The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder.

N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine [ASP2905] is a potent and selective inhibitor of the potassium voltage-gated channel subfamily H member 3 (KCNH3) that was originally identified in our laboratory. KCNH3 is concentrated in the forebrain, and its overexpression in mice leads to cognitive deficits. In contrast, Kcnh3 knockout mice exhibit enhanced performance in cognitive tasks such as attention. These data suggest that KCNH3 plays important roles in cognition. Here we investigated the neurochemical and neurophysiological profiles of ASP2905 as well as its effects on cognitive function, focusing on attention. ASP2905 (0.0313 and 0.0625 mg/kg, po) improved the latent learning ability of mice, which reflects attention. Microdialysis assays in rats revealed that ASP2905 increased the efflux of dopamine and acetylcholine in the medial prefrontal cortex (0.03, 0.1 mg/kg, po; 0.1, 1 mg/kg, po, respectively). The activities of these neurotransmitters are closely associated with attention. We used a multiple-trial passive avoidance task to investigate the effects of ASP2905 on inattention and impulsivity in juvenile stroke-prone spontaneously hypertensive rats. ASP2905 (0.1 and 0.3 mg/kg, po) significantly prolonged cumulative latency as effectively as methylphenidate (0.1 and 0.3 mg/kg, sc), which is the gold standard for treating ADHD. Further, ASP2905, amphetamine, and methylphenidate significantly increased the alpha-band power of rats, suggesting that ASP2905 increases arousal, which is a pharmacologically important activity for treating ADHD. In contrast, atomoxetine and guanfacine did not significantly affect power. Together, these findings suggest that ASP2905, which acts through a novel mechanism, is as effective for treating ADHD as currently available drugs such as methylphenidate

Effects of (+)-bicuculline, a GABAa receptor antagonist, on auditory steady state response in free-moving rats.

Auditory steady-state responses (ASSRs) are states in which the electrical activity of the brain reacts steadily to repeated auditory stimuli. They are known to be useful for testing the functional integrity of neural circuits in the cortex, as well as for their capacity to generate synchronous activity in both human and animal models. Furthermore, abnormal gamma oscillations on ASSR are typically observed in patients with schizophrenia (SZ). Changes in neural synchrony may reflect aberrations in cortical gamma-aminobutyric acid (GABA) neurotransmission. However, GABA's impact and effects related to ASSR are still unclear. Here, we examined the effect of a GABAa receptor antagonist, (+)-bicuculline, on ASSR in free-moving rats. (+)-Bicuculline (1, 2 and 4 mg/kg, sc) markedly and dose-dependently reduced ASSR signals, consistent with current hypotheses. In particular, (+)-bicuculline significantly reduced event-related spectral perturbations (ERSPs) at 2 and 4 mg/kg between 10 and 30 minutes post-dose. Further, bicuculline (2 and 4 mg/kg) significantly and dose-dependently increased baseline gamma power. Furthermore, the occurrence of convulsions was consistent with the drug's pharmacokinetics. For example, high doses of (+)-bicuculline such as those greater than 880 ng/g in the brain induced convulsion. Additionally, time-dependent changes in ERSP with (+)-bicuculline were observed in accordance with drug concentration. This study partially unraveled the contribution of GABAa receptor signals to the generation of ASSR

The centrally acting non-narcotic antitussive tipepidine produces antidepressant-like effect in the forced swimming test in rats

The antidepressant-like effect of tipepidine was studied in rats. Tipepidine at 20 and 40 mg/kg i.p. reduced immobility in the forced swimming test and tipepidine at 40mg/kg, i.p. increased climbing in the test. The drug at 40 mg/kg, i.p. had no effect on the loco-motor activity and motor coordination. These results suggest that tipepidine may be a novel drug with antidepressant-like activity

Antidepressant-like effect of centrally acting non-narcotic antitussive caramiphen in a forced swimming test

Recently, we reported that a centrally acting non-narcotic antitussive (cough suppressant drug),tipepidine produces an antidepressant-like effect in the forced swimming test in rats. Becausepharmacological properties of tipepidine apparently differ from those of typical antidepressantsdeveloped to date, we speculated that caramiphen, another centrally acting antitussive, has anantidepressant-like effect. That effect of caramiphen was studied in rats using the forced swimming test. Caramiphen at 20 and 40 mg/kg i.p. significantly reduced immobility. At 40 mg /kg i.p., it increasedclimbing behavior. Even at 40 mg /kg, this drug had no effect on locomotor activity. Results suggestthat a centrally acting antitussive possessing inhibition of GIRK channels has an antidepressant-likeeffect

Tipepidine enhances the antinociceptive-like action of carbamazepine in the acetic acid writhing test

Several antidepressants have been used to treat severe pain in clinics. Recently, wereported that the centrally acting non-narcotic antitussive (cough suppressant drug),tipepidine produces an antidepressant-like effect in the forced swimming test, althoughthe mechanism of action appears to be quite different from that of knownantidepressants. In the present study, we investigated whether a combination oftipepidine and carbamazepine acts synergistically to induce an antinociceptive effect inthe acetic acid-induced writhing test in mice. Prior to studying the combination oftipepidine and carbamazepine, the analgesic action of tipepidine alone was alsoexamined in mice. Tipepidine at 5–40 mg/kg i.p. significantly reduced the number ofwrithes induced by acetic acid in mice. Carbamazepine at 20 mg/kg i.p. alsosignificantly reduced the writhing reaction. Furthermore, co-administration ofcarbamazepine (5 and 10 mg/kg, i.p.) and tipepidine (2.5 mg/kg i.p.) significantlydecreased the number of writhes induced by acetic acid. This finding suggests that acombination of carbamazepine and tipepidine may be a new strategy for the treatmentof neuropathic pain such as what occurs in trigeminal neuralgia, because the use ofcarbamazepine is often limited by its adverse effects and by reduction of its analgesicefficacy by microsomal enzyme induction