Kazuhiro Ishikawa

Development of tolerance and supersensitivity to phencyclidine in rats after repeated administration of phencyclidine

In rats treated with phencyclidine (PCP) repeatedly (PCP 10 mg/kg per day for 14 days), the back-pedalling, head-weaving and turning induced by PCP were attenuated (tolerance), while PCP-induced sniffing, rearing and ambulation were potentiated (supersensitivity). The behavior induced by the direct and indirect serotonin (5-HT) agonists, 5-methoxy-N,N-dimethyltryptamine and p-chloroamphetamine, was attenuated, while the sniffing, rearing or licking induced by the direct and indirect dopamine (DA) agonists, apomorphine and methamphetamine, were potentiated in the chronic PCP-treated rats. The DA and 5-HT contents in the nucleus accumbens and the ratio of HVA to DA in the striatum increased following the repeated PCP administration. Pentobarbital-induced sleep time did not change in the chronic PCP-treated rats as compared with the control rats. In addition, there was no significant difference between the disappearance rate of PCP in the brain of the rats treated with PCP repeatedly and the rate in the control rats. These results suggest that functional changes in the dopaminergic and serotonergic neuronal systems develop on repeated administration of PCP but that such changes do not develop in the hepatic drug-metabolizing system. In addition, tolerance develops in the serotonergic neuronal system while supersensitivity develops in the dopaminergic neuronal system. Biochemical findings suggest that increased mesolimbic dopaminergic neuronal function plays an important role in the development of the supersensitivity.

The role of tissue plasminogen activator in methamphetamine-related reward and sensitization

In the central nervous system, tissue plasminogen activator (tPA) plays a role in synaptic plasticity and remodeling. Our recent study has suggested that tPA participates in the rewarding effects of morphine by regulating dopamine release. In this study, we investigated the role of tPA in methamphetamine (METH)‐related reward and sensitization. Repeated METH treatment dose‐dependently induced tPA mRNA expression in the frontal cortex, nucleus accumbens, striatum and hippocampus, whereas single METH treatment did not affect tPA mRNA expression in these brain areas. The METH‐induced increase in tPA mRNA expression in the nucleus accumbens was completely inhibited by pre‐treatment with R(+)‐SCH23390 and raclopride, dopamine D1 and D2 receptor antagonists, respectively. In addition, repeated METH treatment increased tPA activity in the nucleus accumbens. There was no difference in METH‐induced hyperlocomotion between wild‐type and tPA‐deficient (tPA–/–) mice. On the other hand, METH‐induced conditioned place preference and behavioral sensitization after repeated METH treatment were significantly reduced in tPA–/– mice compared with wild‐type mice. The defect of behavioral sensitization in tPA–/– mice was reversed by microinjections of exogenous tPA into the nucleus accumbens. Our findings suggest that tPA is involved in the rewarding effects as well as the sensitization of the locomotor‐stimulating effect of METH.

Methysergide-induced precipitated withdrawal syndrome in phencyclidine-dependent rats

Chronic phencyclidine (PCP) administration has been shown to produce tolerance to a number of its pharmacological actions. We have suggested that PCP interacts with the 5-HT2 receptors since it inhibits [3H]spiperone binding to 5-HT2 receptors in vitro. In the present study, we investigated whether methysergide (a 5-HT2 receptor blocker) induces the precipitated withdrawal syndrome in PCP-tolerant rats. The body weight of the rats in the abrupt and precipitated withdrawal groups was significantly lower 5 days and 1-5 days after withdrawal, respectively, than that in the control group. Furthermore, other typical precipitated abstinence syndrome characteristics such as jumping, wet-dog shake and ptosis were also observed in the precipitated withdrawal group. These results suggest that PCP produces its behavioral effects via an agonistic interaction with 5-HT2 receptor sites and that our method may be very useful for the development of a rat model for studying physical dependence on PCP.

Phencyclidine-induced head-weaving and head-twitch through interaction with 5-HT1 and 5-HT2 receptors in reserpinized rats

Phencyclidine mainly produced head-weaving and head-twitches at doses of 5-7.5 mg/kg and of 7.5-12.5 mg/kg, respectively. Phencyclidine-induced head-twitches and head-weaving were blocked by pretreatment with ritanserin (1 mg/kg), a selective serotonin (5-HT)2 receptor antagonist and with pindolol (20 mg/kg, s.c.), a 5-HT1 receptor antagonist, respectively. In reserpine-pretreated rats, the degree of utilization of 5-HT and the number of 5-HT1 ([3H]5-HT) and 5-HT2 ([3H]ketanserin) binding sites were significantly increased compared with the figures for the vehicle-pretreated rats. The intensity of phencyclidine-induced head-weaving (at the dose of 2.5 mg/kg) and head-twitch (at the doses of 2.5 and 5 mg/kg) was significantly increased in reserpine-pretreated rats compared with that of vehicle-pretreated rats. Furthermore, in the reserpine-pretreated rats, the intensity of phencyclidine (1.25 mg/kg)-induced head-weaving and head-twitches was increased in combination with imipramine, while the intensity of phencyclidine (2.5 mg/kg)-induced head-weaving and head-twitch was decreased by pretreatment with mianserin, a non-selective 5-HT receptor antagonist. These results indicate that phencyclidine induced head-weaving by interacting with 5-HT1 receptors, indirectly after the release of 5-HT and/or with some other mechanisms and induced head-twitch by interacting with 5-HT2 receptors directly and/or indirectly.

Phencyclidine-induced head-twitch responses as 5-HT2 receptor-mediated behavior in rats

This study was designed to assess whether phencyclidine (PCP)-induced head-twitch was antagonized by ritanserin, a selective serotonin (5-HT2) receptor antagonist, in mice and rats to confirm the involvement of 5-hydroxytryptamine (5-HT) neurons in PCP actions in comparison with 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced behavior. PCP (7.5, 10 and 12.5 mg/kg, i.p.)-induced head-twitch was completely antagonized by ritanserin (1 mg/kg, s.c.) in mice and rats, and 5-MeODMT (2 and 4 mg/kg, i.p.)-induced head-twitch was also completely antagonized by ritanserin in mice. PCP and 5-MeODMT induced head-weaving in mice after ritanserin treatment, but this did not occur in rats. In rats, 5-MeODMT failed to induce head-twitch. These results suggest that PCP-induced head-twitch response in rats is developed via 5-HT2 receptors and it is a useful 5-HT2 receptor model, while 5-MeODMT-induced head-weaving in rats is developed via 5-HT1 receptors and is a useful 5-HT1 receptor model.

The Risk Factors of Severe Acute Kidney Injury Induced by Cisplatin

Objectives: We reported that the KDIGO (Kidney Disease: Improving Global Outcomes) criteria could stratify the risk of mortality in acute kidney injury (AKI) caused by cisplatin. The purpose of this study was to investigate risk factors of severe cisplatin-induced AKI (CIA). Methods: From January 2006 to December 2012, we identified Japanese cancer patients who were treated with cisplatin as a first-line chemotherapy at Nagoya University Hospital. Serum creatinine levels were used to define CIA. Results: We evaluated 1,721 patients treated with cisplatin. In multivariable analysis, cisplatin dosages/m2 [odds ratio (OR) 1.019] or diagnosis of cancer stage 4 (OR 1.797) were risk factors of moderate CIA. History of diabetes mellitus (OR 3.454), history of cardiovascular disease (OR 3.612) or diagnosis of cancer stage 4 (OR 2.610) were risk factors of severe CIA. Conclusions: Diabetes mellitus, cardiovascular disease and advanced cancer increased the risk of severe CIA. As severe CIA shortens the survival period, we should consider whether the use of cisplatin benefits these patients.

Phencyclidine-induced head-weaving observed in mice after ritanserin treatment

Ritanserin (0.125, 0.25, 0.5, 1.0 and 2.0 mg/kg s.c.), a selective serotonin (5-HT2) receptor antagonist, produced a dose-dependent inhibition of the head-twitch response induced in mice by phencyclidine (PCP) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). In contrast, ritanserin, dose dependently increased PCP- and 5-MeODMT-induced head-weaving. There was a significant inverse relationship between head-twitch and head-weaving responses. Pretreatment with p-chlorophenylalanine (PCPA, 300 mg/kg i.p.), a serotonin synthesis inhibitor, attenuated the head-weaving induced by the combination of PCP (12.5 mg/kg i.p.) and ritanserin but PCPA did not alter the 5-MeODMT-induced head-weaving. These results indicate that PCP induces head-weaving by interacting with a 5-HT receptor (possibly of the 5-HT1 subtype) indirectly after 5-HT release and induces head-twitch by interacting with 5-HT2 receptors directly.

Effects of single and repeated administration of methamphetamine or morphine on neuroglycan C gene expression in the rat brain.

The rearrangement of neural networks associated with the behavioural sensitization and tolerance induced by psychostimulants is poorly understood. We have investigated the effects of repeated administration of methamphetamine (chronic MAP), which induces behavioural sensitization, or morphine (chronic morphine), which induces tolerance to its antinociceptive effect, on the mRNA levels of neural network-related genes in the rat brain. A gene of special interest was that for neuroglycan C (NGC), a neural tissue-specific transmembrane chondroitin sulphate proteoglycan. Single MAP (acute MAP) administration significantly decreased NGC mRNA levels in the frontal cortex, ventral tegmental area (VTA), and amygdala compared to vehicle-treated groups. Repeated MAP (chronic MAP) administration significantly increased NGC mRNA levels in the frontal cortex, nucleus accumbens (NAc), striatum, hippocampus, VTA, and amygdala compared to acute MAP treatment. Single morphine (acute morphine) administration significantly increased NGC mRNA levels in the NAc, striatum, hippocampus, VTA, and amygdala compared to vehicle-treated groups. Chronic morphine administration significantly decreased NGC mRNA levels in the NAc, striatum, VTA, and amygdala compared to acute treatment. In addition, the NGC protein level in the NAc was increased after chronic MAP and acute morphine treatment. Dopamine and opioid receptor antagonists attenuated the effect of MAP and morphine respectively on NGC mRNA levels. These results suggest that the sensitization to MAP is associated with up-regulation of NGC gene expression, while the tolerance to the morphine-induced analgesic effect is associated with the down-regulation of NGC gene expression.

Effects of prenatal and perinatal administration of phencyclidine on the behavioral development of rat offspring.

The effects of prenatal and perinatal administration of a nonteratogenic dose of phencyclidine (PCP) on the behavioral development of Sprague-Dawley rats were examined. In the offspring prenatally treated with PCP (10 mg/kg) between days 7 and 17 of gestation, a decrease in maternal body weight in the gestation period, a decrease in fetal body weight and body length, a decrease in viability of offsprings, and a decrease in the body weights of the offspring in the nursing period were observed. Furthermore, PCP pups had difficulty performing the rota-rod task at 4 weeks and exhibited a decrease in sensitivity to challenged PCP at 5 weeks (female). In the offspring prenatally treated with PCP between days 7 and 21 of gestation, a decrease in the body weights of dams, fetuses and offspring, and a decrease in the viability of offsprings were observed. PCP pups showed an increase in the score for head-twitch response (male), a delay in the development of ambulation, negative geotaxis (male), bar holding and rope-descending behavior (female). However, the PCP administration during prenatal (between days 17 and 21 of gestation) and nursing periods showed only a decrease in viability and body weight of offspring, and a delay in the development of the separation of eyelids. These results suggest that more attention should be given to the developmental toxicity of PCP.

KDIGO (Kidney Disease: Improving Global Outcomes) Criteria Could Be a Useful Outcome Predictor of Cisplatin-Induced Acute Kidney Injury

Objectives: The purpose of this study was to investigate if KDIGO (Kidney Disease: Improving Global Outcomes) criteria could be a useful outcome predictor of cisplatin-induced acute kidney injury (CIA). Methods: In the period between January 2006 and December 2011, we identified Japanese patients who had been diagnosed with cancer and treated with cisplatin as a first-line chemotherapy at Nagoya University Hospital. The serum creatinine was used to define CIA and determine the KDIGO criteria of each patient after chemotherapy within 7 days. Results: Eighty-nine patients (5.4%) were classified as having acute kidney injury (AKI) going by the KDIGO criteria, and the numbers of patients classified into AKI stages 1, 2 and 3 were 65 (3.9%), 18 (1.1%) and 6 (0.4%), respectively. Overall survival times were significantly shorter in AKI stages 2 and 3 than in stage 1. The area under the receiver operating characteristic curve with all patients was 0.68, and that of patients who were diagnosed with cancer stage 4 was 0.80. Conclusion: These results suggest that KDIGO criteria can be a predictor of CIA mortality in patients with different primary cancers.