The voltage-gated sodium channel activator veratrine induces anxiogenic-like behaviors in rats.

In this study, we investigated the anxiogenic-like effects of systemically administered veratrine in rat models of anxiety. In the light/dark test, veratrine (0.6 mg/kg, s.c.) significantly and dose-dependently decreased the time rats spent in and the number of entries into a light box 30 min after administration, suggesting that veratrine increases anxiety-like behaviors. These findings were also supported by results from the elevated-plus maze test and the tail-swing behavior test. In addition, veratrine (0.6 mg/kg, s.c.) significantly increased the plasma concentration of corticosterone, an endogenous biomarker for anxiety, compared to vehicle. On the basis of these results, we conclude that veratrine induces anxiogenic-like behaviors in rats. The anxiogenic-like behaviors induced by veratrine (0.6 mg/kg, s.c.) were completely abolished by co-treatment with the typical benzodiazepine anxiolytic diazepam (1 mg/kg, s.c.), when assessed in the elevated-plus maze test. Similar results were obtained with co-treatment with riluzole (10 mg/kg, p.o.), which directly affects the glutamatergic system and has recently been suggested to have anxiolytic-like effects. In conclusion, this study provides evidence that systemically administered veratrine induces anxiogenic-like behaviors in rats. We propose the veratrine model as a novel pathological animal model to explore possible candidate drugs for anxiolytics.

Lysophosphatidic acid induces anxiety-like behavior via its receptors in mice.

Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator with diverse biological properties. We previously found altered expression of the LPA-related genes in rodents after treatment with sertraline, which is widely used to treat anxiety disorders and depression. However, little is known about the behavioral effects of LPA. In the present study, we investigated the behavioral effects of intracerebroventricular injection of LPA in adult mice. LPA did not significantly affect spontaneous locomotor activity, suggesting that LPA does not induce hyperactivity, ataxia, or sedation. We next investigated the emotional effects of LPA via the hole-board test. LPA significantly increased the number of head-dips in a dose- and time-related manner. A significant induction of head-dip counts occurred 15 and 30 min after LPA administration. To clarify the involvement of LPA receptors, we examined the effect of the non-selective LPA1-4 receptor antagonist, 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA) co-administered with LPA. BrP-LPA dose-dependently inhibited LPA-induced head-dip counts. We next investigated anxiety-like behavior via the elevated plus-maze test. LPA significantly reduced the percentage of time spent in the open arms and BrP-LPA dose-dependently inhibited this anxiety-like behavior. In conclusion, LPA induced anxiety-like behavior in mice via LPA receptors. Our results suggest that LPA signaling plays an important role in regulating anxiety in mice.

Activation of the prelimbic medial prefrontal cortex induces anxiety-like behaviors via N-Methyl-D-aspartate receptor-mediated glutamatergic neurotransmission in mice.

We investigated the possible roles of the prelimbic medial prefrontal cortex (PL) in the regulation of anxiety-like behaviors by pharmacologically activating the terminals of neuronal inputs or postsynaptic efferent neurons with a sodium channel activator veratrine. The extracellular glutamate levels were measured by in vivo microdialysis, and the behaviors were assessed with the open field (OF) test in mice simultaneously. The samples were collected every 10 min for 60 min, as basal levels of glutamate. The medium containing drugs were perfused for 30 min. The OF test was performed in the last 10 min of drug perfusion. After the drug treatments, the perfusion medium containing drugs was switched back to perfusion medium without drugs, and then samples were collected for another 90 min. The extracellular glutamate levels were significantly elevated after local perfusion of veratrine in the PL. At the same time, perfusion of veratrine in the PL produced anxiety-like behaviors in mice. Local coperfusion of a sodium channel blocker, lamotrigine, completely diminished the veratrine-induced elevated extracellular glutamate levels and the behavioral changes. Local coperfusion of an NMDA receptor antagonist, MK-801, but not a non-NMDA (AMPA/kainate) receptor antagonist, CNQX, completely diminished the behavioral changes without any effects on the veratrine-induced elevated extracellular glutamate levels. This study demonstrates that the activation of the PL with veratrine induces anxiety-like behaviors via NMDA receptor-mediated glutamatergic neurotransmission in mice.