Cananga odorata essential oil reverses the anxiety induced by 1-(3-chlorophenyl) piperazine through regulating the MAPK pathway and serotonin system in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cananga odorata essential oil, known as ylang-ylang essential oil (YYO), was commonly used in the aromatherapy for relaxation and mood adjusting use. In our previous study, YYO played anxiolytic effects on the mice in several behavioral tests that based on the instinctive responses to novel environments. AIM OF THE STUDY: To investigate the effects and mechanisms of YYO reversing the anxiety induced by 5-HT2C receptor agonist 1-(3-chlorophenyl) piperazine (m-CPP). MATERIALS AND METHODS: m-CPP was administrated to the male ICR mice to develop an anxiety model. The anxiolytic effect of YYO (0.1%, 1% and 10%, v/v) was evaluated in the elevated plus maze (EPM) test after odor exposure. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) and the expression of c-Fos in the prefrontal cortex (PFC) and hippocampus after the EPM test. Serotonin and its metabolite change in the brain were detected by liquid chromatogram with an electrochemical detector. The effect of YYO on the plasma corticosterone level was evaluated using enzyme-linked immunosorbent assay (ELISA) after the odor exposure. RESULTS: The behavior analysis showed that m-CPP (2 mg/kg and 4 mg/kg) could induce anxiety behaviors in the mice while diazepam (2 mg/kg) reversed the anxiety behavior induced by m-CPP. YYO dose-dependently increased the time and number of entries in the open arms (p < 0.05) compared to the Tween 80 group. YYO reduced the phosphorylation levels of ERK1/2 (p < 0.05) in both PFC and hippocampus. Down-regulations of phosphor-CREB (p < 0.05) and c-Fos (p < 0.05) were only observed in the hippocampus. YYO also affected the brain serotonin metabolism and reduced the blood plasma corticosterone level of the m-CPP treated mice. CONCLUSION: YYO odor exposure could reverse the anxiety behaviors generated by m-CPP. The anxiolytic effect of YYO was associated with the ERK1/2/CREB pathway in the hippocampus and relevant to the serotonin system.

Obsessive-compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus rhamnosus GG).

Two experiments examined probiotic pretreatment (Lactobacillus rhamnosus GG) on obsessive-compulsive disorder (OCD)-like behavior induction by RU 24969 in BALB/cJ house mice. In the first experiment, two groups were defined by their daily pretreatment by oral gavage of either (a) L. rhamnosus (1×109 CFU/day) or (b) the saline vehicle. Both a 2- and 4-week probiotic pretreatment attenuated OCD-like behavior induction (increased perseverative open-field locomotion, stereotypic turning, and marble burying) relative to saline pretreatment. Experiment 2 re-examined the 2-week probiotic pretreatment while also comparing it to a 4-week fluoxetine pretreatment. Again, groups were defined by daily pretreatment of either (a) L. rhamnosus for 2 weeks, (b) the saline vehicle for 2 weeks, or (c) fluoxetine (10 mg/kg) for 4 weeks. Pretreatment by either L. rhamnosus or fluoxetine blocked the induction of OCD-like behavior compared with saline pretreatment. Thus the 2-week probiotic pretreatment was again effective. Although side effects of fluoxetine or L. rhamnosus on androgen-dependent behaviors could not be demonstrated, L. rhamnosus treatment appeared comparable to fluoxetine treatment in attenuating mouse OCD-like behaviors.

Serotonin 5-HT(7) receptor blockade reverses behavioral abnormalities in PACAP-deficient mice and receptor activation promotes neurite extension in primary embryonic hippocampal neurons: therapeutic implications for psychiatric disorders.

The serotonin 5-HT(7) receptor has been linked to various psychiatric disorders, including schizophrenia, anxiety and depression, and is antagonized by antipsychotics such as risperidone, clozapine and lurasidone. In this study, we examined whether inhibiting the 5-HT(7) receptor could reverse behavioral abnormalities in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental mouse model for psychiatric disorders such as schizophrenia. The selective 5-HT(7) antagonist SB-269970 effectively suppressed abnormal jumping behavior in PACAP-deficient mice. SB-269970 tended to alleviate the higher immobility in the forced swim test in PACAP-deficient mice, although SB-269970 reduced the immobility also in wild-type mice. In addition, we found that mutant mice had impaired performance in the Y-maze test, which was reversed by SB-269970. In the mutant mouse brain, 5-HT(7) protein expression did not differ from wild-type mice. In primary embryonic hippocampal neurons, the 5-HT(7) agonist AS19 increased neurite length and number. Furthermore, SB-269970 significantly inhibited the increase in neurite extension mediated by the 5-HT(1A/7) agonist 8-OH-DPAT. These results indicate that 5-HT(7) receptor blockade ameliorates psychomotor and cognitive deficits in PACAP-deficient mice, providing additional evidence that the 5-HT(7) receptor is a rational target for the treatment of psychiatric disorders.

Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice.

BACKGROUND: Perseveration and sensorimotor gating deficits are core features of obsessive-compulsive disorder (OCD). Serotonin 1B receptor (5-HT1BR) agonists exacerbate OCD symptoms in patients and induce perseveration and sensorimotor gating deficits in mice. Serotonin reuptake inhibitors (SRIs), but not noradrenaline reuptake inhibitors (NRIs), reduce OCD symptoms following 4 to 8 weeks of treatment. Using mice, we compared the effects of chronic SRI versus NRI treatment on 5-HT1BR-induced OCD-like behavior and 5-HT1BR sensitivity in orbitofrontal-subcortical OCD circuits. Furthermore, we localized the 5-HT1BR population that mediates OCD-like behavior. METHODS: Mice chronically received the SRI clomipramine or the NRI desipramine and were examined for 5-HT1BR-induced OCD-like behavior or 5-HT1BR binding and G-protein coupling in caudate putamen, nucleus accumbens, and orbitofrontal cortex. Separate mice were tested for OCD- or depression-like behavior following 4, 14, 21, 28, or 56 days of SRI treatment. Finally, OCD-like behavior was assessed following intra-orbitofrontal 5-HT1BR agonist infusion or intra-orbitofrontal 5-HT1BR antagonist infusion coupled with systemic 5-HT1BR agonist treatment. RESULTS: Effective, but not ineffective, OCD treatments reduced OCD-like behavior in mice with a time course that parallels the delayed therapeutic onset in OCD patients and downregulated 5-HT1BR expression in the orbitofrontal cortex. Intra-orbitofrontal 5-HT1BR agonist infusion induced OCD-like behavior, and intra-orbitofrontal 5-HT1BR antagonist infusion blocked OCD-like effects of systemic 5-HT1BR agonist treatment. CONCLUSIONS: These results indicate that orbitofrontal 5-HT1BRs are necessary and sufficient to induce OCD-like behavior in mice and that SRI pharmacotherapy reduces OCD-like behavior by desensitizing orbitofrontal 5-HT1BRs. Our findings suggest an essential role for orbitofrontal 5-HT1BRs in OCD pathophysiology and treatment.

Repeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex.

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.

Cisapride-induced transmural dispersion of repolarization and torsade de pointes in the canine left ventricular wedge preparation during epicardial stimulation.

BACKGROUND: Cisapride, a gastrointestinal prokinetic agent, was recently withdrawn from the market because of its propensity to induce torsade de pointes (TdP) arrhythmias. The present study examines the electrophysiological actions of cisapride in the isolated arterially perfused canine left ventricular wedge preparation. METHODS AND RESULTS: Transmembrane action potentials from epicardial and M regions and a pseudo-ECG were simultaneously recorded. Cisapride (0.1 to 5 micromol/L) was added to the coronary perfusate. Cisapride prolonged the QT interval and increased transmural dispersion of repolarization (TDR) at relatively low but not at high concentrations. TdP could be induced with programmed electrical stimulation only at a low concentration of drug (0.2 micromol/L), when TDR was maximally prolonged. Moreover, TdP could only be induced during epicardial (but not endocardial) activation of the wedge, which was found to augment TDR. At higher concentrations of cisapride, QT was further prolonged, TDR was diminished, and TdP could no longer be induced. Tpeak-Tend interval and Tpeak-Tend area provided reasonable electrocardiographic indices of TDR. CONCLUSIONS: Our data (1) demonstrate a biphasic concentration/response relationship for the effect of cisapride to induce long-QT syndrome and TdP, (2) show the value of the left ventricular wedge preparation in identifying drugs that pose an arrhythmic risk, (3) support the hypothesis that risk for development of TdP is related to the increase in TDR rather than to prolongation of the QT interval, and (4) indicate that epicardial activation of the left ventricle, as occurs during biventricular pacing, can facilitate the development of TdP under long-QT conditions.

Effects of dexfenfluramine on aristolochic acid nephrotoxicity in a rat model for Chinese-herb nephropathy.

Chinese-herb nephropathy (CHN) is a progressive renal interstitial fibrosis initially reported after concomitant intake of an anorexigen, (dex)fenfluramine, and a Chinese herb ( Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acid (AA). We thus tested the possible enhancing effect of the active enantiomer dexfenfluramine (DXF) on AA nephrotoxicity in a rat model for CHN. Groups of 12 salt-depleted male Wistar rats received daily subcutaneous injections of 7 mg/kg body weight DXF (DXF group), 7 mg/kg body weight AA (AA group), a combination of the same doses of AA and DXF (AA+DXF group), or vehicle (control group) for up to 35 days. Six animals per group were killed on day 10 and the remaining six on day 35. Renal function was evaluated by determining serum creatinine and urinary leucine aminopeptidase activity. Histological evaluation of kidney samples was performed and tubulointerstitial injuries were semiquantified. The DXF group did not differ from controls for any parameter. Similarly elevated serum creatinine levels, decreased leucine aminopeptidase enzymuria, and renal lesions were observed in the AA and the AA+DXF groups after both 10 and 35 days. The formation of specific AA-DNA adducts in liver and renal tissue samples was assessed by the (32)P-postlabelling method. Specific AA-DNA adduct levels were significantly increased in kidney tissues from AA+DXF rats compared with AA rats. These functional and histological data suggest that DXF does not enhance AA nephrotoxicity in a rat model for CHN. Further investigations are needed to clarify the mechanism by which DXF may enhance AA-DNA adduct formation.

Repinotan Bayer.

Bayer is developing the aminomethylchroman derivative, repinotan, a 5-HT1A agonist, as a potential treatment for ischemic stroke and traumatic brain injury [216172]. It has completed phase III trials in Canada and the US [342562], [344747]. In June 2001, NDA filing was expected by 2004 [411649]. As of March 2002, it was undergoing phase III trials for both indications, and Bayer expected to launch the product in 2006 in Europe and the US [443846]. Repinotan was being developed initially as an i.v. formulation for the treatment of ischemic stroke and brain injury and as an oral formulation for the treatment of depression; however, development has been discontinued for the latter indication [317452]. In March 2002, Lehman Brothers predicted a launch date of 2006, estimating peak sales of US $1000 million and a 20 to 30% probability of reaching market [450456], while in April 2002, Bank Vontobel also predicted a launch in 2006 with potential sales of Euro450 million in its fifth year of sales [450454]. Bayer predicts peak sales of Euro450 million [397137].

A neuronal nitric oxide synthase inhibitor 7-nitroindazole reduces the 5-HT1A receptor against 8-OH-DPAT-elicited hyperphagia in rats.

The effects of the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole on 8-hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT)-induced hyperphagia, which is mediated by the 5-HT1A autoreceptor, were investigated in rats. 7-Nitroindazole suppressed 8-OH-DPAT-elicited increases in food intake. The inhibitory effects of 7-nitroindazole on 8-OH-DPAT-induced feeding were prevented by the NO precursor L-arginine. Although 8-OH-DPAT decreases 5-hydroxytryptamine (5-HT) synthesis, 7-nitroindazole did not reverse the 8-OH-DPAT-elicited decrease in 5-HT synthesis. Therefore, these results indicate that NO formed in the brain is involved in 8-OH-DPAT-induced hyperphagia and that the hypophagic effects of 7-nitroindazole are not dependent on 5-HT synthesis.

N-Substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D(2) antagonists/5-HT(1A) partial agonists with potential as atypical antipsychotic agents.

A series of N-substituted 1-(2,3-dihydro-1, 4-benzodioxin-2-yl)methylamine derivatives with D(2) antagonist/5-HT(1A) partial agonist activity has been prepared as potential atypical antipsychotic agents. Optimization of in vitro receptor binding activity and in vivo activity in rodent models of psychosis has led to compound 24, which showed good affinities for human D(2), D(3), and 5-HT(1A) receptors but significantly less affinity for human alpha(1) adrenoceptors and rat H(1) and muscarinic receptors. In rodents, 24 showed functional D(2)-like antagonism and 5-HT(1A) partial agonism. After oral dosing, 24 showed good activity in rodent antipsychotic tests and very little potential to cause extrapyramidal side effects (EPS), as measured by its ability to induce catalepsy in rats only at very high doses. In the light of this promising profile of activity, 24 has been selected for clinical investigation as a novel antipsychotic agent with a predicted low propensity to cause EPS.