role of the glutamate system in the cause and nature of psychiatric conditions, encompassing the dysregulation of metabotropic glutamatergic receptor subtype 5 (mGlu5), has drawn considerable attention. WS6 IκB modulator As a result, mGlu5 may become a viable therapeutic target in the context of psychiatric disorders, particularly those precipitated by stress. A comprehensive review of mGlu5 research concerning mood disorders, anxiety, and trauma, alongside its impact on substance use (nicotine, cannabis, and alcohol), is provided. To investigate the implication of mGlu5 in these psychiatric conditions, we present evidence from positron emission tomography (PET) studies whenever suitable and results from treatment trials, whenever data allows. This chapter's review of research strongly supports the argument that mGlu5 dysregulation is a feature common to numerous psychiatric disorders, potentially offering a valuable disease biomarker. We propose that normalizing glutamate neurotransmission through changes in mGlu5 expression or signaling pathways may be an essential component for treating some psychiatric disorders or their related symptoms. In the end, our aspiration is to portray the utility of PET as a critical tool for investigating the impact of mGlu5 on disease mechanisms and therapeutic responsiveness.
Stress and trauma exposure is a factor that can contribute to the manifestation of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), in some individuals. Extensive preclinical investigations have revealed that the metabotropic glutamate (mGlu) family of G protein-coupled receptors modulates a range of behaviors, encompassing symptoms such as anhedonia, anxiety, and fear, which are key components of both post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) symptom clusters. Beginning with a comprehensive summation of the various preclinical models for assessing these behaviors, we now scrutinize this literature. We subsequently analyze the participation of Group I and II mGlu receptors in these behaviors. This comprehensive review of the literature demonstrates that mGlu5 signaling exhibits varied functions in anhedonia, anxiety, and fear responses. mGlu5's fundamental role in fear conditioning learning is paired with its promotion of susceptibility to stress-induced anhedonia and resilience to stress-induced anxiety-like behavior. mGlu5, mGlu2, and mGlu3's role in regulating these behaviors is central to the function of the medial prefrontal cortex, basolateral amygdala, nucleus accumbens, and ventral hippocampus. A significant body of support indicates that stress-related anhedonia is fundamentally linked to decreased glutamate release and impaired postsynaptic mGlu5 signaling. In contrast, a reduction in mGlu5 signaling strengthens the organism's resistance to stress-provoked anxiety-like behaviors. The contrasting functions of mGlu5 and mGlu2/3 in anhedonia suggest that an increase in glutamate transmission could be a therapeutic approach for the extinction of fear-learning. Accordingly, a significant corpus of literature champions the targeting of pre- and postsynaptic glutamate signaling to alleviate post-stress conditions, including anhedonia, fear, and anxiety-like behaviors.
Metabotropic glutamate (mGlu) receptors, present throughout the central nervous system, act as important regulatory components in drug-induced neuroplasticity and subsequent behavior. Studies performed on animals before human trials suggest that mGlu receptors are essential for a multitude of neurological and behavioral effects resulting from methamphetamine. Yet, a systemic evaluation of mGlu-driven processes correlated with neurochemical, synaptic, and behavioral changes induced by meth has been absent. This chapter undertakes a thorough investigation into the role of mGlu receptor subtypes (mGlu1-8) in the neurological consequences of methamphetamine, including neurotoxicity, and related behaviors such as psychomotor activation, reward, reinforcement, and meth-seeking. Moreover, the relationship between altered mGlu receptor function and cognitive deficits following methamphetamine use is carefully scrutinized. The chapter also examines how mGlu receptors and other neurotransmitter receptors interact with each other, contributing to the neural and behavioral changes observed in methamphetamine use. Across various studies, the literature supports the concept that mGlu5 is involved in the modulation of meth's neurotoxic consequences, potentially achieved by decreasing hyperthermia and altering meth-induced dopamine transporter phosphorylation. A consolidated body of work signifies that blocking mGlu5 receptors (accompanied by stimulating mGlu2/3 receptors) reduces the desire for meth, though certain mGlu5-inhibiting drugs simultaneously lessen the drive for food. Moreover, empirical data implies that mGlu5 is a significant contributor to the extinction of methamphetamine-seeking behavior. A historical account of meth use indicates a co-regulatory relationship between mGlu5 and aspects of episodic memory, where mGlu5 activation reinstates impaired memory functions. These discoveries inspire several potential avenues for the development of novel pharmacotherapies targeting Methamphetamine Use Disorder, focusing on the selective modulation of mGlu receptor subtypes.
Multiple neurotransmitter systems, including glutamate, are significantly affected by the complex disorder known as Parkinson's disease. WS6 IκB modulator Many pharmaceutical agents influencing glutamatergic receptor function have been investigated for their ability to reduce Parkinson's disease (PD) symptoms and treatment complications, leading to the approval of amantadine, an NMDA receptor antagonist, for l-DOPA-induced dyskinesia. Several ionotropic and metabotropic (mGlu) receptors are responsible for glutamate's function. Eight sub-types of mGlu receptors are identified; subtypes 4 (mGlu4) and 5 (mGlu5) have been the focus of clinical trials for Parkinson's Disease (PD) related endpoints, whereas mGlu2 and mGlu3 subtypes have been examined in preclinical studies.