Munehiro Masuzawa

Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: A microdialysis study

UNLABELLED Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the actions of various psychotropic and addictive drugs. Ketamine and barbiturates have psychotropic effects and addictive properties, but barbiturates prevent ketamines psychotomimetic effects. We investigated the effects of ketamine and pentobarbital on dopamine release in the NAC. A microdialysis probe was implanted in the NAC in 35 rats, which were randomly assigned to seven groups: a normal saline intraperitoneal injection (ip) group, 50 and 100 mg/kg of ketamine ip groups, 25 and 50 mg/kg of pentobarbital ip groups, and a normal saline or 25 mg/kg of pentobarbital ip followed by 50 mg/kg of ketamine ip groups. Perfusate samples were collected every 20 min, and dopamine concentration was measured by high-performance liquid chromatography. Ketamine at doses of 50 mg/kg and 100 mg/kg significantly increased dopamine release in the NAC. Conversely, pentobarbital significantly decreased dopamine release in the NAC and inhibited the ketamine-induced dopamine release. These data suggest that the dopamine release in the NAC may be involved in ketamine-induced, but not barbiturate-induced, psychotropic effects and addiction. Inhibition of ketamine-induced dopamine release by barbiturates may be a mechanism by which they prevent ketamine emergence reactions. IMPLICATIONS Ketamine increased dopamine release in the nucleus accumbens, which was inhibited by pentobarbital. The mesolimbic dopamine system may be involved in the psychotomimetic effects of ketamine, and the suppression of ketamine emergence reactions by barbiturates may be because of the inhibition of ketamine-induced dopamine release in the nucleus accumbens.

Xenon Inhibits but N2o Enhances Ketamine-induced c-fos Expression in the Rat Posterior Cingulate and Retrosplenial Cortices

Both nitrous oxide (N2O) and xenon are N-methyl-d-aspartate receptor antagonists that have psychotomimetic effects and cause neuronal injuries in the posterior cingulate and retrosplenial cortices. We investigated the effect of xenon, xenon with ketamine, N2O, and N2O with ketamine on c-Fos expression in the rat posterior cingulate and retrosplenial cortices, a marker of psychotomimetic effects. Brain sections were prepared, and c-Fos expression was detected with immunohistochemical methods. A loss of microtubule-associated protein 2, a marker of neuronal injury, was also investigated. The number of Fos-like immunoreactivity positive cells by ketamine IV at a dose of 5 mg/kg under 70% N2O (128 ± 12 cells per 0.5 mm2) was significantly more than those under 30% (15 ± 2 cells per 0.5 mm2) and 70% xenon (2 ± 1 cells per 0.5 mm2). Despite differences in c-fos immunoreactivity, there was no loss of microtubule-associated protein 2 immunoreactivity in any group examined. Xenon may suppress the adverse neuronal effects of ketamine, and combined use of xenon and ketamine seems to be safe in respect to neuronal adverse effects. Implications Xenon may suppress adverse neuronal effects of ketamine. Conversely, combined use of N2O and ketamine may increase the risk of neuronal adverse effects, such as psychotomimetic effects.

Inhibitory effect of propofol on ketamine‐induced c‐Fos expression in the rat posterior cingulate and retrosplenial cortices is mediated by GABAA receptor activation

Background:  Non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists, including ketamine, have psychotomimetic activities and cause neuronal damage in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for their psychotomimetic activities. We previously demonstrated that ketamine induced marked c‐Fos (c‐fos protein) expression in the rat PC/RS, which was inhibited by propofol, and the expression was closely related to ketamine‐induced abnormal behavior. In the present study, we investigated whether the inhibition by propofol was mediated by GABAA receptor receptor activation.

The effect of ketamine isomers on both mice behavioral responses and c-Fos expression in the posterior cingulate and retrosplenial cortices.

Ketamine, a non-competitive NMDA receptor antagonist, is a racemic mixture. S(+) ketamine is presumed to be more potent as an anesthetic than R(-) ketamine, and causes less postanesthetic stimulation of locomotor activity than R(-) ketamine in animals at equihypnotic doses. In the present study, we investigated the effect of S(+), R(-), and racemic ketamines on mice behavioral responses and c-Fos expression in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for NMDA-receptor-antagonist-induced psychotomimetic activity. Ataxia and head weaving and c-Fos expression in the PC/RS were significantly more induced by both S(+) and racemic ketamines than by R(-) ketamine at the same dose. S(+) ketamine induced significantly more potent ataxia than racemic ketamine at the same dose. Ketamine-induced c-Fos expression in the PC/RS correlated well with the intensity of behavioral responses. These results imply that R(-) ketamine is weaker than both S(+) and racemic ketamines in a psychotomimetic effect. Also, S(+) ketamine is more potent than racemic ketamine in a psychotomimetic effect and possibly in an anesthetic effect. They also indicate that PC/RS is at least one of the specific brain regions responsible for ketamine-induced behavioral responses in animals and a psychotomimetic activity in humans.

Ketamine-induced c-Fos expression in the mouse posterior cingulate and retrosplenial cortices is mediated not only via NMDA receptors but also via sigma receptors.

Ketamine induces marked c-fos expression in the posterior cingulate and retrosplenial cortices (PC/RS). We investigated whether NMDA and/or sigma receptors were involved in the c-Fos expression. The number of Fos-LI positive boutons in NMDA receptor knockout mice was significantly lower than that in wild-type mice. Rimcazole but not haloperidol significantly suppressed the c-Fos expression. The results indicate that the ketamine-induced c-Fos expression is mediated not only via NMDA receptors but also via sigma receptors.

Sevoflurane causes greater QTc interval prolongation in elderly patients than in younger patients.

BACKGROUND: Sevoflurane and droperidol prolong the QT interval, and advancing age is not only associated with a prolongation of the QT interval but is also a risk factor for drug-induced QT interval prolongation. In this study, we compared the effect of sevoflurane and droperidol on the corrected QT (QTc) interval and the dispersion of ventricular repolarization (time interval from the peak to the end of the T wave [Tp-e]) in elderly patients with those in younger patients. METHODS: Under sevoflurane anesthesia (1.5%–2.5%) with an antiemetic dose of droperidol (1.25 mg), the QT interval and the Tp-e interval, which indicates transmural dispersion of repolarization across the myocardial wall, were measured in 30 elderly patients (70 years and older) and in 30 younger patients (20–69 years) for 2 hours. The QT interval was normalized for heart rate (QTc) using 3 different formulas: Bazett, Matsunaga, and Van de Water. Data are presented as mean ± sd. RESULTS: The elderly group was 24.4 years older (P < 0.05) than the younger group. The QTc intervals in the 2 groups before anesthesia were not significantly different. Using all 3 formulas, the QTc interval in the elderly patient group was significantly prolonged by sevoflurane (the QTc intervals at preanesthesia and 60, 75, 90, and 120 minutes after sevoflurane exposure were 0.434 ± 0.028 seconds, 0.450 ± 0.037 seconds, 0.463 ± 0.037 seconds, 0.461 ± 0.037 seconds, and 0.461 ± 0.038 seconds, respectively, with the Bazett formula). The sevoflurane-induced QTc interval prolongation in the elderly patient group was significantly greater than that in the younger patient group (0.450 ± 0.037 seconds vs 0.432 ± 0.034 seconds, 60 minutes after sevoflurane exposure; 0.463 ± 0.037 seconds vs 0.441 ± 0.037 seconds, 75 minutes after sevoflurane exposure; and 0.461 ± 0.038 seconds vs 0.436 ± 0.030 seconds, 120 minutes after sevoflurane exposure with the Bazett formula), but the sevoflurane-induced QTc interval prolongation was neither further enhanced with time nor by droperidol. The Tp-e interval was not affected in either group. CONCLUSION: Sevoflurane causes greater QTc interval prolongation in elderly patients than in younger patients. Although sevoflurane does not affect the transmural dispersion of repolarization and sevoflurane-induced QTc prolongation does not advance with time and by droperidol administration, QT interval prolongation and its associated arrhythmias should be carefully monitored during sevoflurane anesthesia in elderly patients.

The differential effects of nitrous oxide and xenon on extracellular dopamine levels in the rat nucleus accumbens: a microdialysis study.

Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the action of various psychotropic and addictive drugs, such as antagonists of the N-methyl-d-aspartate subtype of the glutamate. Although both nitrous oxide and xenon are N-methyl-d-aspartate receptor antagonists, they differ in their potential for producing neuropsychological toxicity; therefore, we decided to examine their effects on both spontaneous and ketamine-induced extracellular dopamine levels in the NAC. A microdialysis probe was implanted into the NAC in each of 35 rats, which were randomly assigned to one of six groups: exposure to 40% O2, exposure to 60% nitrous oxide (0.27 MAC), exposure to 43% xenon (0.27 MAC) for 60 min, and three groups exposed to either 40% O2, 60% nitrous oxide, or 43% xenon for 70 min and 80 mg/kg ketamine was given i.p. 10 min after the initiation of gas exposure. Perfusate samples were collected every 20 min, and the dopamine levels were measured using a high-performance liquid chromatography system. Nitrous oxide, but not xenon, significantly increased the dopamine level. Ketamine significantly increased the dopamine level, and this was significantly inhibited by xenon, but not by nitrous oxide. These data suggest that the difference in neuropsychological activity between nitrous oxide and xenon is partly due to their differential effects on the mesolimbic dopamine system.

Ketamine attenuates hypocapnia-induced neuronal damage in the caudoputamen in a rat model of chronic cerebral hypoperfusion

We previously demonstrated that the caudoputamen was exclusively further damaged by hypocapnia in a rat with chronic cerebral hypoperfusion which is characterized by white matter lesions (WML) and a well-established model for patients with cerebrovascular diseases and/or dementia, and suggest that this process may be the cause of long lasting postoperative delirium or brain dysfunction in such patients. In the present study, we investigated whether ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, could attenuate the neuronal damage in the caudoputamen. Ketamine, at doses of 10 and 20 mg/kg, which was given intraperitoneally before hypocapnia induction, attenuated the aggravation of WML score, neuronal damage, and astroglial proliferation in the rat caudoputamen. These results suggest that ketamine may be beneficial for preventing postoperative brain dysfunction, especially in patients with cerebrovascular diseases and/or dementia induced by hypocapnia, which is likely to occur in the mechanical ventilation used during surgery.

Anticonvulsant effects of sevoflurane on amygdaloid kindling and bicuculline-induced seizures in cats: comparison with isoflurane and halothane

AbstractPurpose. We compared the anticonvulsant effects of sevoflurane with those of isoflurane and halothane in amygdaloid kindling and bicuculline-induced seizures in cats. Methods. In a crossover design, the effects of 70% nitrous oxide, and 0.3, 0.6, and 1.5 minimum alveolar concentration (MAC) of volatile anesthetics were studied in five cats in which the amygdala was electrically stimulated at the current used for establishing the kindled state. The effects of 0.6 and 1.5 MAC of volatile anesthetics were studied in another five cats, in which 0.2 mg·kg−1 of bicuculline was administered IV. Results. In the amygdaloid kindling model, all four anesthetics decreased the duration of after-discharge (AD), the rise of multiunit activity in midbrain reticular formation (R-MUA), and the behavior scores compared with findings without anesthetics. Halothane, at 1.5 MAC, significantly decreased the number of cats showing AD (P < 0.05). In the bicuculline-induced seizure model, all five cats showed repetitive spikes during 1.5 MAC of sevoflurane, whereas only two and three cats, respectively, showed the repetitive spikes during 1.5 MAC of isoflurane and halothane. All three volatile anesthetics decreased the rise of R-MUA, the duration of the repetitive spikes, and the behavior scores. The suppression of the rise in R-MUA and the behavior scores with 1.5 MAC of sevoflurane was significantly less than that with 1.5 MAC of isoflurane. Conclusion. The anticonvulsant effects of sevoflurane were less potent than those of halothane in the amygdaloid kindling model and less potent than those of isoflurane in the bicuculline-induced seizure model.