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While it is normal to be scared of things, some children are so scared that it disrupts their lives. This is called an anxiety disorder. To help children with anxiety disorders, we need to know how anxiety disorders start. From other research we knew that toddlers who avoid new situations are more likely to become anxious later in life. They are more likely, which does not mean they all become more anxious, just some of them. We wanted to know if brain activity could predict which children would become anxious. We studied avoidance in toddlers and invited them back as preteens. We studied their brains while they were resting and while they were making mistakes in front of somebody else. We found that brain responses to mistakes predicted which avoidant toddlers became very anxious as preteens. This helps us understand who might develop anxiety, so that we can help!

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 are highly expressed in the mesolimbic pathways 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 metabotropic glutamate receptors (mGluRs) have 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 mGluRs may also provide novel targets for obesity and BED.

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.

Recent clinical and preclinical studies suggest that selective activators of the M(4) muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M(4) 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 Gα(q/11)-type G proteins whereas M(4) transduction occurs through Gα(i/o)-type G proteins. We now report that the ability of M(4) to inhibit dopamine release and induce antipsychotic-like effects in animal models is dependent on co-activation of the Gα(q/11)-coupled mGlu(1) 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 mGlu(1) (GRM1) are associated with schizophrenia, and points to GRM1/mGlu(1) as a gene within the “druggable genome” that could be targeted for the treatment of schizophrenia. Herein, we report that potentiation of mGlu(1) signaling following thalamo-striatal stimulation is sufficient to inhibit striatal dopamine release, and that a novel mGlu(1) positive allosteric modulator (PAM) exerts robust antipsychotic-like effects through an endocannabinoid-dependent mechanism. However, unlike M(4), mGlu(1) does not directly inhibit dopamine D(1) receptor signaling and does not reduce motivational responding. Taken together, these findings highlight a novel mechanism of cross talk between mGlu(1) and M(4) and demonstrate that highly selective mGlu(1) PAMs may provide a novel strategy for the treatment of positive symptoms associated with schizophrenia.

Background Clinical and preclinical studies suggest that selective activators of the muscarinic M4 receptor have exciting potential as a novel approach for treatment of schizophrenia. M4 reduces striatal dopamine (DA) though release of endocannabinoids (eCB), providing a mechanism for local effects on DA signaling in the striatum. M4 signals through Gαi/o and does not couple to Gαq/11 or induce calcium (Ca++) mobilization. This raises the possibility that M4-induced eCB release and inhibition of DA release may require co-activation of another receptor that activates Gαq/11. If so, this receptor could provide a novel target that may be more proximal to inhibition of DA release. Interestingly, the group 1 metabotropic glutamate (mGlu) receptors (mGlu1 and Glu5), couple to Gαq/11 and activate eCB signaling in multiple brain regions. Methods We tested the hypothesis that M4-induced reductions in DA release and subsequent antipsychotic-effect requires co-activation of group 1 mGlu receptors. The effect of M4 activation on electrically-evoked DA release in striatal slices was assessed using fast-scan cyclic voltammetry (FSCV) in the absence or presence of selective negative allosteric modulators (NAMs) of group 1 mGlu receptor subtypes. To evaluate the potential role of mGlu1, we determined the effects of a selective mGlu1 positive allosteric modulators (PAMs) on striatal DA release and antipsychotic-like activity in rodent models that are dependent on increased DA transmission. Since reductions in DA signaling, including D1 signaling have been implicated in reduced motivation, we also determined the effects of an mGlu1 PAM, M4 PAM, and the typical antipsychotic haloperidol on motivational responding in a progressive ratio (PR) schedule. Results We now present exciting new data in which we found that activation of mGlu1 through application of exogenous agonists or selective stimulation of thalamostriatal afferents induces a reduction of striatal DA release and that selective mGlu1 PAMs have robust antipsychotic-like effects in rodent models. Interestingly, our studies also suggest that mGlu1 activation is required for M4 PAM-induced inhibition of DA release and antipsychotic-like effects. However, in contrast to available antipsychotic agents, the present results and previous studies suggest that mGlu1 and M4 PAMs reduce DA signaling through local release of an eCB from striatal SPNs and activation of CB2 receptors on neighboring DA terminals to reduce DA release. While these studies suggest that the effects of M4 PAMs on DA release require activation of mGlu1, we have also found that these targets have important differences. Most notably, M4 PAMs also directly inhibits D1 signaling in D1-SPN terminals in the substatnia nigra pars reticulata (SNr). Unlike M4, mGlu1 does not directly inhibit DA D1 receptor signaling and does not induce behavioral changes that could be associated with negative symptoms. Discussion Our findings are 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 treatment of schizophrenia. Recent clinical imaging studies suggesting that symptoms in schizophrenia patients are associated with selective increases in striatal DA signaling and while extrastriatal regions display hypo-dopaminergic function; thus, mGlu1 and M4 PAMs may provide a mechanism for selective inhibition of DA release in striatal regions that are important for antipsychotic efficacy, without further disruptions in extrastriatal DA signaling.