Stereospecific Effects of Ketamine on Dopamine Efflux and Uptake in The

British Journal of Anaesthesia 82 (4): 603–8 (1999)

Stereospecific effects of ketamine on dopamine efflux and uptake in the rat nucleus accumbens

P. J. Hancock and J. A. Stamford*

Neurotransmission Laboratory, Academic Department of Anaesthesia and Intensive Care, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Alexandra Wing, Royal London Hospital, Whitechapel, London E1 1BB, UK *To whom correspondence should be addressed at: Anaesthetics Unit, Royal London Hospital, Whitechapel, London E1 1BB, UK

In addition to being a general anaesthetic, ketamine is a recognized drug of abuse. Many, if not all, drugs of abuse have been shown to increase dopamine efflux in the nucleus accumbens (NAc). As ketamine is optically active, we examined if its actions on dopamine efflux in the NAc were stereoselective. Slices of rat NAc were superfused with artificial CSF at 32°C. Dopamine efflux was evoked by electrical stimulation (1 or 20 pulses, 100 Hz) and measured using fast cyclic voltammetry. (Ϯ)-Ketamine 100 µmol litre–1 increased dopamine efflux (to SEM Ͻ 1 mean 174 ( 17)% of control, P 0.05) and slowed dopamine uptake half-time (T2)to164 (17)% of control, as did (ϩ)-ketamine 100 µmol litre–1 (efflux 236 (16)% (PϽ0.001); uptake 1 Ͻ ϩ T2 177 (25)% (P 0.05)). The (–)-isomer was inactive. The effect of ( )-ketamine on dopamine efflux did not correlate with its action on dopamine uptake. (ϩ)-Ketamine increased dopamine efflux on single pulse stimulation but to a lesser extent than on 20 pulse trains (PϽ0.05). (ϩ)-Ketamine was unable to block the inhibitory effect of quinpirole on single pulse dopamine efflux. Neither MK 801 10 µmol litre–1 nor metoclopramide 1 µmol litre–1 had any effect on dopamine release after short train stimuli (20 pulses, 100 Hz). We conclude that the (ϩ)-isomer is the active form of ketamine and increases NAc dopamine efflux not by block of dopamine uptake, autoreceptors or NMDA receptors, but by mobilization of the dopamine storage pool to releasable sites. Br J Anaesth 1999; 82: 603–8 Keywords: anaesthetics i.v., ketamine; rat; dopamine; stereoisomers Accepted for publication: November 11, 1998

Ketamine (2-o-chlorophenenyl-2-methylaminocyclohex- allowed to recover from ketamine anaesthesia in quiet anone hydrochloride) is a rapid-acting dissociative general darkened rooms to reduce stimulation.3 anaesthetic, first used in anaesthesia more than 30 yr ago.1 Ironically, the very properties that restrict its clinical use Current clinical indications for ketamine include shocked have made ketamine an increasingly popular drug of abuse, patients, children and geriatrics,2 who reportedly find it less to the extent that it is often erroneously sold as ‘Ecstasy’.10 distressing.3 Ketamine induction is particularly recom- Its use is particularly prevalent at ‘rave’ parties and night- mended for anaesthesia in patients with asthmatic disorders clubs.11 Indeed, ketamine has been reported to induce or for repeated anaesthesia, such as in burns patients, stereotyped behaviour,8 a common feature of many amphet- where postoperative respiratory depression is undesirable.4 amine-type psychomotor stimulants.12 Ketamine increases pain tolerance thresholds5 and has been Many, if not all, drugs of abuse are thought to increase shown to preserve laryngeal and pharyngeal reflexes.6 These limbic dopamine release.12–14 In the light of its abuse actions have contributed to it becoming the agent of choice potential and capacity to induce stereotypies, it is possible for the extrication and transport of trauma patients.2 that ketamine acts through dopaminergic mechanisms in Despite many otherwise attractive features, the capacity the limbic system to induce hallucinations. Indeed, sub- of ketamine to induce hallucinations, often manifested as anaesthetic doses of ketamine have also been shown to an ‘emergence reaction’, remains an overwhelming clinical precipitate psychoses in schizophrenics.15 drawback.78 These are related directly to the plasma The interactions of ketamine with the brain dopamine concentration of the drug.9 The frequency and intensity of systems are complex and, in some cases, contradictory. For these hallucinatory episodes is such that patients are often instance, ketamine seems not to modulate nigrostriatal

© British Journal of Anaesthesia Hancock and Stamford dopamine function: nigral dopamine cell firing is un- Detection of dopamine efflux and uptake 16 affected and dopamine turnover in the striatum is either Dopamine efflux and uptake were measured at carbon fibre 17 10 unchanged or decreased by ketamine. Conversely, keta- (7 µm in diameter) microelectrodes.25 The protruding carbon mine has been shown to increase the firing rate of ventral fibre was cut to a length of approximately 50–70 µm. The tegmental dopamine neurones16 and induces hyper-locomo- auxiliary electrode was a stainless-steel wire while the tion in mice.18 Both actions suggest that ketamine causes reference electrode was a standard silver–silver chloride an increase in mesolimbic dopamine ‘tone’, consistent with disc (Clark Electromedical). The reference and auxiliary its acknowledged abuse potential. electrodes were placed conveniently in the chamber (sub- Ketamine is a mixture of two optical isomers.19 Although merged in aCSF), approximately 1 cm away from the tissue. the S(ϩ)-isomer is the more potent general anaesthetic,20 The working electrode was positioned in the core of the the R(–)-isomer is, for instance, a more effective antagonist NAc, close to the anterior commissure, while the stimulating of acetylcholine-induced airway smooth muscle contrac- electrode was placed approximately 200 µm away from the tion,21 suggesting that the pharmacological profile of the working electrodes in such an orientation that its tips were two isomers may differ.22 equi-distant from the working electrode tip. 26 Although ketamine causes hallucinations and is a drug Dopamine was detected using fast cyclic voltammetry. of abuse, there is a possibility (as ketamine is essentially a Input to the potentiostat consisted of 1.5 cycles of a mixture of two different drugs) that these properties may triangular waveform (–1.0 to ϩ1.4 V vs silver–silver chloride, scan rate of 480 V s–1) with an initial cathodic not be shared equally by the different isomers. The objective scan direction. This waveform was applied to the potentio- of our study was to examine the effects of ketamine on stat twice per second, with the working electrode discon- mesolimbic dopamine release and to determine the relative nected between scans. Current output and voltage input of potency of the two isomers. the working electrode were displayed on a digital storage oscilloscope (Nicolet 310 DD). Digital subtraction of back- Materials and methods ground current signals, before stimulation, from those obtained in response to a stimulus left the faradic current All experiments were carried out on slices of the rat nucleus peak, resulting from oxidation of dopamine. accumbens (NAc). Dopamine efflux was elicited by local A peak sampling circuit was set to monitor current at electrical stimulation at tungsten microelectrodes and meas- the oxidation potential for dopamine (ϩ600 mV vs silver– ured using fast cyclic voltammetry at carbon fibre microelec- silver chloride). Peak sampled output was displayed on a trode sensors implanted in the slice adjacent to the chart recorder and captured on floppy disk via the digital stimulating electrode. storage oscilloscope, from which all measurements of peak

1 dopamine efflux and uptake half-time (T2) were obtained. Brain slices Drugs and chemicals Slices of NAc were prepared according to the basic method The following drugs and chemicals were obtained from the 23 of Palij and colleagues. In brief, male Wistar rats (150– sources stated: ketamine hydrochloride (Sigma), S(ϩ)- and 200 g) were killed by cervical dislocation and their brains R(–)-ketamine (Parke-Davis), metoclopramide hydro- removed and placed in a bath of ice-cold artificial cerebro- chloride (SmithKline Beecham), MK801 (Tocris Cookson), spinal fluid (aCSF). A block (approximately AP: ϩ11.0 to quinpirole (Eli Lilly) and dopamine hydrochloride (Sigma). ϩ6.0 mm vs the interaural line24) was cut and sequential Stock solutions were prepared in distilled water (or HCl slices of 350 µm were obtained using a vibrotome to acquire 0.1 mol litre–1 for dopamine) and kept frozen until the day the desired rostrocaudal section. The NAc slices were of use. transferred to a holding chamber of aCSF at room temper- Artificial CSF was composed of (mmol litre–1): NaCl . ature for at least 1 h to recover from sectioning. Slices 124, KCl 2.0, KH2PO4 1.25, MgSO4 7H2O 2.0, NaHCO3 were then transferred to the recording chamber and 25, CaCl2 2.0 and (ϩ)-glucose 11. The solution was gassed superfused with aCSF at 32°C throughout the experiment. at 32°C with 95% oxygen–5% carbon dioxide before use. An equilibration time of 30 min before the first stimulation Statistical analysis was used. All group results are expressed as mean (SEM). Groups were compared by one-way analysis of variance (ANOVA) using Electrical stimulation the Student–Newman–Keuls post hoc test (Graphpad Instat Dopamine efflux was evoked by constant current pulses v3.00). Where only two groups were compared, Student’s (0.1 ms, 10 mA) across a bipolar tungsten stimulating t test was used. electrode (A-M Systems, Seattle; 300–400 µm tip separa- tion). Stimulations consisting of either a single pulse or Results trains (20 pulses, 100 Hz) were applied at constant intervals Electrical stimulation in brain slices of the NAc caused (5 min for single pulses, 10 min for trains) throughout. dopamine release that was readily detectable by voltam-

604 Ketamine increases limbic dopamine release

Fig 2 Stereoselective effects of ketamine on dopamine efflux and uptake in the nucleus accumbens. Effects of racemic ketamine 100 µmol litre–1 and its (ϩ)- and (–)-isomers on electrically stimulated (20 pulses, 100 Hz, 0.1 ms) dopamine efflux (A) and uptake T1 (B) in rat nucleus accumbens slices. Data 2 are expressed as percentage of pre-drug controls (mean (SEM), nϭ5). *PϽ0.05, ***PϽ0.001 vs control, ††PϽ0.01, †††PϽ0.001 vs (ϩ)-ketamine Fig 1 Effect of racemic ketamine on dopamine (DA) efflux and uptake in (one-way ANOVA with post hoc Student–Newman–Keuls test). the nucleus accumbens. A: Representative peak sample records of dopamine efflux after local electrical stimulation (20 pulses, 100 Hz, 0.1 ms, 10 mA) –1 in control slices (bottom trace) and in the presence of (Ϯ)-ketamine A concentration of 100 µmol litre was used for all 100 µmol litre–1 (top trace). Each trace shows the time course of dopamine subsequent experiments on ketamine and its isomers. efflux after stimulation at the point marked by the arrow. There is a sharp The effect of ketamine on dopamine efflux and uptake increase in extracellular dopamine concentration, reaching a maximum was stereoselective (Fig. 2). Both (ϩ)-ketamine (PϽ0.001) within 1 s and then decreasing to baseline through dopamine uptake. Note that (Ϯ)-ketamine increases dopamine efflux and slows the rate of and the racemate (PϽ0.05) increased dopamine efflux after dopamine removal. B: Concentration dependency of the effect of a stimulation train (20 pulses, 0.1 ms, 100 Hz). (–)-Ketamine (Ϯ)-ketamine on dopamine efflux. Values are percentage of pre-drug had no effect. Furthermore, the effect of (–)-ketamine on values (mean (SEM), nϭ5). *PϽ0.05, ***PϽ0.001 vs control group dopamine efflux was significantly greater (PϽ0.01) than (Student’s t test). that of the racemate. Both (ϩ)-ketamine and the racemate

1 increased dopamine uptake T2 (both PϽ0.05). (–)-Ketamine metry. This dopamine efflux was followed by removal of had no effect. dopamine from the extracellular space by uptake. In controls, The effects of ketamine on dopamine efflux were not the –1 peak dopamine efflux was mean 279 (SEM 56) nmol litre result of block of NMDA receptors or dopamine D2-type 1 µ and uptake T2 was 1.85 (0.22) s (nϭ14) after a stimulation autoreceptors. The NMDA antagonist MK 801 (10 mol –1 train (20 pulses, 0.1 ms, 100 Hz). litre ) and the dopamine D2-type antagonist metoclopra- Figure 1A shows a typical peak sample trace of dopamine mide (1 µmol litre–1) had no effect on dopamine efflux or efflux and uptake in a control NAc slice and after exposure to uptake on stimulation (20 pulses, 100 Hz, 0.1 ms). Table 1 (Ϯ)-ketamine 100 µmol litre–1. Racemic ketamine increased shows the group data. dopamine release and slowed the rate of dopamine uptake. (ϩ)-Ketamine had no effect on dopamine D2-type auto- The effect of (Ϯ)-ketamine on dopamine efflux was concen- receptors in the NAc. The dopamine D2-type agonist quin- tration-dependent (Fig. 1B). While (Ϯ)-ketamine 1 and pirole 1 µmol litre–1 almost abolished dopamine efflux 10 µmol litre–1 did not exert significant actions, 100 µmol (PϽ0.001) after single pulse stimulation (Fig. 3). This –1 litre doubled dopamine efflux (PϽ0.05). At a still higher effect was largely reversed (PϽ0.001) by the D2-type concentration (1 mmol litre–1), (Ϯ)-ketamine significantly antagonist metoclopramide 1 µmol litre–1 but not by reduced stimulated dopamine efflux (PϽ0.001). This effect (ϩ)-ketamine 100 µmol litre–1. was reversible by reperfusion with aCSF (data not shown). (ϩ)-Ketamine also increased dopamine efflux (PϽ0.05)

605 Hancock and Stamford

Table 1 MK 801 or metoclopramide did not affect dopamine (DA) efflux or uptake on stimulation (20 pulses, 100 Hz, 0.1 ms). All values are mean (SEM) of n observations

MK 801 Metoclopramide Control 10 µmol litre–1 1 µmol litre–1

Peak DA efflux 110.5 (3.0 102.9 (5.1) 111.7 (4.7) (% of pre-drug) DA uptake T1 102.4 (6.2) 108.0 (4.0) 93.6 (5.9) 2 (% of pre-drug) n 95 4

Fig 5 Comparison of the effects of (ϩ)-ketamine on limbic dopamine efflux and uptake. Plot of the effect of (ϩ)-ketamine on electrically stimulated (20 pulses, 100 Hz, 0.1 ms) dopamine efflux (y axis) against its effect on dopamine uptake T1 (x axis) in rat nucleus accumbens slices. 2 The unbroken line shows the best fit linear plot while the broken line is the line of equivalent effect.

Figure 5 shows individual experiments in which the effect of (ϩ)-ketamine 100 µmol litre–1 on peak dopamine

1 efflux and uptake T2 were compared after train stimulations (20 pulses, 100 Hz, 0.1 ms). There was no correlation between the ability of (ϩ)-ketamine to increase dopamine Fig 3 (ϩ)-Ketamine did not block dopamine autoreceptors in the nucleus accumbens. Effects of quinpirole 1 µmol litre–1 on electrically stimulated efflux and block dopamine uptake. dopamine release (1 pulse, 100 Hz, 0.1 ms) in the rat nucleus accumbens slices, given alone and in the presence of (i.t.p.o.) (ϩ)-ketamine Discussion 100 µmol litre–1 or metoclopramide 1 µmol litre–1. Dopamine efflux is expressed as percentage of pre-drug values (mean (SEM), n ϭ5). Despite many valuable properties, the use of ketamine has ***PϽ0.001 vs control; †††PϽ0.001 vs quinpirole (one-way ANOVA been limited by the extent and variety of its side effects. with post hoc Student–Newman–Keuls test). Perhaps the most disturbing are the ‘emergence phenomena’ which include visual and auditory hallucinations. Most commonly, the patient is allowed to recover in a quiet and often darkened room with minimal sensory stimulation. Parallels have repeatedly been drawn between the hallu- cinogenic properties of ketamine and other drugs of abuse, such as the amphetamines. As amphetamines increase limbic dopamine release, one might speculate that ketamine psychoses may also involve the limbic dopamine systems. From our study, it is clear that ketamine has concentration- dependent actions on dopamine efflux and uptake in the NAc. At 100 µmol litre–1, ketamine increased dopamine efflux while it was decreased at 1 mmol litre–1. It has been shown that ketamine blocks sodium channels at high Fig 4 Effects of (ϩ)-ketamine on limbic dopamine efflux and uptake after (mmol litre–1) concentrations27 and this effect may explain µ –1 single pulse stimulation. Effects of (ϩ)-ketamine 100 mol litre on attenuation of dopamine efflux seen here. Indeed, ketamine electrically stimulated (1 pulse, 100 Hz, 0.1 ms) dopamine efflux and uptake T1 in rat nucleus accumbens slices. Data are expressed as percentage has been shown to inhibit most voltage-operated ion chan- 2 28 of pre-drug controls (mean (SEM), nϭ5). *PϽ0.05, **PϽ0.01 vs control nels at these concentrations. However, the reduction in (Student’s t test). dopamine release by the higher concentration is unlikely to be clinically meaningful as previous studies by Livingston and blocked dopamine uptake (PϽ0.01) on single pulse and Waterman29 have shown that rat brain concentra- stimulation (Fig. 4). The effect on dopamine efflux was tions of ketamine during anaesthesia are approximately significantly smaller on single pulse than on train stimula- 100 µmol litre–1 and thus in all subsequent experiments tions (PϽ0.05). we used this concentration. Nevertheless, it is worth

606 Ketamine increases limbic dopamine release remembering that ketamine concentrations in the rat brain 1 µmol litre–1 did not increase dopamine release on 20 pulse can peak as high as 400 µmol litre–1 immediately after stimulation trains (see Table 1), although it blocked the effect induction30 while plasma concentrations are several-fold of the autoreceptor agonist quinpirole (Fig. 3). Metoclopra- lower. Thus a concentration of 100 µmol litre–1 in the aCSF mide can block endogenous autoreceptor activation when the may translate to a higher tissue concentration. stimulus parameters are appropriate.43 Second, (ϩ)-ketamine The effect of ketamine on dopamine efflux and uptake is did not block the effect of quinpirole on dopamine efflux strikingly stereoselective. Data in Figure 2 show clearly that (Fig. 3). Finally, when single pulse stimulations were used, (ϩ)-ketamine is the active form with (–)-ketamine having no (ϩ)-ketamine increased dopamine efflux (Fig. 4) although effect at 100 µmol litre–1. Several studies have shown that under these conditions there is no endogenous autoreceptor ketamine can, under certain conditions, increase limbic dopa- tone to antagonize. mine release in vivo. For example, Lindefors, Barati and The effect of (ϩ)-ketamine on efflux was not caused dir- O’Connor31 showed that ketamine increased dopamine ectly by uptake block. Normally, pure uptake blockers, such release in the prefrontal cortex five-fold, while others have as GBR 12909, increase dopamine efflux equally after single shown increased formation of DOPAC and HVA in the pulse and 20 pulse stimulations.36 Conversely, those drugs nucleus accumbens,16 suggesting enhanced turnover. that mobilize the dopamine storage pool (such as nomifensine Furthermore, ketamine also blocks dopamine uptake in brain and amfonelic acid) increase dopamine efflux to an approxi- slices (Fig. 2B) consistent with previous reports on synapto- mately two-fold greater extent on trains than on single pulse somes32–34 The effects are stereoselective, and are exhibited stimuli.36 (ϩ)-Ketamine had an approximate two-fold larger only by (ϩ)-ketamine and the racemate. effect (PϽ0.05) on dopamine release when trains were used One might conclude that the effects of ketamine on dopa- (Fig. 2A) as opposed to single pulse stimuli (Fig. 4). Thus mine efflux could be explained by action on dopamine uptake. it is likely that ketamine has the capacity to mobilize the We have shown previously that several recognized dopamine dopamine storage pool. This action is independent of uptake

1 uptake blockers increase both dopamine uptake T2 and dopa- block and has been shown to apply to several of the non- mine efflux.83536For those uptake blockers devoid of direct amphetamine class psychomotor stimulants, such as releasing actions, the effects on one measure correlate well amfonelic acid and methylphenidate.44 It is thought that these with those on the other. However, this was not the case with drugs act to transfer or ‘mobilize’ the normally inert neuronal ketamine. Figure 5 shows that there was no direct relationship storage pool of dopamine to the ‘newly synthesized’ pool between the ability of (ϩ)-ketamine to increase dopamine where it is then available for neurogenic, impulse-dependent efflux and block dopamine uptake and that, in general, greater release.45 effects were observed on dopamine efflux than uptake. It In summary, we have shown that ketamine increased dopa- would appear that the ability to increase dopamine efflux is a mine release in the NAc at clinical concentrations. The effect parallel property independent of dopamine uptake block. was stereospecific, being largely (if not wholly) a result of Ketamine is known to block NMDA receptors37 38 with the (ϩ)-isomer. (ϩ)-Ketamine also blocked dopamine the (ϩ)-isomer being the more potent enantiomer. We have uptake. The ability of (ϩ)-ketamine to increase dopamine shownpreviouslythatNMDAreceptor block(byCGS19755) efflux was not the result of uptake block or NMDA receptor increases striatal dopamine efflux on 20 pulse stimulation antagonism. Furthermore, (ϩ)-ketamine did not block dopa- trains39 and thus the effect of ketamine on dopamine release mine autoreceptors. The effects of (ϩ)-ketamine on dopa- could potentially be caused by NMDA receptor block. How- mine efflux were consistent with mobilization of the ever, the potent NMDA antagonist MK 801 (10 µmol litre–1) dopamine storage pool to releasable sites, thus increasing had no effect on stimulated NAc dopamine efflux (Table 1), impulse-dependent efflux. In human studies, (ϩ)-ketamine although this concentration has been shown to modulate isch- is 2–4 times more potent as an anaesthetic.46 If the ability to aemia-induced striatal dopamine release.40 This strongly sug- increase limbic dopamine release causes hallucinations, it gests that NMDA receptors do not modulate limbic dopamine may not be possible to separate this from its anaesthetic efflux under these experimental conditions and thus that the effects. observed action of ketamine on limbic dopamine efflux can- not be explained by its known action at NMDA receptors. References This is supported further by data in the literature which shows 1 Miyasaka M, Domino EF. Neural mechanisms of ketamine-induced that, although there is a strong dopaminergic–glutamatergic anesthesia. Int J Neuropharmacol 1968; 7: 557–73 link in the action of the amphetamine-type stimulants, NMDA 2 Smith SE. Intravenous anaesthesia. In: Churchill-Davidson HC, ed. antagonists typically attenuate the expression of psycho- Wylie and Churchill-Davidson’s Practice of Anaesthesia. London: Lloyd- motor behaviours.41 Luke, 1984; 626–39 As it is known that dopamine release in the NAc is under 3 Yentis SM, Hirsch N, Smith GB. Anaesthesia A-Z: An Encyclopaedia of Principles and Practice. Oxford: Butterworth-Heinemann,1993; autoreceptor control, another possibility is that ketamine 263–4 could increase dopamine efflux by autoreceptor block. Such 4 Adams HA, Werner C. From the racemate to the eutomer: 42 a mechanism has been speculated by others. However, for (S)-ketamine. Renaissance of a substance? Anaesthesist 1997; 46: several reasons, this was not the case. First, metoclopramide 1026–42

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