ABSTRACT
To address the development of early anxiety disorders across the lifespan, the High USV line of rats was bred based on rates of infant ultrasonic vocalization in the 40-50 kHz range of predominant frequencies (USV) to maternal separation at postnatal day (P) 10. In this study, rates of USV in High line infants (pups: Postnatal Day 11+/-1) were compared to those of randomly-bred controls in response to EPIX compound PRX-00023, a unique serotonin (5-HT) agonist, acting exclusively at the 5-HT1A receptor, or buspirone, a nonspecific 5HT1A agonist. After testing, pups were examined for sedation and other drug-related effects. The results indicated that all doses of buspirone reduced USV rates in isolation, consistent with other reports. PRX-00023 significantly reduced USV rates at the lowest doses (0.01-0.05 mg/kg). None of the PRX-00023 doses produced sedation, whereas all but the lowest dose of buspirone (0.1 mg/kg) produced sedation effects. The results suggest that this compound alleviates infantile anxiety-like behavior with great specificity in rats bred for high anxiety/depressive phenotypes by selectively targeting 5-HT1A receptors, possibly by both pre- and post-synaptic mechanisms.
Subject(s)
Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Buspirone/pharmacology , Piperazines/pharmacology , Serotonin 5-HT1 Receptor Agonists , Sulfonamides/pharmacology , Vocalization, Animal/drug effects , Aging , Animals , Anti-Anxiety Agents/administration & dosage , Anxiety/genetics , Anxiety Disorders/drug therapy , Anxiety, Separation/drug therapy , Ataxia/chemically induced , Body Temperature/drug effects , Buspirone/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Eliminative Behavior, Animal/drug effects , Female , Grooming/drug effects , Hybridization, Genetic , Male , Movement/drug effects , Piperazines/administration & dosage , Rats , Reaction Time/drug effects , Sex Characteristics , Social Isolation , Sulfonamides/administration & dosage , UltrasonicsABSTRACT
The Wnt pathway is a key regulator of development and tumorigenesis. Dpr (Dact/Frodo) influences Wnt signaling in part through the interaction of its PDZ-B domain with Dsh's PDZ domain. Studies have shown that XDpr1a and its close relative, Frodo, are involved in multiple steps of the Wnt pathway in either inhibitory or activating roles. We found that XDpr1a is phosphorylated by casein kinase Idelta/epsilon (CKIdelta/epsilon), an activator of Wnt signaling, in the presence of XDsh. Abrogating XDpr1a's ability to bind XDsh through mutation of XDpr1a's PDZ-B domain blocks CK1delta/epsilon's phosphorylation of XDpr1a. Conversely, XDsh possessing a mutation in its PDZ domain that is unable to bind XDpr1a does not promote XDpr1a phosphorylation. Phosphorylation of XDpr1a and XDsh by CKIdelta/epsilon decreases their interaction. Moreover, the phosphorylation of XDpr1a by CKIdelta/epsilon not only abrogates XDpr1a's promotion of beta-catenin degradation but blocks beta-catenin degradation. Our data suggest that XDpr1a phosphorylation by CKIdelta/epsilon is dependent on the interaction of XDpr1a's PDZ-B domain with XDsh's PDZ domain, and that the phosphorylation state of XDpr1a determines whether it inhibits or activates Wnt signaling.
