Katsuya Suemaru

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.

Chronic nicotine treatment potentiates behavioral responses to dopaminergic drugs in rats

In the present study, the behavioral effects of apomorphine, methamphetamine, and haloperidol were examined in nicotine-treated rats. All animals were SC administered nicotine at a dose of 0.5 mg/kg or saline once daily for 14 days. Hyperlocomotion induced by apomorphine (0.2 mg/kg, IP) and methamphetamine (1.0 mg/kg, IP) was greater in nicotine-treated rats than in control rats. Stereotyped behaviors induced by apomorphine (1.0 mg/kg, IP) and methamphetamine (5.0 mg/kg, IP) were also potentiated in nicotine-treated rats. However, the incidence of catalepsy induced by haloperidol (0.25-1.5 mg/kg, IP) was slightly lower in nicotine-treated rats. These results suggest that chronic nicotine treatment may increase the susceptibility of the dopaminergic system to dopaminergic drugs.

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.

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 24 h 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.

Effects of imipramine and lithium on wet-dog shakes mediated by the 5-HT2A receptor in ACTH-treated rats

We examined the influence of imipramine and lithium on wet-dog shakes induced by the (+/-)-DOI, 5-HT2A receptor agonist in adrenocorticotropic hormone (ACTH)-treated rats. The administration of imipramine for 14 days decreased the (+/-)-DOI-induced wet-dog shakes response; chronic administration of lithium for 14 days, however, had no effect. Chronic ACTH (100 microg/rat sc) treatment increased the wet-dog shake response induced by (+/-)-DOI. This effect of ACTH for 14 days, increasing the (+/-)-DOI-induced wet-dog shakes, was not inhibited by a 14-day administration of imipramine. Chronic coadministration of imipramine and lithium, lasting 14 days, decreased the wet-dog shakes response induced by (+/-)-DOI in rats treated with ACTH for 14 days. These findings indicate that lithium inhibits the hyperfunction of the 5-HT2A receptor in rats treated with ACTH when coadministered with imipramine.

Estimation of the Initial Dose Setting of Vancomycin Therapy With Use of Cystatin C as a New Marker of Renal Function

In recent years, it has been suggested that the glomerular filtration rate (GFR) can be predicted on the basis of serum cystatin C concentrations and that this measurement is more sensitive than serum creatinine concentration as a marker of renal function. In this study, to investigate the clinical utility of the initial dose setting of vancomycin by the population mean method with use of serum cystatin C as a marker of renal function, we compared the correlations between measured vancomycin concentrations and predicted vancomycin concentrations based on serum cystatin C or serum creatinine concentrations in elderly (≥65 years old) and nonelderly (<65 years old) patients. An analysis of prediction accuracy (bias) and precision was evaluated by calculating the mean prediction error (ME), the mean absolute error (MAE), and the root mean squared prediction error (RMSE). For nonelderly patients (n = 50), there was no significant difference in the MAE based on the use of serum creatinine or serum cystatin C concentration. However, for elderly patients (n = 105), the MAE based on serum cystatin C concentration was significantly better than that based on serum creatinine level. These results suggest that serum cystatin C is a good marker of renal function in comparison with serum creatinine for dose setting of vancomycin, especially in an elderly population.

Nicotine-induced tail-tremor and drug effects

Tail-tremor induced by repeated and daily administration (0.5 mg/kg SC x 6 times/day) of nicotine as well as effects of various drugs on this response were investigated in Wistar strain male rats. Daily administration of nicotine in doses of 0.5 mg/kg SC caused tail-tremors to appear beginning on the 3rd day. Tail-tremor induced by the first injection of each day gradually increased with the daily injections, however, the heightened effect of this first injection at the beginning of each day decreased during the day upon repeated administration of 6 times/day at 2-hr intervals. Basically, tail-tremor appeared about 5 min after SC administration of nicotine and reached a peak approximately 7-9 min after injection, declining to zero afterwards. Different drugs showed various effects on this response. While mecamylamine (0.5 and 1.0 mg/kg IP) abolished nicotine-induced tail-tremor, arecoline (0.5 and 1.0 mg/kg IP), atropine (2.5 and 5.0 mg/kg IP), scopolamine (1.0 and 2.0 mg/kg IP) and hexamethonium (0.5 and 1.0 mg/kg IP) showed no such effects. Furthermore, physostigmine (0.1 mg/kg IP) actually potentiated this action. These results suggest that tail-tremor induced by nicotine may be mediated through central nicotine receptor system.

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.

Inhibition of neuronal dopamine uptake by some antiallergic drugs

The effects of 10 antiallergic drugs (astemizole, azelastine, ebastine, emedastine, epinastine, ketotifen, oxatomide, terfenadine, pemirolast and tranilast) on neuronal dopamine uptake were examined. Some drugs examined showed a concentration-dependent inhibition of [3H]dopamine uptake into synaptosomal preparations of the rat striatum. The inhibition constant (Ki) values were 231-876 nM for ebastine, terfenadine, oxatomide and astemizole. The specific binding of [3H] (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine) (GBR12935) to the rat striatal membranes was also inhibited by these antiallergic drugs. There was a good correlation between the degrees of inhibition of [3H]dopamine uptake and [3H]GBR12935 binding. Then, the behavioral excitement induced by L-DOPA (100 mg/kg, s.c.) plus pargyline hydrochloride (80 mg/kg, i.p.) in mice was significantly enhanced by i.p. treatment with ebastine (10 mg/kg) and astemizole (5 mg/kg). These results suggest that the neuronal dopamine uptake is inhibited by some antiallergic drugs, especially ebastine.