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ANESTHETIC PHARMACOLOGY

Pentobarbital Inhibits Ketamine-Induced Dopamine Release in the Rat Nucleus Accumbens: A Microdialysis Study

Department of Anesthesiology, Kansai Medical University, Osaka, Japan

Address correspondence and reprint requests to Shinichi Nakao, MD, PhD, Department of Anesthesiology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-shi, Osaka 570-8507, Japan. Address e-mail to nakaos{at}takii.kmu.ac.jp

	Abstract

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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 ketamine’s 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.

	Introduction

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Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, causes behavioral abnormalities in animals (1) and has psychotomimetic effects such as hallucination, agitation, and disorientation in humans (2). It also exacerbates symptoms in schizophrenia (3). Psychotomimetic reactions, also termed emergence reactions, such as vivid dreaming, extracorporeal experiences, and illusion occur during awakening from ketamine anesthesia (2). Although the precise mechanism of ketamine emergence reactions is not known, they are attenuated by benzodiazepines and barbiturates, which are also effective in treating them (4,5).

The mesolimbic dopamine system (MLDS), which consists of dopaminergic neurons in the ventral tegmental area (VTA) and their various projection regions, notably the nucleus accumbens (NAC), is thought to be an important site responsible for actions of various psychotropic drugs (6,7) and schizophrenia (8). Indeed, noncompetitive NMDA receptor antagonists such as phencyclidine (PCP), a precursor of ketamine, and MK-801 cause abnormal behavioral responses in animals such as hyperlocomotion, head weaving, and sniffing. They also activate dopamine neurons in the VTA and increase dopamine release in the NAC (9). The abnormal behavioral responses are correlated with an increase in dopamine release in the NAC, and it has been proposed that they represent an animal model of schizophrenia and are a manifestation of psychotomimetic activity in humans (9). Furthermore, MLDS also plays a crucial role in the effect of many addictive drugs such as opioids, cocaine, amphetamine, and cannabinoids (6,7). Almost all addictive drugs increase the extracellular dopamine concentration in the terminal region of midbrain dopaminergic neurons, especially in the NAC (6,7). PCP and ketamine are also substances of abuse (10). Various anesthetics, such as barbiturates (11,12), inhaled anesthetics (13,14), and benzodiazepines (12,15), also have addictive potential. However, there is still no available information concerning the effects of these anesthetics on dopamine release in the NAC.

We hypothesized that ketamine-induced psychotomimetic effects and its addictive potential are related to an increase in dopamine release in the NAC. In the present study, we first investigated whether ketamine increased dopamine release in the NAC and then examined the effect of pentobarbital, which also has psychotropic properties and addictive potential, on the dopamine release in the NAC. Furthermore, we studied the effect of pentobarbital on ketamine-induced dopamine release because pentobarbital prevents ketamine emergence reactions (5).

	Methods

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The Animal Research Committee in our institution approved the study. Thirty-five male Wistar rats weighing 250–300 g were randomly assigned to seven groups. They were kept under controlled environmental conditions (ambient temperature 23°C–25°C; 12/12 light-dark cycle; light on at 7:00 AM) for at least 1 wk before being used. Food and tap water were allowed ad libitum. All experiments were performed between 10:00 AM and 4:00 PM in a laboratory at an ambient temperature of 23°C–25°C.

The rats were mounted on a stereotaxic frame under pentobarbital anesthesia (50 mg/kg intraperitoneal [ip]). A stainless guide cannula was stereotaxically implanted unilaterally into the NAC with the following coordinates in relation to the bregma, AP: +1.6, ML: +1.2, DV: -6.2 mm, according to the atlas by Paxinos and Watson (16). The cannula was fixed to the skull with dental resin and stainless steel screws. The location of the probe was verified by visual examination at the end of each experiment. The rats were allowed to recover for at least 2 days. On the day of study, the stylet was removed from the cannula, and a microdialysis probe (A-I-12-2, Eicom, Kyoto, Japan) was inserted through the cannula. After placing the rat in a plexiglas box (25 x 25 x 25 cm) in which it could move freely, the microdialysis probe was connected to the perfusion pump and sample loop of an automated sample injector (Model 10; Eicom) using polyethylene tubing. The microdialysis probe was perfused continuously at a rate of 2.0 µL/min with an artificial cerebrospinal fluid solution (NaCl 147 mM, KCl 4 mM, and CaCl₂ 2.3 mM; pH 6.0).

Perfusate samples obtained during the first 120 min after implantation of the probe were discarded. The dialysate samples were then collected every 20 min. After verifying the stability of baseline dopamine release, three basal samples were collected.

Experiment 1: The Effects of Ketamine and Pentobarbital on Dopamine Release in the NAC
In Group 1 (n = 5), the rats were subsequently given sterilized normal saline ip. In Group 2 (n = 5), the rats were administered 50 mg/kg of ketamine ip. In Group 3 (n = 5), the rats were given 100 mg/kg of ketamine ip. In Group 4 (n = 5), the rats were given 25 mg/kg of pentobarbital ip. In Group 5 (n = 5), the rats were given 50 mg/kg of pentobarbital ip.

Experiment 2: The Effect of Pentobarbital on Ketamine-Induced Dopamine Release in the NAC
In Group 6 (n = 5), the rats were given sterilized normal saline ip followed 10 min later by 50 mg/kg of ketamine ip. In Group 7 (n = 5), the rats were given 25 mg/kg of pentobarbital ip followed 10 min later by 50 mg/kg of ketamine ip.

Dopamine in the dialysates was measured using a high-performance liquid chromatography column equipped with an electrochemical detector. The samples were injected by auto-injector into an ODS-C18 reverse-phase column (2.1 x 150 mm CA-5ODS; Eicom) maintained at 25°C. The mobile phase, at a flow rate of 230 µL/min, consisted of 0.1 M of phosphate buffer (pH value of 6.0) containing 50 mg/L of EDTA2Na, 500 mg/L of 1-octanesulfonate, and 20% methanol. The oxidation potential of the graphite electrode was set at 450 mV against an Ag/AgCl reference electrode (ECD-300; Eicom). The detection limit of the assay was 0.2 pg/40 µL. Ketamine was purchased from Sankyo Co. (Tokyo, Japan) and sodium pentobarbital from Nacalai Tesque (Kyoto, Japan). All drugs were dissolved in sterile normal saline (0.9% NaCl).

The results are expressed as the percentage of basal dopamine release (mean ± SEM). Basal release was taken as the mean of three initial collections just before administration of the test drugs. Statistical evaluation was performed using the StatView 5.0 (SAS Institute Inc, Cary, NC). The significance of differences between Groups 1 to 5 and between Groups 6 and 7 were determined independently using two-way analysis of variance with repeated measures, followed by the Scheffé test for multiple comparisons. P < 0.05 was considered statistically significant.

	Results

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After ketamine and pentobarbital ip, all rats showed behavioral changes. Ketamine, at a dose of 50 mg/kg ip, induced abnormal behavior such as head weaving and ataxia, and at a dose of 100 mg/kg, it induced complete ataxia within 10 min. After 25 mg/kg of pentobarbital ip, the rats became quiet, and after 50 mg/kg ip, they showed complete ataxia within 10 min. Pentobarbital 25 mg/kg almost completely suppressed ketamine-induced head weaving but augmented ketamine-induced ataxia.

Figure 1 shows the effects of ketamine and pentobarbital on dopamine release in the NAC. Ketamine significantly increased dopamine release compared with the basal level. The maximal increases produced by ketamine 50 mg/kg and 100 mg/kg ip were 133% and 227% of the basal level. These were observed in the second (20–40 min after the ketamine injection) and third (40–60 min after the ketamine injec-tion) sample fractions after the ketamine injection, respectively. After reaching a maximum value, the dopamine release decreased gradually. Conversely, 50 mg/kg of pentobarbital significantly decreased dopamine release compared with the basal level. A decrease of 58% of the basal level was observed in the fifth sample fraction after the pentobarbital injection (the last fraction, 80–100 min after the pentobarbital injection).

View larger version (17K): [in this window] [in a new window]   Figure 1. Effects of normal saline, ketamine (50 mg/kg and 100 mg/kg), and pentobarbital (25 mg/kg and 50 mg/kg) on dopamine release in the nucleus accumbens (NAC), as assayed by microdialysis in freely moving rats. Data are presented as mean (± SEM) percent of basal values before drug injection. Saline = Group 1 (saline ip); Ket 50 = Group 2 (ketamine 50 mg/kg ip); Ket 100 = Group 3 (ketamine 100 mg/kg ip); Pento 25 = Group 4 (pentobarbital 25 mg/kg ip); Pento 50 = Group 5 (pentobarbital 50 mg/kg ip). *P < 0.05 versus basal values. +P < 0.001 versus Saline, Ket 50, Pent 25, and Pent 50 groups at a given time. P < 0.05 versus Saline, Ket 50, and Ket 100 groups at a given time.

View larger version (13K): [in this window] [in a new window]   Figure 2. Effects of normal saline and pentobarbital (25 mg/kg) on ketamine-induced (50 mg/kg) dopamine release in the nucleus accumbens (NAC). Pentobarbital significantly suppressed the ketamine-induced increase in dopamine release. Data are presented as mean (± SEM) percent of basal values before drug injection. *P < 0.05 versus basal values in the pentobarbital preinjection group. +P < 0.001 versus basal values in the saline preinjection group. P < 0.001 versus the pentobarbital preinjection group at a given time.

	Discussion

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Several potential limitations of our model should be considered. First, we did not systematically examine the behavioral changes in response to the test drugs because the main purpose of this experiment was to investigate dopamine release in the NAC, and it was rather difficult to obtain reliable data on the behavioral responses in probe-implanted rats. Furthermore, we previously examined the effects of 50 and 100 mg/kg of ketamine on the behavioral changes in mice or rats (1,17). However, the behavioral changes were checked after the test drug injections to confirm that they had been correctly injected. Second, we used pentobarbital rather than benzodiazepines to investigate the effect on ketamine-induced dopamine release in the NAC, although benzodiazepines are more widely used for preventing ketamine emergence reactions. We thought that the effects of benzodiazepines and barbiturates on dopamine release in the NAC, and consequently on ketamine emergence reactions, would be the same because the primary molecu-lar mechanism of both drugs is to potentiate -aminobutyric acid (GABA_A) receptor activity. Indeed, thiopental is quite effective in preventing the ketamine emergence reactions (5). Third, we did not perform studies that could differentiate between a change in dopamine release and re-uptake because a dopamine uptake inhibitor itself affects the extracellular dopamine concentration and behaviors. However, because ketamine activates VTA dopamine neurons (18), it is more probable that the ketamine-induced increase in dopamine concentration in the NAC is attributed to the increase in dopamine release.

Our data clearly demonstrated that ketamine significantly increased dopamine release in the NAC in a dose-dependent manner, which we thought might be responsible for both the psychotomimetic activity and the addictive potential of ketamine. Noncompetitive NMDA receptor antagonists such as PCP and ketamine have psychotomimetic effects in humans. In rodents, they evoke characteristic behavioral changes such as head weaving, sniffing, and ataxia, which are considered to be equivalent to the psychotomimetic effects in humans. Activation of the MLDS and increase in dopamine release in the NAC play a crucial role in the behavioral stimulation induced by PCP and MK-801 (9). There are two reports of ketamine-induced increases in dopamine release in the NAC. Irifune et al. (19) reported that 30 mg/kg of ketamine injected ip increased mouse locomotor activity in association with an increase in dopamine turnover in the NAC by 21% of control. However, they did not measure the time course of dopamine release but assayed the level of dopamine and its metabolites in brain homogenates at 20 minutes after the ketamine administration. Hancock and Stamford (20) demonstrated that ketamine stereospecifically increased dopamine efflux from brain slices of the rat NAC.

Barbiturates are addictive in humans (11,12), and an animal model of tolerance, physical dependence, and withdrawal effects for barbiturates has been established (21). In the present study, we demonstrated that pentobarbital significantly decreased dopamine release in the NAC. Our results are compatible with the finding that GABA containing interneurons within the VTA and long-loop GABA-ergic feedback projections cause tonic inhibition on the VTA dopamine neurons (6,7). Diazepam, which potentiates GABA_A receptor activity in response to GABA, decreases dopamine release in the NAC (22), although the diazepam-induced reinforcing properties, which are recognized as the basis of drug addiction, seem to be mediated via the MLDS (15). Unfortunately, we can neither elucidate the meaning of the decrease in dopamine release in the NAC in response to pentobarbital nor explain the mechanism of addiction and psychotropic effects by barbiturates. However, because the neurons that receive the dopaminergic signal in the NAC innervate and interact with final target brain regions related to drug addiction, such as the cortex, hypothalamus, amygdala, and hippocampus (7), barbiturates and benzodiazepines may act directly on those brain regions.

Our data also demonstrated that pentobarbital completely inhibited the increase in ketamine-induced dopamine release. This inhibition may be a mechanism by which barbiturates prevent ketamine emergence reactions. However, if we had used smaller doses of pentobarbital and/or larger doses of ketamine, the ketamine-induced increase in dopamine release in the NAC would not have been completely inhibited by pentobarbital because ketamine dose-dependently increased and pentobarbital dose-dependently decreased dopamine release in the NAC. Conversely, it is noticeable that values for 50 mg/kg of ketamine in Experiment 2 are much higher than those in Experiment 1, and 25 mg/kg of pentobarbital in Experiment 2 seems much more effective than would be expected from Experiment 1. These data may mainly be attributed to the fact that Experiments 1 and 2 were completely independently performed. In addition, in the former case, a previous ip injection of saline or pentobarbital in Experiment 2, which may cause stress and pain, might potentiate the dopamine release induced by the following ketamine injection. In the latter case, in addition to the specific effects of pentobarbital, some general anesthetic effects of both ketamine and pentobarbital, which depress the cerebral metabolism nonspecifically, might affect the dopamine release.

Alternatively, Olney et al. (23) have demonstrated that noncompetitive NMDA receptor antagonists such as PCP, MK-801, and ketamine cause neuronal damage specifically in the posterior cingulate and retrosplenial cortices (PC/RS). They hypothesized that these brain regions might be the regions responsible for the psychotomimetic effects of these drugs and for schizophrenia. They also demonstrated that barbiturates and diazepam inhibited the neuronal damage, probably through activation of GABA_A receptors, and suggested that this might be the mechanism by which diazepam and barbiturates inhibit ketamine emergence reactions (23). We have also reported that ketamine induces marked and specific c-fos expression in the PC/RS (24), and this is inhibited by diazepam, halothane, and propofol (17,25), probably through GABA_A receptor activation. However, there have been no reports investigating the relationship between the MLDS and PC/RS, both of which are considered to be brain regions responsible for the psychotomimetic activity induced by noncompetitive NMDA receptor antagonists and schizophrenia.

In conclusion, we demonstrated that ketamine increased and pentobarbital decreased dopamine release in the NAC in freely moving rats and that pentobarbital completely inhibited the ketamine-induced dopamine release increase. We suggest that the increase in dopamine release in the NAC may be responsible for the psychotomimetic activity and addictive potential of ketamine. The suppression of the ketamine-induced increase in dopamine release in the NAC may be a mechanism by which barbiturates prevent ketamine emergence reactions.

	Acknowledgments

 
Supported, in part, by Grant-in-Aid C-11671529 for Scientific Research from the Japan Society for the Promotion of Science, Tokyo.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999