MGlu5 receptor-mediated polyphosphoinositide (PI) hydrolysis is classically measured by determining the amount of radioactivity incorporated in inositolmonophosphate (InsP) after labeling of membrane phospholipids with radioactive inositol. Although this method is historically linked to the study of mGlu receptors, it is inappropriate for the assessment of mGlu5 receptor signaling in vivo. Using a new ELISA kit we showed that systemic treatment with the selective positive allosteric modulator (PAM) of mGlu5 receptors VU0360172 enhanced InsP formation in different brain regions of CD1 or C57Black mice. The action of VU0360172 was sensitive to the mGlu5 receptor, negative allosteric modulator (NAM), MTEP, and was abolished in mice lacking mGlu5 receptors. In addition, we could demonstrate that endogenous activation of mGlu5 receptors largely accounted for the basal PI hydrolysis particularly in the prefrontal cortex. This method offers opportunity for investigation of mGlu5 receptor signaling in physiology and pathology, and could be used for the functional screening of mGlu5 receptor PAMs in living animals.

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.

Perinatal hypoxia causes long‐term neurobiological consequences, including alterations in mechanisms of activity‐dependent synaptic plasticity and cognitive dysfunction. Changes in neurotransmitter receptors have been associated with these alterations, but little is known on how early hypoxia influences the expression and function of metabotropic glutamate (mGlu) receptors in adult life. This is an important issue because mGlu receptors are implicated in mechanisms of synaptic plasticity. Here, we examined the expression of mGlu1, mGlu5, and mGlu2/3 receptor subtypes in the hippocampus, nucleus accumbens, prefrontal cortex, and dorsal striatum in 6‐month old Wistar rats (a) born by vaginal delivery; (b) born by caesarean section; and (c) born by caesarean section followed by 20 min of asphyxia. Unexpectedly, we found a large reduction of mGlu1α protein levels in the hippocampus of rats born by caesarean section regardless of the presence of asphyxia. No changes in mGlu1α receptor protein levels were found in the other brain regions. Levels of mGlu5 and mGlu2/3 receptors and levels of GluA2/3 and GluN1 subunits of AMPA and NMDA receptors did not differ among the three groups of rats in any brain region. These results are consistent with previous findings showing that changes in mGlu1 receptors occur within the epigenetic programming caused by early‐life events.

Although costly in energy and time, social play is present and evolutionarily conserved in nearly all young mammals. Ontogenetic factors responsible for this particular form of supposed rewarding behavior are incompletely understood. Here, we have focused our attention on maternal glucocorticoid hormone. We used a model in which neonate rats are fed by mothers in which drinking water has been supplemented with 0.2 mg/ml corticosterone. The control groups were lactated by water-drinking mothers. Both male and female adolescent offspring of corticosterone (CORT) supplemented dams (CORT-nursed) showed an increase in social play behavior (i.e., pinning, pouncing, wrestling/boxing and social exploration) when compared to controls. No differences were observed between CORT-nursed progeny of both sexes and controls in the exploration of the arena during the social encounter. Finally, no differences were found in CORT plasma levels in basal conditions and following a social play session in both male and female CORT-nursed rats. These results indicate that variations in the maternal glucocorticoid status are able, directly or indirectly, to influence social play behavior in the offspring, although there is no direct relationship between the level of social play behavior and the intensity of adrenocortical activation

The global burden of obesity continues to rise, demanding effective pharmacological strategies for individuals in whom prevention alone is insufficient. Recent incretin‐based and multi‐agonist therapies have delivered unprecedented weight loss, demonstrating that the simultaneous modulation of multiple metabolic pathways can optimize body weight control and improve obesity‐related comorbidities. However, biological heterogeneity, interindividual variability in treatment response and uncertainties regarding long‐term outcomes highlight the need to explore complementary regulatory mechanisms. Oleoylethanolamide (OEA) is an endogenous lipid mediator synthesized on demand in the small intestine in response to dietary lipid intake. Acting primarily through peroxisome proliferator‐activated receptor‐α (PPAR‐α), OEA functions as a physiological satiety signal that promotes fatty acid oxidation and coordinates gut–brain communication. Preclinical evidence indicates that OEA reduces food intake without inducing malaise, enhances lipid utilization and improves metabolic dysfunction in models of diet‐induced obesity, while engaging both homeostatic and reward‐related neural circuits. Emerging clinical studies report modest but consistent effects on body weight and selected cardiometabolic parameters. In this review, we summarize the current evidence on OEA biosynthesis, molecular targets and mechanisms of action, with particular focus on its role in the regulation of feeding behaviour, metabolic homeostasis and obesity‐related comorbidities, and discuss its potential positioning within the evolving landscape of anti‐obesity pharmacotherapy.