The signaling cascades emanating from membrane-bound estrogen receptors (mERs) swiftly modify cellular excitability and gene expression, especially via CREB phosphorylation. A principle method of neuronal mER action involves glutamate-independent activation of metabotropic glutamate receptors (mGlu), resulting in a spectrum of signaling consequences. Research has shown that interactions between mERs and mGlu are crucial for a variety of female functions, including the driving force behind motivated behaviors. Studies demonstrate that a significant amount of estradiol's influence on neuroplasticity and motivated behaviors, both beneficial and detrimental, arises from the activation of mGlu receptors by estradiol-dependent mERs. Within this review, we will scrutinize estrogen receptor signaling, both classical nuclear and membrane-bound forms, along with estradiol's signaling cascade involving 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.

Significant disparities in the manifestation and frequency of various psychiatric conditions are observed between the sexes. Women are affected by major depressive disorder at a higher rate than men, and the progression through drinking milestones in women with alcohol use disorder is typically faster compared to men. When considering responses to psychiatric treatments, women tend to respond more favorably to selective serotonin reuptake inhibitors compared to men, while men experience improved outcomes with tricyclic antidepressants. Despite the considerable documentation of sex-related variations in incidence, presentation, and treatment response, this biological factor remains underrepresented in both preclinical and clinical research. Broadly distributed throughout the central nervous system, the emerging family of druggable targets for psychiatric diseases, metabotropic glutamate (mGlu) receptors, are G-protein coupled receptors. Synaptic plasticity, neuronal excitability, and gene transcription all experience the diverse neuromodulatory actions of glutamate, driven by mGlu receptors. This chapter encapsulates the current body of preclinical and clinical evidence regarding sex-based variations in mGlu receptor function. Starting with the primary sex differences in mGlu receptor expression and operation, we subsequently elucidate how gonadal hormones, notably estradiol, govern mGlu receptor signaling. association studies in genetics We then present sex-distinct mechanisms through which mGlu receptors modify synaptic plasticity and behavior in normal conditions and in models linked to disease. Concluding our discussion, we present findings from human research and emphasize the urgent need for further research in specific areas. Collectively, the review points out that mGlu receptor function and expression vary as a function of sex. For the development of broadly effective psychiatric treatments, a deeper understanding of how sex modifies mGlu receptor function in disease is critical.

The last two decades have seen a substantial increase in the understanding of the glutamate system's contribution to the origins and progression of psychiatric disorders, highlighted by the dysregulation of the metabotropic glutamatergic receptor subtype 5 (mGlu5). Therefore, mGlu5 receptors could potentially be a promising therapeutic focus for psychiatric illnesses, particularly those linked to stress. This analysis investigates mGlu5's implications in mood disorders, anxiety, and trauma, in conjunction with substance use (nicotine, cannabis, and alcohol). Data from positron emission tomography (PET) studies, wherever possible, and treatment trial results, where obtainable, are used to discuss the part mGlu5 plays in these psychiatric conditions. From the evidence presented in this chapter, we posit that dysregulation of mGlu5 is a key element in various psychiatric disorders, possibly functioning as a diagnostic marker, and that normalization of glutamate neurotransmission through alterations in mGlu5 expression or signaling pathways is a potentially necessary therapeutic component for some psychiatric disorders or 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.

The combination of stress and trauma plays a role in the emergence of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), in certain populations. Preclinical studies exploring the metabotropic glutamate (mGlu) family of G protein-coupled receptors have established that these receptors influence various behaviors, often part of the symptom clusters observed in post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), such as anhedonia, anxiety, and fear. This literature review commences with a summary of the varied preclinical models used in assessing these behaviors. In the subsequent section, the contributions of Group I and II mGlu receptors to these behaviors are discussed in detail. This comprehensive analysis of existing research shows that mGlu5 signaling mechanisms are differentially involved in anhedonic, fearful, and anxious-related behaviors. mGlu5's influence extends to fear conditioning learning, alongside its role in susceptibility to stress-induced anhedonia and resilience to stress-induced anxiety. The medial prefrontal cortex, basolateral amygdala, nucleus accumbens, and ventral hippocampus are crucial sites for the modulation of these behaviors by mGlu5, mGlu2, and mGlu3. Strong evidence indicates that the development of stress-induced anhedonia is closely tied to a reduction in glutamate release and a corresponding impairment of postsynaptic mGlu5 signaling. Biometal chelation By contrast, a decrease in the activation of mGlu5 receptors fortifies the organism's resistance to stress-induced anxiety-like behaviors. Based on the different roles of mGlu5 and mGlu2/3 in anhedonia, evidence suggests that increasing glutamate transmission might promote the extinction of fear learning. Indeed, a large number of research papers underscore the potential benefits of modifying pre- and postsynaptic glutamate signaling to combat post-stress anhedonia, fear, and anxiety-like behaviors.

Drug-induced neuroplasticity and behavior are modulated by the pervasive expression of metabotropic glutamate (mGlu) receptors throughout the central nervous system. Initial preclinical investigations highlight mGlu receptors' pivotal function in the range of neural and behavioral effects following methamphetamine exposure. 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. The evidence linking altered mGlu receptor function to post-methamphetamine cognitive and learning deficits is thoroughly evaluated. Furthermore, the chapter investigates the function of receptor-receptor interactions, including those involving mGlu receptors and other neurotransmitter receptors, in the context of methamphetamine-induced neural and behavioral modifications. SANT-1 The collective findings from the literature suggest mGlu5 modulation of meth's neurotoxic effects, achieved by diminishing hyperthermia and potentially through modifying meth-induced dopamine transporter phosphorylation. A consistent body of scientific work highlights that mGlu5 receptor antagonism (coupled with mGlu2/3 receptor activation) attenuates the pursuit of methamphetamine, though some mGlu5-blocking drugs also diminish food-seeking behavior. Furthermore, the evidence points to mGlu5's crucial involvement in the suppression of methamphetamine-motivated behavior. In the context of past methamphetamine use, mGlu5 participates in the co-regulation of episodic memory elements, with mGlu5 activation improving the impaired memory. Given these findings, we suggest multiple pathways for creating innovative pharmacological treatments for Methamphetamine Use Disorder, centered on selectively adjusting the activity of mGlu receptor subtypes.

Multiple neurotransmitter systems, including glutamate, are significantly affected by the complex disorder known as Parkinson's disease. In this manner, a number of medications acting on glutamatergic receptors have been evaluated for their capacity to improve PD symptoms and treatment-related adverse events, culminating in the acceptance of the NMDA antagonist amantadine for alleviating l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia. The actions of glutamate are mediated by various ionotropic and metabotropic (mGlu) receptors. Subtypes of mGlu receptors encompass eight variations; clinical trials have evaluated modulators of subtypes 4 (mGlu4) and 5 (mGlu5) for Parkinson's Disease (PD)-related outcomes, whereas subtypes 2 (mGlu2) and 3 (mGlu3) have been investigated in preclinical studies. An overview of mGlu receptors, specifically focusing on mGlu5, mGlu4, mGlu2, and mGlu3, is presented in this section of the book. For each subtype, we analyze, if relevant, their anatomical location and the possible mechanisms that contribute to their efficacy in managing specific disease symptoms or treatment-related side effects. By combining the outcomes of preclinical research and clinical trials with pharmacological agents, we then offer a summary and examine the prospective merits and shortcomings of each target's potential. We summarize the potential applications of mGlu modulators in PD treatment.

Frequently, traumatic injuries lead to direct carotid cavernous fistulas (dCCFs), high-flow shunts that connect the internal carotid artery (ICA) to the cavernous sinus. Detachable coils, often used in endovascular interventions, sometimes paired with stenting, can be the preferred treatment approach, yet coil migration or compaction can arise from the high-flow characteristics of dCCFs.