Activation of the mGlu1 metabotropic glutamate receptor has antipsychotic-like effects and is required for efficacy of M4 muscarinic receptor allosteric modulators.

Recent clinical and preclinical studies suggest that selective activators of the M4 muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M4 activation inhibits striatal dopamine release by mobilizing endocannabinoids, providing a mechanism for local effects on dopamine signaling in the striatum but not in extrastriatal areas. G protein-coupled receptors (GPCRs) typically induce endocannabinoid release through activation of Gαq/11-type G proteins whereas M4 transduction occurs through Gαi/o-type G proteins. We now report that the ability of M4 to inhibit dopamine release and induce antipsychotic-like effects in animal models is dependent on co-activation of the Gαq/11-coupled mGlu1 subtype of metabotropic glutamate (mGlu) receptor. This is especially interesting in light of recent findings that multiple loss of function single nucleotide polymorphisms (SNPs) in the human gene encoding mGlu1 (GRM1) are associated with schizophrenia, and points to GRM1/mGlu1 as a gene within the "druggable genome" that could be targeted for the treatment of schizophrenia. Herein, we report that potentiation of mGlu1 signaling following thalamo-striatal stimulation is sufficient to inhibit striatal dopamine release, and that a novel mGlu1 positive allosteric modulator (PAM) exerts robust antipsychotic-like effects through an endocannabinoid-dependent mechanism. However, unlike M4, mGlu1 does not directly inhibit dopamine D1 receptor signaling and does not reduce motivational responding. Taken together, these findings highlight a novel mechanism of cross talk between mGlu1 and M4 and demonstrate that highly selective mGlu1 PAMs may provide a novel strategy for the treatment of positive symptoms associated with schizophrenia.

Family accommodation in pediatric anxiety: Relations with avoidance and self-efficacy.

Pediatric anxiety disorders are common, impairing, and chronic when not effectively treated. A growing body of research implicates family accommodation in the maintenance of pediatric anxiety. The present study aimed to quantify previously untested relations among family accommodation and two theoretically linked constructs: avoidance and self-efficacy. Eighty youths between ages 8 and 17 (53 with anxiety disorders, 27 non-anxious controls) completed measures of family accommodation and self-efficacy. In addition, avoidance was assessed using two distinct measures of avoidance: a clinician rating of real-world behaviors and a laboratory task-based index. As predicted, youths with anxiety disorders reported greater family accommodation than non-anxious controls. Across the sample, greater family accommodation was associated with greater avoidance, as measured using both clinician rating and the laboratory task, as well as with lower self-efficacy. In an exploratory mediation model, self-efficacy partially mediated the relation between family accommodation and clinician-rated avoidance; however, it did not mediate the relation between family accommodation and task-based avoidance. Considering the robust association between family accommodation and anxiety in youths, this addition to our understanding of related cognitive and behavioral factors provides important preliminary insight, which can guide future research on potential targets for early identification and intervention for pediatric anxiety.

Shared Behavioral and Neurocircuitry Disruptions in Drug Addiction, Obesity, and Binge Eating Disorder: Focus on Group I mGluRs in the Mesolimbic Dopamine Pathway.

Accumulated data from clinical and preclinical studies suggest that, in drug addiction and states of overeating, such as obesity and binge eating disorder (BED), there is an imbalance in circuits that are critical for motivation, reward saliency, executive function, and self-control. Central to these pathologies and the extensive topic of this Review are the aberrations in dopamine (DA) and glutamate (Glu) within the mesolimbic pathway. Group I metabotropic glutamate receptors (mGlus) are highly expressed in the mesolimbic pathway and are poised in key positions to modulate disruptions in synaptic plasticity and neurotransmitter release observed in drug addiction, obesity, and BED. The use of allosteric modulators of group I mGlus has been studied in drug addiction, as they offer several advantages over traditional orthosteric agents. However, they have yet to be studied in obesity or BED. With the substantial overlap between the neurocircuitry involved in drug addiction and eating disorders, group I mGlus may also provide novel targets for obesity and BED.