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Synaptic Physiology Laboratory, Institute of Physiology and Biophysics, University of Aarhus, Aarhus, Denmark
Submitted 22 June 2006; accepted in final form 3 January 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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-aminobutyric acid type A (GABAA) receptors containing 
-subunits. It is important to study the physiology and pharmacology of these extrasynaptic receptors and to determine how THIP interacts with other hypnotics and anesthetics. Here, we study the modulation of the extrasynaptic response to THIP using three classes of GABAA-receptor ligands. In whole cell recordings from mouse neocortical layer 2/3 pyramidal cells, THIP induced an extrasynaptic tonic current of 44 ± 5 pA. The benzodiazepine site agonist and hypnotic zolpidem (500 nM), which displays selectivity for 
1/2/3- and 2-containing receptors, did not alter the tonic current induced by THIP. The anesthetic etomidate (1 µM), which shows selectivity for 
2- and 3-containing GABAA receptors, potentiated the THIP current by 126%. Etomidate also induced a small tonic GABAA current per se. The anesthetic propofol (1 µM), which displays broad-spectrum modulatory effects on several GABAA-receptor subtypes, enhanced the tonic THIP current by 117%. Finally, all three compounds modulated the function of intrasynaptic receptors activated by synaptically released GABA. Our study shows that the extrasynaptic GABAA receptors responsible for the tonic THIP conductance likely do not contain 1-, 2-, 3-, and 2-subunits. Thus the tonic GABAergic conductance in the neocortex is presumably mediated by 42/3 receptors, which are likely to play a major role for neocortical excitability. Furthermore, our study has deepened the knowledge about the cellular actions of THIP as well as THIP's interactions with other hypnotics and anesthetics. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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-aminobutyric acid type A (GABAA) receptors are responsible for fast inhibitory neurotransmission. These pentameric ligand-gated chloride channels are composed of combinations of 
20 different subunits, which control the physiological and pharmacological receptor profile (Wafford and Ebert 2006
). It was recently discovered that distinct subtypes of GABAA receptors are located at unconventional sites outside the synapses, where they give rise to an important extrasynaptic chloride conductance (Semyanov et al. 2004). Such "tonic" GABAA conductances are activated by spillover of synaptically released GABA and are thereby regulated by physiological mechanisms, such as removal of extracellular GABA by GABA transporters (Jensen et al. 2003; Keros and Hablitz 2005).
We recently studied the GABAA agonist THIP, which has the remarkable ability of activating extrasynaptic GABAA receptors in a selective manner (Drasbek and Jensen 2006). THIP (or Gaboxadol) will now enter the U.S. market as a sleep aid, with a pharmacological profile very different from that of traditional sleep drugs such as benzodiazepines (Wafford and Ebert 2006). We earlier found that low concentrations of THIP (from 0.3 µM) enhanced an extrasynaptic tonic GABAA conductance in mouse neocortex in a cell-specific manner, which was related to the cortical expression of GABAA receptor -subunits. Furthermore, miniature inhibitory postsynaptic currents (mIPSCs), which reflect the activation of synaptic GABAA receptors by quantal release of GABA, were not affected by 1 µM THIP supporting an extrasynaptic site of action. Correspondingly, others recently found that THIP activates -containing receptors in the thalamus (Jia et al. 2005) and that THIP induces slow-wave activity by enhancing a tonic GABAA conductance in thalamocortical neurons (Belelli et al. 2005) probably by promoting burst firing (Cope et al. 2005b).
Although THIP activates extrasynaptic GABAA receptors in mouse neocortex, little is known about the regulation and modulation of the THIP response by pharmacological agents. The aims of the present paper were twofold: First we wanted to use allosteric GABAA-receptor modulators with some subunit selectivity to obtain information about the molecular makeup of the extrasynaptic GABAA receptors in the neocortex. Second, we sought to examine how THIP in fact interacts with other hypnotics and anesthetics, which are used clinically. Addressing the last issue would have some important implication for the clinical situation where combinations of THIP and other hypnotics or anesthetics are given. We performed whole cell patch-clamp recordings from layer 2/3 pyramidal neurons in mouse neocortex. Examining three classes of GABAA-receptor modulators, we found that propofol and etomidate, but not zolpidem, potentiated the tonic current induced by THIP. All three modulators affected the synaptic GABAA receptors as the decay of IPSCs was prolonged. Our findings increase the knowledge about GABAA receptors in neocortical layer 2/3 responsible for extrasynaptic tonic currents and their activation and pharmacological modulation.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Animals were kept in a university animal facility with a 12/12-h light/dark cycle and unrestricted access to food and water. Brain slices were prepared as described previously (Drasbek and Jensen 2006). Briefly, postnatal day 14–19 (P14–P19) male C57BL/6 mice were anesthetized using isoflurane in accordance with guidelines of the University of Aarhus and Danish and European legislation regarding laboratory animals. The mice were decapitated and the brains were dissected out and transferred to ice-cold artificial cerebrospinal fluid (ACSF) composed of (in mM): 126 NaCl, 2.5 KCl, 2 CaCl2, 2 MgCl2, 1.25 NaH2PO4, 26 NaCO3, 10 D-glucose (osmolality 305–315 mosmol kg–1), pH 7.4 when bubbled with carbogen (5% CO2-95% O2). To improve the quality of the slices, 3 mM kynurenic acid, 0.2 mM ascobic acid, and 0.2 mM pyruvic acid were added during slicing and storage. Coronal slices (thickness: 350 µm) were cut on a Vibratome 3000 Plus (Vibratome, St. Louis, MO). Slices were allowed to rest for 1 h before recording.
Electrophysiology
Slices were placed in a recording chamber and perfused with 33–34°C bubbled ACSF at 2–3 ml min–1. Patch-clamp recordings in the whole cell mode were carried out using a MultiClamp 700B amplifier (Molecular Devices, Union City, CA). Neurons were visualized by a custom-built infrared microscope (Versascope, E. Marton Electronics, Cacoga Park, CA) equipped with a x40 water-immersion objective (Olympus, Ballerup, Denmark) and a CCD100 camera (DAGE-MTI, Michigan City, IN). Patch pipettes were pulled from borosilicate glass (OD = 1.5 mm, ID = 0.8 mm; Garner Glass, Claremont, CA) on a DMZ Universal Puller (Zeitz Instruments, Munich, Germany). Pipette resistances were 3–5 M
when filled with intracellular solution containing (in mM): 140 CsCl, 2 MgCl2, 0.05 EGTA, 10 HEPES, adjusted to pH 7.2 with CsOH (280–290 mosmol kg–1). Voltage-clamp recordings were carried out at a holding potential (Vhold) of –70 mV. Throughout the experiment, whole cell capacitance and series resistance were noted and resistances were compensated by 70% (lag 10 µs). Recordings were discontinued if series resistance increased by >50% or exceeded 20 M.
To ensure sufficient drug penetration into the brain slices, the GABAA-receptor modulators were included in the slice incubation medium. Although the anesthetic effect of propofol in humans appears very rapidly on intravenous injection (Marik 2004), long incubation times (>60 min) are often necessary for the full effect in rodent brain slices (Gredell et al. 2004). For this reason, we incubated all slices in the drug of interest for 1 h before and during experiments. In the experiments that included THIP, this drug was perfused acutely for 5 min in each experiment.
Data acquisition and analysis
Currents were low-pass filtered (eight-pole Bessel) at 3 kHz, digitized at 20 kHz, and acquired using a BNC-2110 DA converter and a PCI-6014 board (National Instruments, Austin, TX) and custom-written LabVIEW 6.1–based software (EVAN v. 1.4, courtesy of Istvan Mody). Injection of the GABAA-receptor antagonist 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyridazinium bromide (SR95531, >100 µM) into the slice chamber revealed a GABAA-receptor–mediated tonic current as an outward shift in the holding current. Samples (length: 5 ms) were obtained every 100 ms and plotted against time to estimate the tonic current (Fig. 2D). Contamination of the holding current by spontaneous inhibitory postsynaptic currents (sIPSCs) was removed as described by Nusser and Mody (2002). The mean tonic current was calculated in 4-s-long segments at three time points: just before SR95531 injection (denoted b) and 20 s before (a) and after (c) this time point. The tonic current was taken as c – b, whereas the variations in the baseline (b – a) were used to assess the stability of the recording. For presentation in histograms, the tonic currents were normalized to the cell capacitance (pA/pF), although variations in capacitance between pyramidal cells were small (24.0 ± 0.7 pF, n = 49). Custom-written software (EVAN v. 1.4) was used to detect and analyze sIPSCs. Typical amplitude detection thresholds were 7–8 pA. All events were inspected before an average of 50–100 events was made. Event amplitude, 10–90% rise time, and frequency were measured, whereas the IPSC weighted decay-time constant (
w) was calculated using double-exponential fits. Unpaired Student's t-tests were used to compare means with two-tailed P < 0.05 as the significance level. Data are presented as means ± SE, with n indicating the number of neurons. To evaluate the supraadditive effects of etomidate and THIP, the tonic currents and their SD for the two compounds alone were combined and compared with the coapplied drugs by calculating the t-value using unpaired Student's t-test. The P value was obtained by TuesT statistical tables software (T. Tjur, Copenhagen, Denmark).
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In addition to identifying the pyramidal cells under infrared videomicroscopy, we validated this approach using post hoc confocal microscopy. Alexa Fluor 488 (100 µM, Invitrogen, Carlsbad, CA) was included in the patch pipette during whole cell recordings from putative pyramidal cells (n = 9). After removal of the patch pipette, the fresh brain slices were mounted in a Ludin chamber (Life Imaging Services, Reinach, Switzerland) and a z-stack of the neuron was generated using a confocal microscope [Zeiss Laser Scanning Microscope (LSM) 510 META, Göttingen, Germany] using a x20 objective. The Zeiss LSM Image Browser software was used to obtain a transparency projection in the maximum mode of the recorded z-stack. Both green and red channels are shown to visualize Alexa fluorescence and tissue orientation, respectively. Nine of nine neurons examined were pyramidal cells.
Solutions and drugs
Kynurenic acid, ascorbic acid, SR95531, zolpidem, and propofol were obtained from Sigma (St. Louis, MO). Pyruvic acid was purchased from MP Biomedicals (Irvine, CA), whereas etomidate was from Tocris (Bristol, UK). Stock solutions of zolpidem, propofol, and etomidate (1–10 mM) were prepared in DMSO, whereas SR95531 stock (6 mM) was prepared in ACSF containing 50% DMSO. On SR95531 application, the final concentration of DMSO was estimated to 0.8–1.4%. In control experiments, DMSO concentrations as high as 1.8% had no effect on the tonic THIP current (n = 2, not shown).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). This tonic GABAA current was most likely mediated by extrasynaptic receptors and the response to THIP generally correlates with the expression of -subunits (Brown et al. 2002; Drasbek and Jensen 2006; Jia et al. 2005; Shen et al. 2005). To examine the pharmacological modulation of the THIP current, we performed whole cell patch-clamp recordings from layer 2/3 neurons. When filled with the fluorescent dye Alexa Fluor 488 by the patch pipette, these neurons displayed a pyramidal-shaped soma, a spinous apical dendrite projecting toward layer 1, and several basal dendrites projecting toward the deeper cortical layers (Fig. 1). Zolpidem does not affect the THIP-induced GABAA-receptor–mediated tonic current in neocortex
The hypnotic zolpidem is a benzodiazepine receptor agonist and a positive allosteric modulator of GABAA receptors. At the concentration used here, zolpidem preferentially modulates 1-, 2-, and 3-containing receptors and requires the presence of 2-subunits. To test the effect of zolpidem on the tonic THIP current, we used CsCl-filled pipettes (ECl 
0 mV) to record from layer 2/3 neurons. GABAA-receptor–mediated sIPSCs appeared as fast inward currents (Vhold = –70 mV) in the presence of kynurenic acid (3 mM), which blocks ionotropic glutamate receptors (Fig. 2A). Injection of the selective GABAA-receptor agonist SR95531 (>100 µM) into the slice chamber blocked all sIPSCs and revealed any tonic current by shifting the holding current outward (Brickley et al. 2001; Nusser and Mody 2002). In control conditions without drugs added, no tonic current was present (1.2 ± 0.9 pA, n = 4) (Fig. 2, A and C). THIP (1 µM) elicited a robust tonic GABAA-mediated current of 44.4 ± 4.6 pA, n = 8) (Fig. 2, B and D). In the presence of zolpidem (500 nM), the THIP-induced current was not altered (48.8 ± 4.7 pA, n = 10; P = 0.52). This suggests that the GABAA receptors responsible for the tonic THIP current contain little or no 1-, 2-, or 3-subunits (see DISCUSSION). The effects of zolpidem on tonic THIP currents are summarized in Fig. 2F. In the histograms, currents are normalized to the cell capacitance (pA/pF) to correct for minor differences in cell size.
The anesthetic etomidate induces a tonic current per se and potentiates the THIP current
Turning our attention to -subunit–containing GABAA receptors in layer 2/3 neurons, we tested whether the 2/3-subunit preferring GABAA modulator etomidate affected the tonic THIP conductance. First, etomidate (1 µM) per se induced a tonic current of 32.5 ± 3.4 pA (n = 4) (Fig. 3A). Etomidate (1 µM) in combination with THIP (1 µM) induced a tonic current of 100.2 ± 5.3 pA (n = 8) (Fig. 3C), which is 30% larger than the sum of the individual etomidate and THIP currents alone (32.5 and 44.4 pA, respectively). When its concentration was lowered to 0.3 µM, etomidate lacked a positive modulatory effect on the THIP current (58.4 ± 8.8 pA, n = 6, P = 0.16; data not shown). Thus etomidate induces a tonic current per se and positively modulates the extrasynaptic THIP conductance in the mouse neocortex.
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Compared with the two allosteric modulators above, the general anesthetic propofol has greater broad-spectrum modulatory effects on GABAA-receptor subtypes (Franks 2006). As opposed to etomidate, propofol (1 µM) did not elicit any tonic current per se in layer 2/3 neurons (1.9 ± 1.4 pA, n = 3) (Fig. 4A). However, propofol strongly potentiated the tonic THIP current to 96.2 ± 15.4 pA (by 117%, n = 7) (Fig. 4C). Increasing the concentration of propofol to 10 µM, which is within a clinically relevant range (Bieda and MacIver 2004), dramatically increased the tonic GABAA current when THIP (1 µM) and propofol (10 µM) were coapplied (356.8 ± 55.5 pA, by 51%, n = 3, not shown). However, this higher concentration of propofol also showed a GABA-mimetic effect inducing a tonic current of 236.0 ± 47.1 pA (n = 5). Overall, this shows that low concentrations of propofol can potentiate the tonic GABAA-receptor–mediated conductance in neocortex without exerting a GABA-mimetic effect.
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Finally, the effects of THIP and of the allosteric modulators on sIPSCs were analyzed (Fig. 5). THIP (1 µM, n = 9) alone depressed the amplitude and frequency of sIPSCs with little or no effects on kinetics. Zolpidem (500 nM, n = 11) prolonged the weighted decay-time constant of the average sIPSC by 28%, whereas 0.3 µM etomidate (n = 6) prolonged the decay by 92% and 1 µM etomidate (n = 9) by 235%. In addition, propofol (1 µM, n = 6) prolonged the decay by 87%. The effects on sIPSCs are summarized in Table 1. For zolpidem and propofol, these findings are in accordance with earlier studies of neocortical neurons (Hájos et al. 2000; Kitamura et al. 2003). For etomidate, however, to our knowledge its effects on IPSCs in the neocortex were not previously determined. Therefore we went on to assess the effect of etomidate on miniature IPSCs (mIPSCs) reflecting the quantal release of GABA onto intrasynaptic receptors (Table 2). In layer 2/3 neurons, etomidate (1 µM) did not alter the mean mIPSC frequency, 10–90% rise time, or peak amplitude. However, the weighted decay-time constant was prolonged from 6.4 ± 0.8 ms in control to 10.2 ± 1.2 ms by etomidate (by 60%, P = 0.02, n = 5). This shows that only the decay phase of quantal GABAA-receptor–mediated events is altered by etomidate in the neocortex.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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-subunit–preferring agonist THIP as a tool to enhance a "tonic" GABAA-mediated conductance. We found that these receptors are modulated by the anesthetics etomidate and propofol, but not by the hypnotic benzodiazepine agonist zolpidem. On the other hand, all three modulators modulated synaptic GABAA receptors mediating "phasic" GABAergic transmission. This illustrates how the novel sleep aid THIP (Gaboxadol) interacts with the hypnotic zolpidem and the intravenous anesthetics etomidate and propofol. Our study clearly shows that also in the neocortex distinct subtypes of GABAA receptors are expressed at extrasynaptic versus synaptic sites. The most likely receptors to underlie tonic inhibition in neocortex are 42/3 subunit combinations. These channels are probably located extrasynaptically or perisynaptically, although electron microscopy studies are needed to confirm this. THIP conductances in mouse neocortex mediated by extrasynaptic GABAA receptors
Because -subunits typically incorporate in receptors located away from the synapse (Nusser et al. 1998), we and others used THIP as a tool to activate an extrasynaptic tonic conductance in several brain regions (Drasbek and Jensen 2006; Liang et al. 2004; Maguire et al. 2005). This tonic conductance is correlated to the differential expression of -subunits in various brain areas (Belelli et al. 2005; Cope et al. 2005b; Jia et al. 2005). In neocortex, tonic inhibition was explored by only a few groups so far (Keros and Hablitz 2005), although it is hypothesized to play important roles for phenomena such as shaping binocular vision (Iwai et al. 2005), the response to sedatives and anesthetics (Bieda and MacIver 2004), and the development and maintenance of epileptic states (Peng et al. 2004). Therefore we found it was important to examine the pharmacological modulation of the THIP-enhanced extrasynaptic conductances in the neocortex.
Zolpidem is a modulator of synaptic, but not tonic, GABAA-receptor currents in neocortex
Zolpidem is a hypnotic that potentiates GABAA receptors by the benzodiazepine site located between the - and -subunits. Binding of benzodiazepines leads to an increase in GABAA channel opening frequency (Perrais and Ropert 1999), which at synapses prolongs the decay of IPSCs. Synaptic receptors are prototypically composed of 1/2/3/52 receptors (Essrich et al. 1998; Sieghart and Sperk 2002). When 1-subunits are knocked out in mice or 2-subunits are point mutated, the cellular actions of zolpidem are reduced or abolished (Cope et al. 2004, 2005a; Kralic et al. 2002).
At the concentration of zolpidem used in our study (500 nM), the drug has specificity for 1-, 2-, and 3-containing GABAA receptors (Sanna et al. 2002). Therefore we deduce that the receptors underlying the tonic current in this study probably do not contain 1-, 2-, and 3-subunits. They are also unlikely to contain -subunits because these subunits are normally associated with benzodiazepine actions. Based on these experiments, we conclude that THIP and zolpidem do not interact, corroborating in vivo studies where the two compounds were used in combination (Voss et al. 2003). Also, based on studies with expressed receptors, the most likely candidate receptor composition responsible for the tonic current is 4 receptors, at which THIP at low concentrations is a quite selective agonist with a high relative efficacy and high potency (Brown et al. 2002).
Etomidate as a GABA-mimetic compound and positive GABAA-receptor modulator
The fast-acting general anesthetic etomidate directly activates as well as potentiates GABAA receptors. The most remarkable property of etomidate is its preference for the 2- and 3-subunits in vitro (Belelli et al. 1997), which has also been linked to its anesthetic effects in vivo. Although 2-subunits are thought to be responsible for the sedative and hypothermic effects, 3-subunits confer the anesthetic and immobilizing effects (Jurd et al. 2003; O'Meara et al. 2004; Reynolds et al. 2003). In mouse neocortex, we found that etomidate potentiated the tonic current induced by THIP, indicating that the receptors contain 2- or 3-subunits. Although 1 µM propofol and 1 µM etomidate similarly potentiated the tonic THIP conductance, their mechanisms of action appeared to differ. The enlarged response to coapplication of etomidate and THIP would be a summation of the GABA-mimetic and GABAA-receptor modulatory effects of etomidate. For the latter effect, etomidate could in fact have potentiated the response to the minute concentrations of GABA in the slice. In the well-perfused slice with intact GABA uptake (Jensen et al. 2003), GABA concentrations are rather low and were estimated to be around 160 nM (Santhakumar et al. 2006). This GABA concentration in combination with etomidate could contribute to the tonic current.
Finally, etomidate prolonged the decay of sIPSCs and mIPSCs in neocortex, indicating that this substance modulated synaptic GABAA receptors (Tables 1 and 2). The prolongation of mIPSC is similar to that found recently in cultured hippocampal pyramidal neurons (Cheng et al. 2006). Also, etomidate depressed the sIPSC amplitudes and frequencies, suggesting that the firing of presynaptic interneurons was reduced. In fact, etomidate brought the sIPSC frequency and amplitude toward the level of IPSCs recorded in tetrodotoxin (TTX, Table 2). The possible depression of presynaptic interneuronal firing could be caused by a potentiation of both phasic and tonic inhibitions on interneurons. Altogether, this shows that etomidate modulates both synaptic and extrasynaptic GABAA receptors in layer 2/3 neocortex.
Propofol as a positive modulator of GABAA-receptor–mediated currents
Propofol, the final compound tested in the neocortex, is also a positive modulator at GABAA receptors, which is a major component of its general anesthetic effect (Franks 2006). At low micromolar concentrations propofol potentiates the response to GABAA agonists, whereas at higher concentrations propofol displays a GABA-mimetic effect (Hales and Lambert 1991; Sanna et al. 1995). The actions of propofol appear to occur at a variety of GABAA-receptor subtypes (Krasowski et al. 1997) and, as opposed to etomidate, propofol does not discriminate much between -subunits (Franks 2006). Propofol equally well potentiates -containing (43) and -containing (432) receptors (Brown et al. 2002). In neocortex, we found that propofol strongly potentiated the tonic THIP current in pyramidal cells, in accordance with its known positive effects on receptors (Brown et al. 2002). In addition, propofol prolonged the decay of IPSCs, confirming that propofol also modulates synaptic GABAA receptors likely to contain -subunits. Thus propofol exerts multiple effects on both synaptic and extrasynaptic GABAA receptors, which may underlie its powerful anesthetic effects in vivo. A recent study in hippocampal CA1 interneurons showed that propofol induced a tonic GABAA-mediated conductance able to suppress burst activity (Bieda and MacIver 2004). We have now shown that concentrations as low as 1 µM propofol, when incubated in slices for 1 h, strongly potentiate a tonic conductance in neocortex. Our study adds to the growing literature concerning the enhancement of a tonic GABAA-mediated conductance by propofol in many distinct brain regions. It also shows that THIP and propofol in combination will induce a strongly augmented tonic conductance, which could be used therapeutically in the future.
Clinical perspectives
THIP will soon enter the market for the treatment of insomnia under the commercial name Gaboxadol (Wafford and Ebert 2006). From a clinical perspective, our present study has revealed new mechanistic features of THIP actions in neocortex and strengthens the general hypothesis that THIP acts on extrasynaptic GABAA receptors. The neocortex is believed to participate in corticothalamocortical loops relevant for normal sleep physiology (Steriade 2005). Although the actions of THIP in the thalamus were also recently scrutinized (Belelli et al. 2005; Cope et al. 2005b; Jia et al. 2005), our study nonetheless offers insight with respect to the effects of THIP in neocortex, which may be linked to its sleep-promoting effects. Finally, we have demonstrated how THIP interacts with other hypnotics such as zolpidem and the anesthetics etomidate and propofol. This knowledge is central to understand the clinical effect of THIP when used in combination with other GABAergic drugs therapeutically, experimentally, or accidentally.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. Jensen, Institute of Physiology and Biophysics, Building 1160, Room 116, Faculty of Health Sciences, University of Aarhus, DK-8000 Aarhus C, Denmark (E-mail: kimmo{at}fi.au.dk)
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REFERENCES |
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