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In this study, we investigated the effect of histamine on capsaicin-induced current and its influence by suplatast in rat trigeminal ganglia neurons using a patch-clamp technique. We found that histamine directly potentiated capsaicin-induced currents in rat sensory neurons, and suplatast had little effect on this potentiation. Since it has been known that suplatast suppresses histamine release from mast cells, it is possible that suplatast inhibits the activation of nociceptive fibers in the pathological condition via prevention of histamine-induced potentiation of the transient receptor potential vanilloid 1 receptor-mediated currents. [ABSTRACT FROM AUTHOR]

We previously reported that non-narcotic antitussives possessing inhibitory actions on G protein-coupled inwardly rectifying potassium (GIRK) channels have antidepressant-like effects in the forced swimming test in normal and adrenocoticotropic hormone (ACTH) treated rats. Furthermore, the antidepressant-like effects of the antitussives such as tipepidine were blocked by dopamine D 1 receptor antagonist, and inhibitory actions on GIRK channels of dopamine neurons may be involved in the antidepressant-like effects of tipepidine. In this study, we generated GIRK2 DAT KO mice with Girk2/Kcnj6 conditional deletion and assessed depression-related behavior of the mice. The Cre/ loxP system was used to selectively delete GIRK2 subunit containing GIRK channels in the neurons expressing dopamine transporter. First, deletion of GIRK2 subunits in the ventral tegmental area (VTA) neurons expressing dopamine transporters was confirmed by hisitochemically and electrophysiologically. In the mice, a significant decrease in the immobility time of forced swimming test was observed. Locomotor activity of the mice was not changed compared to that of GIRK2 floxed mice, when tested in the open field. These results suggest that the antidepressant-like effect of antitussives such as tipepidine may be caused partly through the inhibitory actions on GIRK channels in the dopamine neurons. [ABSTRACT FROM AUTHOR]

We investigated whether tipepidine exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone (ACTH)-treated rats, which is known as a treatment-resistant depression model, and we studied the pharmacological mechanisms of the effects of tipepidine. Male Wistar rats (5–7 weeks old) were used in this study. Tipepidine (20 and 40 mg/kg, i.p.) decreased the immobility time in the forced swimming test in ACTH-treated rats. The anti-immobility effect of tipepidine was blocked by a catecholamine-depleting agent, alpha-methyl- p -tyrosine (300 mg/kg, s.c.), but not by a serotonin-depleting agent, p -chlorophenylalanine. The anti-immobility effect of tipepidine was also blocked by a dopamine D 1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) and an adrenaline α 2 receptor antagonist, yohimbine (2 mg/kg, i.p.). In microdialysis technique, tipepidine (40 mg/kg, i.p.) increased the extracellular dopamine level of the nucleus accumbens (NAc) in ACTH-treated rats. These results suggest that tipepidine exerts an antidepressant-like effect in the forced swimming test in ACTH-treated rats, and that the effect of tipepidine is mediated by the stimulation of dopamine D 1 receptors and adrenaline α 2 receptors. The results also suggest that an increase in the extracellular dopamine level in the NAc may be involved in the antidepressant-like effect of tipepidine in ACTH-treated rats. [ABSTRACT FROM AUTHOR]

We previously reported that the novel antidepressant-like effect of tipepidine may be produced at least partly through the activation of mesolimbic dopamine neurons via inhibition of G protein-coupled inwardly rectifying potassium channels. In this study, we investigated whether tipepidine increases dopamine levels in the nucleus accumbens (NAc) in rats using an in vivo microdialysis technique. We further assessed whether tipepidine at antidepressant-like effective doses induces behavioral- and cross-sensitization of locomotor activity in rats using the open field test. We found that acute administration of tipepidine increased dopamine levels in the NAc in freely moving rats without increasing locomotor activity. Tipepidine at antidepressant-like effective doses (20 and 40 mg/kg, i.p.) did not cause behavioral sensitization in rats. Furthermore, cross-sensitization between tipepidine and methamphetamine was not observed in rats. These results further support our working hypothesis that tipepidine may produce a novel antidepressant-like effect through activation of ventral tegmental area-NAc dopaminergic neurons whose mechanisms differ from those contributing to the reinforcing effects of addictive drugs. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported that tipepidine, a centrally acting non-narcotic antitussive, has an antidepressant-like effect in normal and imipramine treatment-resistant depression model rats. Recently, mapping the induction of c-fos-like immunoreactivity (FLI) in the rat brain showed FLI-positive neurons in several brain areas after acute administration of different classes of antidepressants. Here, the effect of a single injection of an antidepressive dose of tipepidine on FLI was studied in seven areas of the rat brain including the central nucleus of the amygdala (CeA) and the nucleus accumbens (NAc). Desipramine was also used for comparison. Rats were anesthetized and perfused 2h after injection with tipepidine (20 and 40mg/kg, i.p.), desipramine (10mg/kg, i.p.), or saline. Then, immunostaining of FLI-positive neurons in brain slices was performed with conventional methods. A single injection of tipepidine increased FLI-positive neurons in the CeA, similar to preexisting antidepressants, and induced the characteristic pattern of an increase in FLI-positive neurons in six other brain areas including the NAc, an effect that was different from other antidepressants. In addition, a single injection of desipramine (10mg/kg) or tipepidine (20mg/kg) decreased the immobility time in the forced swimming test to a similar extent. The results obtained from the previous behavioral study and the current immunohistochemical study suggest that tipepidine may be a novel antidepressant. [Copyright &y& Elsevier]

Abstract: We previously reported that the centrally acting non-narcotic antitussive, tipepidine, produces a novel antidepressant-like effect in the forced swimming test in rats, but the mechanism of the antidepressant-like effect of tipepidine is not clear. We investigated the pharmacological mechanism of the antidepressant-like effect of tipepidine in the forced swimming test in rats. A catecholamine-depleting agent, alpha-methyl-p-tyrosine (AMPT; 300mg/kg, s.c.), was given 6h before the first injection and with the last injection of tipepidine (40mg/kg, i.p.). A serotonin (5-HT)-depleting agent, p-chlorophenylalanine (PCPA; 350mg/kg, i.p.), was given 72h and 48h before the pretest session. The dopamine D1 receptor antagonist, SCH23390 (0.02mg/kg, s.c.) was given 15min before each of the three injections of tipepidine. The dopamine D2 receptor antagonist raclopride (0.2mg/kg, s.c.), the alpha 1 adrenoceptor antagonist prazosin (1mg/kg, i.p.), the alpha 2 adrenoceptor antagonist yohimbine (2mg/kg, i.p.) and the beta adrenoceptor antagonist propranolol (2mg/kg, i.p.) were given 30min before each of the three injections of tipepidine. AMPT, but not PCPA, significantly inhibited the immobility time-reducing effect of tipepidine in the forced swimming test. Furthermore, the effect of tipepidine was significantly inhibited by SCH23390 and yohimbine. However, raclopride, prazosin, and propranolol failed to block the effect of tipepidine. The results suggest that the antidepressant-like effect of tipepidine in the forced swimming test may be due at least in part to the effects of dopamine and noradrenaline released at the dopamine D1 receptor and alpha 2 adrenoceptor, respectively. [Copyright &y& Elsevier]

Abstract: The antidepressant-like effect of tipepidine was studied in rats. Tipepidine at 20 and 40mg/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 40mg/kg, i.p. had no effect on the locomotor activity and motor coordination. These results suggest that tipepidine may be a novel drug with antidepressant-like activity. [Copyright &y& Elsevier]

Abstract: 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. Because pharmacological properties of tipepidine apparently differ from those of typical antidepressants developed to date, we speculated that caramiphen, another centrally acting antitussive, has an antidepressant-like effect. That effect of caramiphen was studied in rats using the forced swimming test. Caramiphen at 20 and 40mg/kg i.p. significantly reduced immobility. At 40mg/kg i.p., it increased climbing behavior. Even at 40mg/kg, this drug had no effect on locomotor activity. Results suggest that a centrally acting antitussive possessing inhibition of GIRK channels has an antidepressant-like effect. [ABSTRACT FROM AUTHOR]