The expression and function of mGlu8 receptors in certain limbic areas undergo persistent adaptive modifications in animal models of these brain disorders. These modifications could significantly influence the restructuring of glutamatergic transmission, a key aspect of the illness's development and symptom presentation. This review synthesizes the current knowledge of mGlu8 receptor biology and explores its potential involvement in common psychiatric and neurological disorders.

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. Contemporary research demonstrates that estrogen receptors, specifically estrogen receptor alpha and beta, can also be targeted to act at the cellular surface membrane. Rapid shifts in cellular excitability and gene expression, initiated by signaling cascades from membrane-bound estrogen receptors (mERs), are frequently mediated through the phosphorylation of CREB. The transactivation of metabotropic glutamate receptors (mGlu), untethered to glutamate, represents a crucial pathway in neuronal mER activity, causing various signaling events. MTX-531 manufacturer Studies on mER-mGlu interactions have demonstrated their significance across diverse female functions, including the promotion of motivated behaviors. 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. 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. The study of motivated behaviors in females will delve into the complex relationship between these receptor interactions and subsequent signaling cascades. Reproduction as an adaptive behavior and addiction as a maladaptive one will be explored.

Sex-linked variations are apparent in the way several psychiatric conditions are presented and in their respective occurrences. Major depressive disorder is more prevalent in women than in men; women with alcohol use disorder also demonstrate more rapid progression through drinking milestones than men. With respect to psychiatric treatment outcomes, women often demonstrate a more favorable reaction to selective serotonin reuptake inhibitors, while men often experience improved outcomes with tricyclic antidepressants. Despite the documented impact of sex on disease incidence, presentation, and treatment outcomes, a significant oversight exists in preclinical and clinical research regarding its biological importance. G-protein coupled receptors, widely distributed throughout the central nervous system, are metabotropic glutamate (mGlu) receptors, an emerging family of druggable targets for psychiatric diseases. The neuromodulatory actions of glutamate, diversified by mGlu receptors, significantly influence synaptic plasticity, neuronal excitability, and gene transcription processes. Current preclinical and clinical evidence for sex-related differences in mGlu receptor function is summarized in this chapter. To begin, we emphasize the basal differences in mGlu receptor expression and function between the sexes, then describe how gonadal hormones, primarily estradiol, affect mGlu receptor signaling. We subsequently investigate sex-distinct mechanisms by which mGlu receptors modulate synaptic plasticity and behavior in standard conditions and in models relevant to disease. Lastly, we analyze human research results, highlighting critical areas needing further study. This review, when evaluated in its entirety, accentuates the difference in mGlu receptor function and expression between the sexes. A deeper comprehension of sex-based disparities in mGlu receptor function's role in psychiatric illnesses is essential for creating novel, universally effective treatments.

Psychiatric disorders' etiology and pathophysiology have seen mounting interest in the glutamate system's involvement over the last two decades, particularly concerning the dysregulation of the metabotropic glutamatergic receptor subtype 5 (mGlu5). MTX-531 manufacturer Thus, mGlu5 receptors could potentially be a promising avenue for therapeutic intervention in psychiatric illnesses, particularly in stress-related conditions. Findings on mGlu5's influence in mood disorders, anxiety, trauma, and substance use (nicotine, cannabis, and alcohol) are presented below. We explore the role of mGlu5 in these psychiatric disorders, drawing on insights from positron emission tomography (PET) studies where applicable and treatment trial findings when available. This chapter's analysis of research data suggests that mGlu5 dysregulation is a common feature of numerous psychiatric disorders, possibly indicating its utility as a biomarker. We posit that restoring normal glutamate neurotransmission through modifications in mGlu5 expression or signaling may be integral to treating specific psychiatric conditions or associated symptoms. Our ultimate objective is to reveal the utility of PET as a significant tool in researching the participation of mGlu5 in disease mechanisms and treatment responsiveness.

People exposed to stress and trauma may experience the development of psychiatric disorders, like post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), in specific instances. A significant body of preclinical research has uncovered that the metabotropic glutamate (mGlu) family of G protein-coupled receptors exerts regulatory control over various behaviors, which are a part of the symptom clusters observed in both post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), including anhedonia, anxiety, and fear. To review this literature, we first present a summary of the many different preclinical models that evaluate these behaviors. A subsequent section summarizes the roles played by Group I and II mGlu receptors in influencing these behaviors. Across a vast range of studies, it is apparent that mGlu5 signaling exhibits various roles in the manifestation of anhedonia, fear, and anxiety-like behaviors. mGlu5 underlies fear conditioning learning, acting as a mediator between stress-induced anhedonia susceptibility and stress-induced anxiety resilience. Within the brain regions of the medial prefrontal cortex, basolateral amygdala, nucleus accumbens, and ventral hippocampus, mGlu5, mGlu2, and mGlu3 are key players in the regulation of these behaviors. Evidence strongly suggests that stress-induced anhedonia stems from a reduction in glutamate release and subsequent diminished post-synaptic mGlu5 signaling. Alternatively, a diminished mGlu5 signaling pathway enhances the capacity to withstand stress-related anxiety-like responses. Similar to the opposing roles of mGlu5 and mGlu2/3 in anhedonia, the evidence highlights the possibility that intensified glutamate signaling could contribute to the eradication 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.

Central nervous system expression of metabotropic glutamate (mGlu) receptors significantly impacts the regulation of drug-induced neuroplasticity and behavioral responses. Studies performed on animals before human trials suggest that mGlu receptors are essential for a multitude of neurological and behavioral effects resulting from methamphetamine. Despite this, an assessment of mGlu-dependent pathways contributing to neurochemical, synaptic, and behavioral changes from meth has been deficient. A comprehensive review of the role of mGlu receptor subtypes (mGlu1-8) in methamphetamine's neurological impacts, such as neurotoxicity, and associated behaviors, like psychomotor activation, reward, reinforcement, and methamphetamine-seeking, is presented in this chapter. Additionally, a critical evaluation of the evidence supporting an association between mGlu receptor dysfunction and post-methamphetamine learning and cognitive deficits is presented. The chapter addresses the role of mGlu receptors and other neurotransmitter receptors in receptor-receptor interactions, which are integral to understanding meth-induced modifications in neural and behavioral functions. A review of the literature demonstrates mGlu5's role in mitigating meth's neurotoxicity, possibly through a reduction in hyperthermia and changes to meth-induced dopamine transporter phosphorylation. A unified body of research indicates that the blocking of mGlu5 receptors (alongside the stimulation of mGlu2/3 receptors) decreases methamphetamine-seeking behavior, though some mGlu5-blocking drugs also reduce the motivation to search for food. Additionally, research suggests mGlu5 has a pivotal role in the termination of meth-seeking tendencies. A history of meth intake is associated with the co-regulation of episodic memory by mGlu5; stimulation of mGlu5 promotes recovery of impaired memory. Following these outcomes, we propose various paths forward for the development of novel medications to address Methamphetamine Use Disorder, through selectively adjusting the activity of mGlu receptor subtypes.

The complex disorder, Parkinson's disease, is linked to alterations in a multitude of neurotransmitter systems, with glutamate prominently affected. MTX-531 manufacturer Therefore, a selection of drugs acting on glutamatergic receptors were investigated to lessen the presence of Parkinson's disease (PD) symptoms and treatment-related issues, resulting in the approval of the NMDA antagonist amantadine for l-DOPA-induced dyskinesias. Several ionotropic and metabotropic (mGlu) receptors are responsible for glutamate's function. MGlu receptors display eight subtypes; modulators of subtypes 4 (mGlu4) and 5 (mGlu5) have been tested clinically for Parkinson's Disease (PD) outcomes, and subtypes 2 (mGlu2) and 3 (mGlu3) have been examined in a pre-clinical setting.