Membrane-bound estrogen receptors (mERs) orchestrate rapid alterations in cellular excitability and gene expression, primarily through the phosphorylation of the CREB protein. Neuronal mER action often employs glutamate-independent transactivation of metabotropic glutamate receptors (mGlu), yielding diverse signaling outcomes. The importance of mERs interacting with mGlu in the context of diverse female functions, including motivating behaviors, has been established. Estradiol-induced neuroplasticity and motivated behaviors, both adaptive and maladaptive, appear to be substantially influenced by estradiol-dependent mER activation of mGlu receptors, as indicated by experimental evidence. Estrogen receptor signaling, encompassing classic nuclear and membrane receptors, and estradiol's mGlu signaling will be examined within this review. Focusing on females, we will explore how these receptors interact with their downstream signaling cascades to influence motivated behaviors, using reproduction as an example of an adaptive behavior and addiction as an example of a maladaptive one.

The presentation and prevalence of a range of psychiatric disorders are demonstrably different between the sexes. Female individuals experience major depressive disorder more frequently than males, and women exhibiting alcohol use disorder typically progress through drinking milestones more rapidly than their male counterparts. In terms of psychiatric treatment outcomes, women tend to respond more positively to selective serotonin reuptake inhibitors, contrasting with men, who often experience better results when treated with tricyclic antidepressants. Despite the substantial evidence of sex-related biases in disease incidence, presentation, and treatment outcomes, preclinical and clinical research frequently fails to acknowledge the biological role of sex. 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. At the levels of synaptic plasticity, neuronal excitability, and gene transcription, mGlu receptors are crucial in mediating glutamate's varied neuromodulatory actions. Within this chapter, we synthesize the existing preclinical and clinical findings regarding sex differences in the performance of mGlu receptors. We start by highlighting the basic sex-based disparities in mGlu receptor expression and function, then we go on to describe how gonadal hormones, especially estradiol, control mGlu receptor signaling. Sunvozertinib in vitro In the following section, we delineate sex-specific mechanisms through which mGlu receptors differentially regulate synaptic plasticity and behavior in basal states, including disease models. To summarize, we explore human research outcomes and pinpoint areas warranting further research initiatives. This review, when evaluated in its entirety, accentuates the difference in mGlu receptor function and expression between the sexes. Achieving a more complete knowledge of how sex-dependent variations in mGlu receptor function relate to psychiatric disorders is essential for creating broadly effective treatments for all individuals.

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. We delve into mGlu5's effects on mood disorders, anxiety, and trauma, coupled with its association with substance use (specifically nicotine, cannabis, and alcohol). Positron emission tomography (PET) studies, where relevant, and treatment trial findings, where documented, are used to illuminate the role of mGlu5 in these psychiatric conditions. 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. We are ultimately hopeful to illustrate the usefulness of PET as a vital tool in understanding mGlu5's involvement in disease mechanisms and therapeutic efficacy.

Certain individuals, when subjected to stress and trauma, might develop psychiatric conditions, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Investigations into the preclinical effects of the metabotropic glutamate (mGlu) family of G protein-coupled receptors have shown their regulation of several behaviors, including those that manifest in the symptom clusters for both post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), specifically anhedonia, anxiety, and fear. Beginning with a general survey of the wide assortment of preclinical models used in assessing these behaviors, this literature is now examined. Following this, we detail the roles of Group I and II mGlu receptors in the context of these behaviors. Integrating the extensive literature suggests that mGlu5 signaling plays differentiated roles in the occurrence of anhedonia, fear, and anxiety-like behaviors. mGlu5's influence extends to fear conditioning learning, alongside its role in susceptibility to stress-induced anhedonia and resilience to stress-induced anxiety. Crucially, the interplay of mGlu5, mGlu2, and mGlu3 within the medial prefrontal cortex, basolateral amygdala, nucleus accumbens, and ventral hippocampus significantly shapes these behaviors. 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. Sunvozertinib in vitro Unlike the case of increased mGlu5 signaling, decreased signaling fosters a heightened resistance to anxiety-like behaviors triggered by stress. Observational data on the opposing contributions of mGlu5 and mGlu2/3 in anhedonia implies that heightened glutamate transmission could be therapeutic in the extinction of learned fear. Subsequently, a wealth of published works endorse the pursuit of modifying pre- and postsynaptic glutamate signaling as a means to alleviate the symptoms of post-stress anhedonia, fear, and anxiety-like behaviors.

The central nervous system's extensive network of metabotropic glutamate (mGlu) receptors has a key regulatory effect on the neuroplasticity induced by drugs and subsequent behaviors. Preclinical studies suggest that mGlu receptors hold a key position in the wide variety of neurobiological and behavioral repercussions stemming from methamphetamine exposure. However, the exploration of mGlu-mediated systems linked to neurochemical, synaptic, and behavioral changes resulting from meth has been incomplete. This chapter offers a thorough examination of the function of mGlu receptor subtypes (mGlu1-8) in meth-induced neurological effects, including neurotoxicity, and meth-related behaviors, including psychomotor stimulation, reward, reinforcement, and meth-seeking. Furthermore, the evidence connecting modified mGlu receptor function to post-methamphetamine learning and cognitive impairments is rigorously examined. Receptor-receptor interactions involving mGlu receptors and other neurotransmitter receptors are also analyzed in the chapter, with a focus on their roles in the neural and behavioral consequences of meth use. Sunvozertinib in vitro 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 cohesive body of research indicates that blocking mGlu5 receptors (and activating mGlu2/3 receptors) lessens the pursuit of meth, although some mGlu5-blocking agents concomitantly diminish the desire for food. Consequently, data reveals mGlu5's vital function in the extinction of methamphetamine-seeking activities. 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 results lead us to propose several avenues for creating innovative pharmaceutical interventions for Methamphetamine Use Disorder, specifically through selective modulation of mGlu receptor subtype activity.

The intricate disorder of Parkinson's disease causes alterations in neurotransmitter systems, with glutamate being a prominent example. 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. Glutamate's physiological response is triggered by its interaction with ionotropic and metabotropic (mGlu) receptors. The mGlu receptor family includes eight subtypes; subtypes 4 (mGlu4) and 5 (mGlu5) are the subjects of clinical testing for Parkinson's Disease (PD) related measures, in comparison to the preclinical studies on subtypes 2 (mGlu2) and 3 (mGlu3). The current chapter is dedicated to the overview of mGlu receptors in Parkinson's disease (PD), with a key focus on the actions of mGlu5, mGlu4, mGlu2, and mGlu3. 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. A synthesis of pre-clinical study and clinical trial results using pharmacological agents is presented, along with a discussion of the potential advantages and disadvantages of each specific target. Our final observations revolve around the possible therapeutic roles of mGlu modulators in Parkinson's Disease.

Direct carotid cavernous fistulas (dCCFs), high-flow shunts between the internal carotid artery (ICA) and the cavernous sinus, are often the consequence of traumatic events. Endovascular interventions, often including the use of detachable coils, possibly supplemented by stents, are frequently the treatment of choice, nevertheless the high-flow dynamics of dCCFs can sometimes cause coil migration or compaction.