Hiroaki Araki

Nicotine blocks apomorphine‐induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5–5 mg kg−1, s.c.), an α7 nicotinic receptor antagonist, nor dihydro‐β‐erythroidine (0.5–2 mg kg−1, s.c.), an α4β2 nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01–0.2 mg kg−1, s.c.) dose‐dependently reversed the disruption of PPI induced by apomorphine (1 mg kg−1, s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg−1, s.c.). The reversal of apomorphine‐induced PPI disruption by nicotine (0.2 mg kg−1) was eliminated by mecamylamine (1 mg kg−1, i.p.), but not by hexamethonium (10 mg kg−1, i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine‐induced PPI disruption was dose‐dependently blocked by methyllycaconitine (1 and 2 mg kg−1, s.c.). However, dihydro‐β‐erythroidine (1 and 2 mg kg−1, s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine‐induced PPI through central α7 nicotinic receptors.

Nicotine attenuates place aversion induced by naloxone in single-dose, morphine-treated rats

RationaleAcute physical dependence refers to the withdrawal syndrome precipitated by an opioid antagonist administered several hours after either a single dose or a short-term infusion of an opioid agonist.ObjectivesWe examined the mechanism of nicotine-induced attenuation of naloxone-precipitated withdrawal syndrome when used to produce an aversive motivational state in a place-conditioning paradigm.MethodsThe effect of nicotine was investigated through place aversion induced by naloxone in morphine-pretreated rats. Additionally, the mechanism of nicotine action in this model was explored specifically in relation to the dopaminergic system through the use of dopamine receptor antagonist and agonist.ResultsPlace avoidance behavior was potently elicited by naloxone (0.5xa0mg/kg s.c.) 24xa0h after a single exposure to morphine (10xa0mg/kg s.c.). Avoidance behavior was attenuated by pretreatment with a 0.2-mg/kg dose of nicotine 15xa0min prior to naloxone administration. The effect of nicotine was completely blocked by mecamylamine, but not hexamethonium. The dopamine receptor antagonists haloperidol (0.05, 0.1xa0mg/kg, s.c.), SCH23390 (0.1xa0mg/kg, s.c.), raclopride (1.0xa0mg/kg, s.c.) and eticlopride (0.1 mg/kg, s.c.) showed effects similar to mecamylamine. Additionally, the dopamine receptor agonist apomorphine (0.03, 0.1, 0.3xa0mg/kg, s.c.) inhibited naloxone-induced place aversion in morphine-treated rats.ConclusionThe inhibitory effect of nicotine on place aversion induced by naloxone-precipitated morphine withdrawal may involve a dopaminergic portion of the central nervous system.

A Multi-institutional Study Analyzing Effect of Prophylactic Medication for Prevention of Opioid-induced Gastrointestinal Dysfunction

Objectives:The aim of this study was to evaluate the effectiveness of prophylactic treatment with laxatives and antiemetics on the incidence of gastrointestinal adverse reactions such as constipation, nausea and vomiting in cancer patients who received oral opioid analgesics for the first time. Methods:A multi-institutional retrospective study was carried out, in which 619 eligible hospitalized patients receiving oral opioid analgesics for cancer pain were enrolled from 35 medical institutions. The primary endpoint was the incidence of opioid-induced side effects in patients receiving prophylactic medication. Odds ratios of the incidence of adverse reactions in the absence or presence of premedication obtained from several institutions were subjected to a meta-analysis. Results:Among 619 patients, the incidence of constipation was significantly lower in patients receiving laxatives, including magnesium oxide, as premedication than in those without them (34% vs. 55%, odds ratio=0.432, 95% confidence interval=0.300-0.622, P<0.001). However, the incidence of nausea or vomiting was similar regardless of prophylactic medication with dopamine D2 blockers. The results of the meta-analysis revealed that prophylactic laxatives significantly reduced the incidence of constipation (overall odds ratio=0.469, 95% confidence interval=0.231-0.955, P=0.037), whereas dopamine D2 blockers were not effective in preventing opioid-induced nausea or vomiting. Discussion:We showed evidence for the effectiveness of premedication with laxatives for prevention of opioid-induced constipation. However, premedication with dopamine D2 blockers was not sufficient to prevent nausea or vomiting.

Factors producing a menopausal depressive-like state in mice following ovariectomy

RationaleBilateral ovariectomy in female mice produces a menopausal depressive-like state but the factors responsible for the phenomenon are unknown.ObjectivesWe elucidated methodological issues related to establishing this mouse model and investigated a possible mechanism underlying the depressive-like state of ovariectomized mice.MethodsWe removed both ovaries of female ICR mice at 9xa0weeks of age. Changes in the immobility time during the forced swimming test as a function of the time interval between ovariectomy and behavioral testing were determined on nine different days after surgery. To assess behavioral specificity, the elevated plus-maze (EPM) behavior and spontaneous activity were measured. With respect to the effect of ovariectomy on the immobility time, we compared ICR mice with three other strains of mice (C57BL/6J, DBA/2N, and CD-1). Finally, we investigated the effects of (−)-2,5-dimethoxy-4-iodoamphetamine (DOI) and (±)-8-hydroxy-2-(N,N-di-n-propylamino) tetralin (8-OH-DPAT) on the immobility time of ovariectomized mice.ResultsA significant effect on the prolongation of immobility was observed between 12 and 18xa0days after ovariectomy. Ovariectomy did not alter either the EPM behavior or spontaneous activity. Of the four strains of mice, only DBA mice did not show any significant prolongation of immobility after ovariectomy. Acute or chronic treatment with DOI (0.5 or 1.0xa0mg kg−1) significantly prevented the prolongation of immobility time, whereas acute and chronic treatments with 8-OH-DPAT (0.05, 0.5, or 1.0xa0mg kg−1) were ineffective.ConclusionThe present findings have potentially important implications for evaluating a candidate substance for the management of mood disorders in menopausal women.

Antidepressant-like action of nicotine in forced swimming test and brain serotonin in mice.

An antidepressant-like action of nicotine has been suggested in the forced swimming test. The aim of the present study was to evaluate the relationship between the antidepressant-like action of nicotine and brain serotonin (5-HT) in mice. Nicotine at a dose of 0.2 mg/kg significantly (p < 0.05) decreased the duration of immobility time in forced swimming test. However, nicotine (0.01-1 mg/kg, s.c.) had no effect on locomotor activity in open-field test. Dopamine turnover in mouse whole brain was increased by nicotine (0.01-1 mg/kg, s.c.) in a dose-dependent manner, and nicotine at a dose of 0.05 mg/kg showed a significant increases in 5-HT turnover. Nicotine at a dose of 0.05 mg/kg markedly enhanced head twitch responses induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT2A/2C receptor agonist. These findings suggest that the involvement of nicotinic and serotonergic systems in the antidepressant-like effects of nicotine.

Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats

1 The neurobiological mechanism underlying the negative motivational component of withdrawal from acute opiate dependence is far from understood. 2 Our objectives were to determine whether the glutamatergic system is involved in the motivational component of morphine withdrawal in acutely dependent rats and such an involvement is associated with dopaminergic neurotransmission. 3 We examined the effects of various kinds of glutamate receptor antagonists on conditioned place aversion (CPA) induced by naloxone‐precipitated withdrawal from a single morphine exposure 24u2003h before. Furthermore, the influence of pretreatment with the dopamine receptor antagonist haloperidol on those effects of glutamate receptor antagonists was also investigated. 4 CPA was attenuated in a dose‐dependent manner by all glutamate receptor antagonists examined including the NMDA receptor antagonists (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclo‐hepten‐5,10‐imine maleate (MK‐801) and phencyclidine hydrochloride (PCP), AMPA receptor antagonist 1‐(4‐aminophenyl)4‐methyl‐7,8‐methylenedioxy‐5H‐2,3‐benzodiazepine hydrochloride (GYKI 52466), and metabotropic receptor antagonists (±)‐2‐amino‐3‐phosphonopropionic acid (AP‐3) and (±)‐α‐methyl‐4‐carboxyphenylglycine (MCPG). The effects of MK‐801, GYKI 52466 and MCPG were blocked by haloperidol. 5 These results suggest that the glutamatergic system involving multiple classes of receptors plays a role in the motivational component of withdrawal from acute morphine dependence, and the function of the glutamatergic system would be closely associated with dopaminergic neurotransmission.

Identification of antidepressant-like ingredients in ginseng root (Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: participation of 5-HT2A receptors

RationaleAfter reports of adverse effects with hormone replacement therapy, such as reproductive and breast cancer and coronary heart disease, much attention has been given to the development of new remedies to alleviate menopausal depression in women, but methods for their preclinical evaluation have not been clarified. We previously developed a procedure to predict the drug effect on the menopausal depressive-like state in female mice.ObjectivesWe attempted to identify psychoactive components from ginseng root, one of the earliest known materials for menopausal disorder, and to clarify the possible mechanism involved.MethodsAs an index of a depressive-like state, we used the prolongation of immobility time induced by an ovariectomy during the forced swimming test. Chronic treatment with the candidate substance began the day after ovariectomy and continued for 14xa0days. To examine whether the 5-HT2A receptor antagonist ritanserin antagonized the antidepressant-like effect of ginsenoside Rb1, ritanserin was given as pretreatment 15xa0min before the daily administration of ginsenoside Rb1 and the antagonistic effect was compared with ginsenoside Rb1 alone.ResultsGinsenoside Rb1 and compound K were active ingredients that dose-dependently prevented the prolongation of immobility time induced by ovariectomy. Co-administration of ritanserin, a 5-HT2A-receptor antagonist, antagonized the effect of ginsenoside Rb1.ConclusionsWe suggest that ginsenoside Rb1 and its metabolite, compound K, are antidepressant-like components of the ginseng root, and that 5-HT2A receptors may play an important role in mediating the antidepressant-like effect of ginsenoside Rb1.

Withdrawal-induced c-Fos expression in the rat centromedial amygdala 24 h following a single morphine exposure.

RationaleAn opiate antagonist was found to induce motivational withdrawal signs 24xa0h or even up to 48xa0h after a single dose of morphine in rats.ObjectiveThe present study was undertaken to determine whether such a withdrawal state would modify the neuronal activity in the brain.MethodsA conditioned place aversion was established following a one-trial paradigm in rats undergoing a single exposure to morphine (10xa0mg/kg) 24xa0h prior to naloxone administration (0.5xa0mg/kg). Subsequently, the expression of the protein product of c-fos gene (c-Fos) following naloxone administration was measured within the extended amygdala.ResultsA significant increase in c-Fos immunoreactivity was seen in the centromedial amygdala (CMA), but not in the bed nucleus of the stria terminalis (BST) and the shell (AcbSh) of the nucleus accumbens (Acb) in rats treated with both morphine and naloxone. Further examination of the distribution of c-Fos-positive neurons along the rostrocaudal axis within CMA showed that the positive neurons distributed throughout this brain area and the caudal level of its central division (the central nucleus of the amygdala, CeA) exhibited the most robust labeling.ConclusionsNeuronal activity can be increased by naloxone at a dose that produces conditioned place aversion 24xa0h after a single morphine exposure. CMA, particularly the caudal level of its central division, was of high sensitivity. The current data also suggest a possible involvement of CMA in negative motivational component of precipitated withdrawal from acute morphine dependence.

Population Pharmacokinetic Analysis of Vancomycin Using Serum Cystatin C as a Marker of Renal Function

ABSTRACT We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoeks formula correlated linearly with VAN clearance (VAN clearance [ml/min] = 0.825 × GFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (−3.45 to −1.38) of the difference in each value of the mean absolute error (−2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.

Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the α7 nicotinic acetylcholine receptor in Wistar rats

Nicotine has ameliorating effects on sensorimotor gating deficits in schizophrenia. We have shown that nicotine ameliorated disruption of prepulse inhibition (PPI) via the alpha(7) nicotinic acetylcholine receptor (nAChR) in Wistar rats. The 5-HT(3) receptor antagonist tropisetron was recently found to be an alpha(7) nAChR partial agonist. We initially investigated the effects of tropisetron on disruption of PPI induced by phencyclidine (PCP) (2mg/kg) or apomorphine (1mg/kg). Tropisetron had no effect on the disruption of PPI induced by PCP, but ameliorated the disruption by apomorphine. The ameliorating effect of tropisetron was antagonized by methyllycaconitine (2 or 5mg/kg), a partially selective alpha(7) nAChR antagonist. Next, to find the action site of tropisetron, we examined c-Fos protein expression in the nucleus accumbens (NAc), dorsolateral striatum (DLst) and ventral tegmental area (VTA). Tropisetron alone did not change the number of c-Fos-positive cells, whereas apomorphine increased the number of positive cells in the NAc and DLst. Tropisetron administration followed by apomorphine administration decreased the number of positive cells in the VTA compared with the apomorphine-alone group. These results suggest that tropisetron has an ameliorating effect on the sensorimotor gating deficits via the alpha(7) nAChR, and that one possible site of its action is the VTA.