It has been previously suggested that oxytocin (Oxt) may act as a natural antipsychotic. To test this hypothesis, we investigated whether disruption of the oxytocin gene (OxtÀ/À) made mice more susceptible to the psychosis-related effects of amphetamine (Amp), apomorphine (Apo) and phencyclidine (PCP). We examined drug-induced changes in the prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating deficits characteristic of several psychiatric and neurological disorders, including schizophrenia. We found that treatment with Amp, Apo and PCP all had effects on PPI. However, in OxtÀ/À mice, but not Oxt þ / þ mice, PCP treatment resulted in large PPI deficits. As PCP is a noncompetitive N-methyl-D-aspartic acid receptor antagonist, these findings suggest that the absence of Oxt alters the glutamatergic component of the PPI.

Objective: Thoracic aortic aneurysms (TAAs) develop by a multifactorial process involving maladaptive signaling pathways that alter the aortic vascular environment. Transforming growth factor-beta (TGF-β) has been implicated in regulating the structure and composition of the extracellular matrix by differential activation of various intracellular signaling pathways. However, whether and to what degree TGF-β signaling contributes to TAA development remains unclear. Accordingly, the hypothesis that alterations in TGF-β signaling occur during aneurysm formation was tested in a murine model of TAA. Methods: TAAs were surgically induced in mice (C57BL/6J) and aortas were analyzed at predetermined time points (1, 2, and 4 weeks post-TAA induction). Quantitative real-time PCR (QPCR) was performed to evaluate the expression of 84 relevant TGF-β superfamily genes, and the protein levels of key signaling intermediates were measured by immunoblotting. Results were compared to unoperated reference control mice. Results: QPCR revealed increased expression of TGF-β superfamily ligands (Gdf-2, -6, -7, Inhba), ligand inhibitors (Bmper, Chrd, Gsc), and transcriptional regulators (Dlx2, Evi1), among other genes (Cdkn2b, Igf1, IL-6). Protein levels of TGF-β receptor_II, Smad2, Smad1/5/8, phospho-Smad1/5/8, and Smurf1 were increased from control values post-TAA induction. Both TGF-β receptor_I and Smad4 were decreased from control values, while ALK-1 levels remained unchanged. Conclusions: These alterations in the TGF-β pathway suggest a mechanism by which primary signaling is switched from a TGF-βR_I/Smad2-dependent response, to an ALK-1/Smad1/5/8 response, representing a significant change in signaling outcome, which may enhance matrix degradation.

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