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Traditionally, patients receiving cancer treatment contend with the potentially life-threatening side effects of cytotoxic chemotherapy. The recent emergence of newer cancer therapies, such as the epidermal growth factor receptor (EGFR) inhibitors, present new management challenges for oncology pharmacists, nurses, and physicians. Even though EGFR inhibitors are generally considered to be 'well tolerated,' this does not mean that they are devoid of side effects. Prior to the initiation of anti-EGFR therapy, it is imperative that patients be able to recognize the early signs of toxicity and seek prompt intervention to minimize such reactions. Patients should also understand that side-effect management may improve compliance with therapy and can lead to better outcomes. Importantly, pharmacists play a central role in such patient education. [ABSTRACT FROM AUTHOR]

Exposure of immature rat cerebellar granule cell cultures to the type 4 metabotropic glutamate (mGlu4) receptor enhancer N-phenyl-7(hydroxyimino)cyclopropa[b]chromen-la-carboxamide (PHCCC) reduced [³H]thymidine incorporation. Its action was sensitive to the growth conditions and was attenuated by two mGlu4 receptor antagonists. An antiproliferative action of PHCCC was also seen in cultures from wild-type, but not mGlu4, knock-out mice. At least in rat cultures, PHCCC was not neurotoxic and enhanced neuritogenesis. Although PHCCC reduced the increase in cAMP formation and phospho-AKT levels induced by forskolin, none of these transduction pathways significantly contributed to the reduction of [³H]thymidine incorporation. Interestingly, PHCCC reduced the expression of Gli-1, a transcription factor that mediates the mitogenic action of Sonic hedgehog. Finally, we treated newborn rats with PHCCC either intracerebrally (infusion of 5 nmol/2 µl in the cerebellar region once every other day) or systemically (5 mg/kg, i.p., once daily) from postnatal days 3-9. Local infusion of PHCCC induced substantial changes in the morphology of the developing cerebellum. In contrast, systemic injection of PHCCC induced only morphological abnormalities of the cerebellar lobule V, which became visible 11 d after the end of the treatment. These data suggest that mGlu4 receptors are involved in the regulation of cerebellar development. [ABSTRACT FROM AUTHOR]

Cellular responses to metabotropic glutamate (mGlu) receptor activation are shaped by mechanisms of receptor-receptor interaction. mGlu receptor subtypes form homodimers, intra- or inter-group heterodimers, and heteromeric complexes with other G protein-coupled receptors (GPCRs). In addition, mGlu receptors may functionally interact with other receptors through the βγ subunits released from G proteins in response to receptor activation or other mechanisms. Here, we discuss the interactions between (i) mGlu 1 and GABA B receptors in cerebellar Purkinje cells; (ii) mGlu 2 and 5-HT 2A serotonergic receptors in the prefrontal cortex; (iii) mGlu 5 and A 2A receptors or mGlu 5 and D 1 dopamine receptors in medium spiny projection neurons of the indirect and direct pathways of the basal ganglia motor circuit; (iv) mGlu 5 and A 2A receptors in relation to the pathophysiology of Alzheimer's disease; and (v) mGlu 7 and A 1 adenosine or α- or β 1 adrenergic receptors. In addition, we describe in detail a novel form of non-heterodimeric interaction between mGlu 3 and mGlu 5 receptors, which appears to be critically involved in mechanisms of activity-dependent synaptic plasticity in the prefrontal cortex and hippocampus. Finally, we highlight the potential implication of these interactions in the pathophysiology and treatment of cerebellar disorders, schizophrenia, Alzheimer's disease, Parkinson's disease, l-DOPA-induced dyskinesias, stress-related disorders, and cognitive dysfunctions. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy"., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms, with weaker and more variable effects on cognitive deficits. Using the sub-chronic phencyclidine rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the PFC. Although not effective at 0.05 and 1 mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Using an in vivo method for the assessment of polyphosphoinositide (PI) hydrolysis, we examine whether spatial learning and memory extinction cause changes in mGlu5 metabotropic glutamate receptor signaling in the hippocampus and prefrontal cortex. We use the following five groups of mice: (i) naive mice; (ii) control mice exposed to the same environment as learner mice; (iii) leaner mice, trained for four days in a water maze; (iv) mice in which memory extinction was induced by six trials without the platform; (v) mice that spontaneously lost memory. The mGlu5 receptor-mediated PI hydrolysis was significantly reduced in the dorsal hippocampus of learner mice as compared to naive and control mice. The mGlu5 receptor signaling was also reduced in the ventral hippocampus and prefrontal cortex of learner mice, but only with respect to naive mice. Memory extinction was associated with a large up-regulation of mGlu5 receptor-mediated PI hydrolysis in the three brain regions and with increases in mGlu5 receptor and phospholipase-Cβ protein levels in the ventral and dorsal hippocampus, respectively. These findings support a role for mGlu5 receptors in mechanisms underlying spatial learning and suggest that mGlu5 receptors are candidate drug targets for disorders in which cognitive functions are impaired or aversive memories are inappropriately retained.

Absence epilepsy is frequently associated with cognitive dysfunction, although the underlying mechanisms are not well understood. Here we report that some forms of hippocampal synaptic plasticity are abnormal in symptomatic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Metabotropic Glu 1/5 receptor-mediated long term depression (LTD) at Schaffer collateral CA1 synapses is significantly reduced in symptomatic, 5-6 months old WAG/Rij rats compared to age-matched non epileptic control rats. There were no significant changes in mGlu1/5-dependent LTD in pre-symptomatic, 4-6 weeks old WAG/Rij rats compared to age matched controls. The changes in LTD found in symptomatic WAG/Rij forms are not indicative of general deficits in all forms of synaptic plasticity as long term potentiation (LTP) was unchanged. Immunoblot analysis of hippocampal tissue showed a significant reduction in mGlu5 receptor expression, a trend to an increase in pan Homer protein levels and a decrease in GluA1 receptor expression in the hippocampus of symptomatic WAG/Rij rats vs non-epileptic control rats. There were no changes in mGlu1α receptor or GluA2 protein levels. These findings suggest that abnormalities in hippocampal mGlu5 receptor-dependent synaptic plasticity are associated with the pathological phenotype of WAG/Rij rats. This lays the groundwork for the study of mGlu5 receptors as a candidate drug target for the treatment of cognitive dysfunction linked to absence epilepsy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Perinatal inflammation is a key factor of brain vulnerability in neonates born preterm or with intra-uterine growth restriction (IUGR), two leading conditions associated with brain injury and responsible for neurocognitive and behavioral disorders. Systemic inflammation is recognized to activate microglia, known to be the critical modulators of brain vulnerability. Although some evidence supports a role for metabotropic glutamate receptor 3 (mGlu3 receptor) in modulation of neuroinflammation, its functions are still unknown in the developing microglia., Methods: We used a double-hit rat model of perinatal brain injury induced by a gestational low-protein diet combined with interleukin-1β injections (LPD/IL-1β), mimicking both IUGR and prematurity-related inflammation. The effect of LPD/IL-1β on mGlu3 receptor expression and the effect of mGlu3 receptor modulation on microglial reactivity were investigated using a combination of pharmacological, histological, and molecular and genetic approaches., Results: Exposure to LPD/IL-1β significantly downregulated Grm3 gene expression in the developing microglia. Both transcriptomic analyses and pharmacological modulation of mGlu3 receptor demonstrated its central role in the control of inflammation in resting and activated microglia. Microglia reactivity to inflammatory challenge induced by LPD/IL-1β exposure was reduced by an mGlu3 receptor agonist. Conversely, both specific pharmacological blockade, siRNA knock-down, and genetic knock-out of mGlu3 receptors mimicked the pro-inflammatory phenotype observed in microglial cells exposed to LPD/IL-1β., Conclusions: Overall, these data show that Grm3 plays a central role in the regulation of microglial reactivity in the immature brain. Selective pharmacological activation of mGlu3 receptors may prevent inflammatory-induced perinatal brain injury.

Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)