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Meeting Abstracts  |   August 2005
Propofol Inhibits Long-term Potentiation but Not Long-term Depression in Rat Hippocampal Slices
Author Affiliations & Notes
  • Kimimoto Nagashima, M.D.
    *
  • Charles F. Zorumski, M.D.
  • Yukitoshi Izumi, M.D. Ph.D.
  • * Visiting Research Associate, Department of Psychiatry, Washington University School of Medicine. Instructor, Department of Anesthesiology Asahikawa University School of Medicine, Asahikawa, Japan.† Professor,‡ Associate Professor, Department of Psychiatry, Washington University School of Medicine.
Article Information
Meeting Abstracts   |   August 2005
Propofol Inhibits Long-term Potentiation but Not Long-term Depression in Rat Hippocampal Slices
Anesthesiology 8 2005, Vol.103, 318-326. doi:
Anesthesiology 8 2005, Vol.103, 318-326. doi:
AMNESIA, analgesia, and hypnosis are important properties of agents used for general anesthesia. The goal of anesthetic amnesia is to prevent painful memories from developing during medical or surgical procedures. Under certain circumstances, however, patients may retain memories of events occurring during invasive procedures, a phenomenon known as awareness during anesthesia  . Patients who experience awareness during anesthesia may have recurring nightmares of events experienced during anesthesia, resulting in insomnia, anxiety, and even suicidal thoughts.1 Therefore, amnesia for the procedure is a key feature of effective anesthesia.
Propofol (2,6-diisopropylphenol) has proven to be a highly effective intravenous anesthetic with rapid onset and short recovery time after injection. Because of these advantages, propofol is now widely used both for general anesthesia and for sedation with local anesthesia.2,3 Propofol is also useful for sedation in intensive care units.4 
Like other anesthetics, propofol has amnesic effects.5 Although suppression of memory function can persist for several hours after propofol administration,6 the amnesic effects of propofol do not seem to be particularly strong with inhibition of explicit memory being weaker than that observed with midazolam.7 In animal studies using a Morris water maze, rats did not show inhibition of memory tasks immediately after recovery from propofol administration.8 
To improve anesthetic amnesia in clinical situations, it is important to understand how various anesthetics alter memory processing. Although the mechanisms involved in memory are complex, it is believed that persistent changes in synaptic function contribute to memory formation. Long-term potentiation (LTP) of synaptic transmission is one model for cellular processes thought to contribute to memory and learning, and understanding how pharmacologic treatments affect LTP can be useful for assessing mechanisms by which these agents disrupt memory.9 It has been reported previously that propofol inhibits the maintenance but not the induction of LTP in vivo  .10 Effects on LTP in ex vivo  preparations, however, have not yet been studied. LTP studies in hippocampal slices offer the opportunity to examine potential mechanisms contributing to propofol-induced amnesia under a high degree of experimental control. Using rat hippocampal slices, we studied the effects of propofol on several forms of long-term synaptic plasticity, including N  -methyl-d-aspartate (NMDA) receptor–dependent forms of LTP and long-term depression (LTD) as well as a form of LTP not involving NMDA receptors.
Materials and Methods
Hippocampal Slice Preparation
Hippocampal slices were prepared from 30-day-old male Sprague-Dawley rats. Rats were decapitated under deep halothane anesthesia. The hippocampus was quickly dissected into gassed (95% oxygen–5% carbon dioxide) artificial cerebrospinal fluid containing 124 mm NaCl, 5 mm KCl, 1.25 mm NaH2PO4, 2 mm MgSO4, 22 mm NaHCO3, 10 mm glucose, and 2 mm CaCl2at 4°–6°C. Transverse slices (500 μm thick) were cut with a vibrotome (WPI, Sarasota, FL). After recovering for at least 1 h at 30°C in an incubation chamber, each slice was submerged in a constant-flow (2 ml/min) recording chamber and maintained at 30°C during the course of an experiment. Procedures for animal studies were approved by the Animal Care and Use Committee at Washington University School of Medicine (St. Louis, Missouri).
Extracellular Recordings
Extracellular recordings were obtained from the apical dendritic layer of the CA1 region using 5- to 10-MΩ glass electrodes filled with 1 m NaCl. Evoked synaptic responses were elicited with 0.1- to 0.2-ms constant current pulses through a bipolar electrode placed in the Schaffer collateral pathway. Stimuli, 50 μs in duration, were applied every minute. In all experiments, baseline synaptic transmission was monitored for 20 min before drug administration or delivery of tetanic stimulation. The stimulus intensity was set to evoke 50–60% of the maximal amplitude of field excitatory postsynaptic potentials (EPSPs). In another set of experiments, extracellular recordings were obtained from the pyramidal cell layer of the CA1 region to investigate the effects of propofol and pentobarbital on paired pulse inhibition of population spikes. For these studies, two stimuli of maximal intensity were delivered through a bipolar electrode placed in the Schaffer collateral pathway at an interval of 21 ms. Paired pulse inhibition was estimated as a ratio of the amplitude of the second population spike to the first population spike.
To induce LTP, θ-burst–patterned stimulation (TBS) was used. For most experiments, TBS consisted of 10 bursts (unless otherwise indicated) of 4 pulses at 100 Hz, applied at 5 Hz. In another set of experiments, LTP was induced by TBS consisting of 200-Hz stimulation in the presence of 1 μm MK-801, an NMDA receptor antagonist. LTD was induced using 900 pulses at 1 Hz. We also examined effects of 900-pulse stimulation at 10 Hz to examine effects on synaptic plasticity threshold.
For recording NMDA receptor–mediated synaptic responses, artificial cerebrospinal fluid containing low Mg2+(0.1 mm) and high Ca2+(2.5 mm) was used to facilitate activation of NMDA receptor–gated channels. Non-NMDA receptor–mediated components of synaptic responses were blocked using 6-cyano-7-nitro-quinoxaline-2, 3-dione (CNQX; 30 μm).
Field EPSPs were monitored and analyzed using the pCLAMP software data acquisition system (version 9.0; Axon Instruments, Foster, CA). EPSP slopes were measured as the maximum slope of the negative rising phase of the waveform. Changes in EPSP slopes were compared at the 50% point on baseline input–output curves. All responses were normalized as a percentage of control.
Chemicals
To evaluate effects of anesthetic agents on synaptic plasticity, each chemical was administered starting 20 min before conditioning stimulation. Picrotoxin (1 μm) was dissolved in ethanol. The final concentration of ethanol in artificial cerebrospinal fluid was 0.1%. All chemicals were purchased from Sigma-Aldrich (St. Louis, MO).
Propofol was made up as a 300-mm stock solution in dimethyl sulfoxide. The final concentration of dimethyl sulfoxide in artificial cerebrospinal fluid was 0.1%.
Statistics
Data are expressed as mean ± SE, and levels of significance were set at P  < 0.05. Statistical significance was determined using the Student t  test or Mann–Whitney U test to compare values between groups.
Results
We initially evaluated the effects of propofol on basal synaptic transmission at Schaffer collateral synapses in the CA1 region. At concentrations of 30 μm or less, 20-min administration of propofol had little effect on baseline EPSPs. Administration of 100 μm propofol depressed EPSPs by 81 ± 5% (n = 4). We also examined the ability of propofol to modulate paired pulse plasticity of CA1 population spikes (PSs) using an interpulse interval of 21 ms and a stimulus intensity sufficient to elicit a maximal second PS. Under these conditions, there is little depression of the second PS, but treatments that augment γ-aminobutyric acid–mediated (GABAergic) tone promote paired pulse inhibition of the second spike. Propofol suppressed the second PS in a concentration-dependent manner with an IC50of 19 ± 5 μm (fig. 1). For comparison, we also examined the effects of pentobarbital, an anesthetic known to augment GABAergic function. Pentobarbital enhanced paired pulse inhibition with an IC50of 29 ± 3 μm (fig. 1). At a fixed concentration of 30 μm, propofol and pentobarbital changed the ratio of second to first PS by −80 ± 9% (n = 6) and −53 ± 9% (n = 6), respectively. As reported by other investigators,11 the enhancement of paired pulse inhibition by propofol was blocked by 1 μm picrotoxin, a γ-aminobutyric acid type A (GABAA) receptor antagonist (change in the ratio of second to first PS by 30 μm propofol was −1 ± 3%, n = 5; data not shown). Similarly, enhancement of paired pulse inhibition by pentobarbital was also masked by picrotoxin (change in the ratio of second to first PS by 30 μm pentobarbital was −6 ± 2%, n = 5).
Fig. 1. Concentration–response curves for paired pulse inhibition of population spikes by propofol and pentobarbital. Each point represents six or more samples. Paired pulse stimulation was delivered to the Schaffer collateral pathway at an interval of 21 ms and an intensity sufficient to evoke maximal responses. Paired pulse inhibition of population spikes (PSs) was expressed as a change in the ratio of the second PS amplitude to the first PS amplitude after 20 min of drug administration. The IC50for propofol was 19 ± 12 μm, and the IC50for pentobarbital was 29 ± 1 μm. The  upper two traces on the right  depict PSs evoked by paired pulse stimulation before (  upper trace  ) and during (  second trace  ) administration of propofol. The  lower two traces  depict PSs evoked by paired pulse stimulation before (  third trace  ) and during (  bottom trace  ) administration of pentobarbital.  Scale bar  : 2.5 mV, 5 ms  .
Fig. 1. Concentration–response curves for paired pulse inhibition of population spikes by propofol and pentobarbital. Each point represents six or more samples. Paired pulse stimulation was delivered to the Schaffer collateral pathway at an interval of 21 ms and an intensity sufficient to evoke maximal responses. Paired pulse inhibition of population spikes (PSs) was expressed as a change in the ratio of the second PS amplitude to the first PS amplitude after 20 min of drug administration. The IC50for propofol was 19 ± 12 μm, and the IC50for pentobarbital was 29 ± 1 μm. The  upper two traces on the right  depict PSs evoked by paired pulse stimulation before (  upper trace  ) and during (  second trace  ) administration of propofol. The  lower two traces  depict PSs evoked by paired pulse stimulation before (  third trace  ) and during (  bottom trace  ) administration of pentobarbital.  Scale bar  : 2.5 mV, 5 ms 
	.
Fig. 1. Concentration–response curves for paired pulse inhibition of population spikes by propofol and pentobarbital. Each point represents six or more samples. Paired pulse stimulation was delivered to the Schaffer collateral pathway at an interval of 21 ms and an intensity sufficient to evoke maximal responses. Paired pulse inhibition of population spikes (PSs) was expressed as a change in the ratio of the second PS amplitude to the first PS amplitude after 20 min of drug administration. The IC50for propofol was 19 ± 12 μm, and the IC50for pentobarbital was 29 ± 1 μm. The  upper two traces on the right  depict PSs evoked by paired pulse stimulation before (  upper trace  ) and during (  second trace  ) administration of propofol. The  lower two traces  depict PSs evoked by paired pulse stimulation before (  third trace  ) and during (  bottom trace  ) administration of pentobarbital.  Scale bar  : 2.5 mV, 5 ms  .
×
Because most forms of long-term plasticity require activation of NMDA receptors, we examined the effects of propofol on isolated NMDA receptor–mediated EPSPs (NMDA EPSPs). At concentrations of 300 μm or less, propofol exhibited only partial inhibition of NMDA EPSPs (fig. 2A), with 30 μm propofol producing 36 ± 3% inhibition (n = 9). This partial depression of NMDA EPSPs by 30 μm propofol was not altered when propofol was coapplied with 1 μm picrotoxin (EPSP change: 38 ± 6% inhibition, n = 4). To determine whether the partial inhibitory effects of propofol reflect NMDA receptor subtype selectivity, we examined interactions between propofol and ifenprodil on NMDA EPSPs. Ifenprodil inhibits NMDA receptors expressing NR2B subunits fairly selectively at low micromolar concentrations. NMDA EPSPs were depressed by approximately 40% by 10 μm ifenprodil. In the presence of ifenprodil, 30 μm propofol still partially depressed EPSPs, indicating that its effects were not completely occluded by ifenprodil (21 ± 2% depression, n = 5; fig. 2B). Based on these observations, it does not seem that propofol is selective for NMDA receptors containing NR2B subunits.
Fig. 2. Partial inhibition of  N  -methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic potentials (EPSPs) by propofol. (  A  ) Slopes of NMDA EPSPs, recorded in the presence of CNQX and low magnesium, were concentration-dependently inhibited by propofol with an IC50greater than 100 μm. Each point represents five or more samples.  Traces on the right  show NMDA EPSPs in the absence (  bold trace  ) and presence of 30 μm (  dotted trace  ) and 300 μm propofol (  thin trace  ). (  B  ) Ifenprodil-insensitive NMDA EPSPs were only partially depressed by propofol. After partial depression of NMDA receptor–mediated EPSPs by 10 μm ifenprodil (  open bar  ), 30 μm propofol (  filled bar  ) additively but only partially depressed the ifenprodil-insensitive NMDA receptor–mediated EPSPs.  Traces on the right  show representative EPSP waves recorded before ifenprodil (  bold trace  ) and before propofol (  dotted trace  ) and during propofol administration (  thin trace  ) in the presence of ifenprodil.  Scale bar  : 2 mV, 5 ms  .
Fig. 2. Partial inhibition of  N  -methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic potentials (EPSPs) by propofol. (  A  ) Slopes of NMDA EPSPs, recorded in the presence of CNQX and low magnesium, were concentration-dependently inhibited by propofol with an IC50greater than 100 μm. Each point represents five or more samples.  Traces on the right  show NMDA EPSPs in the absence (  bold trace  ) and presence of 30 μm (  dotted trace  ) and 300 μm propofol (  thin trace  ). (  B  ) Ifenprodil-insensitive NMDA EPSPs were only partially depressed by propofol. After partial depression of NMDA receptor–mediated EPSPs by 10 μm ifenprodil (  open bar  ), 30 μm propofol (  filled bar  ) additively but only partially depressed the ifenprodil-insensitive NMDA receptor–mediated EPSPs.  Traces on the right  show representative EPSP waves recorded before ifenprodil (  bold trace  ) and before propofol (  dotted trace  ) and during propofol administration (  thin trace  ) in the presence of ifenprodil.  Scale bar  : 2 mV, 5 ms 
	.
Fig. 2. Partial inhibition of  N  -methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic potentials (EPSPs) by propofol. (  A  ) Slopes of NMDA EPSPs, recorded in the presence of CNQX and low magnesium, were concentration-dependently inhibited by propofol with an IC50greater than 100 μm. Each point represents five or more samples.  Traces on the right  show NMDA EPSPs in the absence (  bold trace  ) and presence of 30 μm (  dotted trace  ) and 300 μm propofol (  thin trace  ). (  B  ) Ifenprodil-insensitive NMDA EPSPs were only partially depressed by propofol. After partial depression of NMDA receptor–mediated EPSPs by 10 μm ifenprodil (  open bar  ), 30 μm propofol (  filled bar  ) additively but only partially depressed the ifenprodil-insensitive NMDA receptor–mediated EPSPs.  Traces on the right  show representative EPSP waves recorded before ifenprodil (  bold trace  ) and before propofol (  dotted trace  ) and during propofol administration (  thin trace  ) in the presence of ifenprodil.  Scale bar  : 2 mV, 5 ms  .
×
We next determined the effects of propofol on NMDA receptor–dependent forms of synaptic plasticity. In control slices, TBS consistently induced LTP (EPSPs 60 min after TBS: 163 ± 10% of control, n = 6) and this degree of LTP was not altered by 0.1% dimethyl sulfoxide, the agent used as a solvent for propofol (159 ± 8% of control, n = 5; fig. 3A). Continuous administration of 3 μm propofol starting 20 min before the delivery of TBS and maintained throughout the experiment did not alter LTP induction (166 ± 21% of control, n = 5; fig. 3B), whereas 10 μm propofol partially inhibited LTP induction (121 ± 10% of control, n = 5, P  < 0.05 vs.  control; fig. 3C). In the presence of 30 μm propofol administered continuously throughout the experiment, TBS did not induce LTP (99 ± 1%, n = 6; fig. 3D).
Fig. 3. Effects of various concentrations of propofol on long-term potentiation. Propofol was dissolved in dimethyl sulfoxide (DMSO) and continuously administered for the duration shown by the  solid bars  . One hundred–hertz θ-burst stimulation (TBS) was delivered at time 0 (  arrow  ). TBS induced long-term potentiation when 0.1% DMSO alone was administered (  A  ) or when 3 μm propofol was administered (  B  ). Administration of 10 μm propofol significantly depressed long-term potentiation production (  C  ), whereas 30 μm propofol completely blocked long-term potentiation (  D  ).  Traces to the right of the graphs  depict representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from slices treated with DMSO alone (  upper traces  ), 3 μm propofol (  second set of traces  ), 10 μm propofol (  third traces  ), and 30 μm propofol (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
Fig. 3. Effects of various concentrations of propofol on long-term potentiation. Propofol was dissolved in dimethyl sulfoxide (DMSO) and continuously administered for the duration shown by the  solid bars  . One hundred–hertz θ-burst stimulation (TBS) was delivered at time 0 (  arrow  ). TBS induced long-term potentiation when 0.1% DMSO alone was administered (  A  ) or when 3 μm propofol was administered (  B  ). Administration of 10 μm propofol significantly depressed long-term potentiation production (  C  ), whereas 30 μm propofol completely blocked long-term potentiation (  D  ).  Traces to the right of the graphs  depict representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from slices treated with DMSO alone (  upper traces  ), 3 μm propofol (  second set of traces  ), 10 μm propofol (  third traces  ), and 30 μm propofol (  bottom traces  ).  Scale bar  : 2 mV, 5 ms 
	.
Fig. 3. Effects of various concentrations of propofol on long-term potentiation. Propofol was dissolved in dimethyl sulfoxide (DMSO) and continuously administered for the duration shown by the  solid bars  . One hundred–hertz θ-burst stimulation (TBS) was delivered at time 0 (  arrow  ). TBS induced long-term potentiation when 0.1% DMSO alone was administered (  A  ) or when 3 μm propofol was administered (  B  ). Administration of 10 μm propofol significantly depressed long-term potentiation production (  C  ), whereas 30 μm propofol completely blocked long-term potentiation (  D  ).  Traces to the right of the graphs  depict representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from slices treated with DMSO alone (  upper traces  ), 3 μm propofol (  second set of traces  ), 10 μm propofol (  third traces  ), and 30 μm propofol (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
×
Although these results suggest that low micromolar concentrations of propofol do not alter LTP, it is possible that 20-min administration before TBS is insufficient for propofol to exhibit full activity. Therefore, we preincubated slices for 4 h in moderate concentrations of propofol and delivered TBS during continuous administration of propofol at the same concentration. Even after preincubation with 3 μm propofol, TBS consistently induced LTP (172 ± 6%, n = 5). However, preincubation with 10 μm propofol completely inhibited LTP (100 ± 4%, n = 5; data not shown).
To determine whether propofol blocks the induction or maintenance of LTP, propofol was administered either during or after TBS. Administration of 30 μm propofol for 20 min before and during the delivery of TBS blocked LTP induction (EPSP slope: 109 ± 1%, n = 6, figs. 4B and 5; P  < 0.05 vs.  control, fig. 4A). Administration of propofol starting 5 min after TBS, however, did not block LTP completely (139 ± 9%, n = 6; fig. 4C), although the degree of LTP was statistically less than control (P  < 0.05). These findings indicate that propofol inhibits the induction but has less effect on the maintenance of NMDA receptor–dependent LTP.
Fig. 4. Effects of 30 μm propofol on long-term potentiation induction and maintenance. (  A  ) One hundred–hertz θ-burst stimulation (TBS;  arrow  ) induced long-term potentiation in control slices (  open circles  ). (  B  ) Administration of 30 μm propofol for 20 min before and during TBS (  solid bar  ) blocked long-term potentiation induction (  solid circles  ). (  C  ) TBS induced long-term potentiation in slices treated with 30 μm propofol (  filled circles  ) when propofol administration was begun 5 min after delivery of TBS (  solid bar  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from a control slice (  upper traces  ), a slice treated with propofol before and during the delivery of TBS (  middle set of traces  ), and a slice treated with propofol after TBS (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
Fig. 4. Effects of 30 μm propofol on long-term potentiation induction and maintenance. (  A  ) One hundred–hertz θ-burst stimulation (TBS;  arrow  ) induced long-term potentiation in control slices (  open circles  ). (  B  ) Administration of 30 μm propofol for 20 min before and during TBS (  solid bar  ) blocked long-term potentiation induction (  solid circles  ). (  C  ) TBS induced long-term potentiation in slices treated with 30 μm propofol (  filled circles  ) when propofol administration was begun 5 min after delivery of TBS (  solid bar  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from a control slice (  upper traces  ), a slice treated with propofol before and during the delivery of TBS (  middle set of traces  ), and a slice treated with propofol after TBS (  bottom traces  ).  Scale bar  : 2 mV, 5 ms 
	.
Fig. 4. Effects of 30 μm propofol on long-term potentiation induction and maintenance. (  A  ) One hundred–hertz θ-burst stimulation (TBS;  arrow  ) induced long-term potentiation in control slices (  open circles  ). (  B  ) Administration of 30 μm propofol for 20 min before and during TBS (  solid bar  ) blocked long-term potentiation induction (  solid circles  ). (  C  ) TBS induced long-term potentiation in slices treated with 30 μm propofol (  filled circles  ) when propofol administration was begun 5 min after delivery of TBS (  solid bar  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from a control slice (  upper traces  ), a slice treated with propofol before and during the delivery of TBS (  middle set of traces  ), and a slice treated with propofol after TBS (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
×
Fig. 5. Summary of the effects of propofol and pentobarbital on the induction of  N  -methyl-d-aspartate receptor–dependent long-term potentiation and  N  -methyl-d-aspartate receptor–independent long-term potentiation. One hundred–hertz or 200-Hz θ-burst stimulation was delivered in control slices (  open bars  ), in the presence of 30 μm propofol (  filled bars  ) or 30 μm pentobarbital (  hatched bars  )  . *P  < 0.05 by Student  t  test  .
Fig. 5. Summary of the effects of propofol and pentobarbital on the induction of  N  -methyl-d-aspartate receptor–dependent long-term potentiation and  N  -methyl-d-aspartate receptor–independent long-term potentiation. One hundred–hertz or 200-Hz θ-burst stimulation was delivered in control slices (  open bars  ), in the presence of 30 μm propofol (  filled bars  ) or 30 μm pentobarbital (  hatched bars  ) 
	. *P  < 0.05 by Student  t  test 
	.
Fig. 5. Summary of the effects of propofol and pentobarbital on the induction of  N  -methyl-d-aspartate receptor–dependent long-term potentiation and  N  -methyl-d-aspartate receptor–independent long-term potentiation. One hundred–hertz or 200-Hz θ-burst stimulation was delivered in control slices (  open bars  ), in the presence of 30 μm propofol (  filled bars  ) or 30 μm pentobarbital (  hatched bars  )  . *P  < 0.05 by Student  t  test  .
×
The induction of LTP using 100-Hz TBS requires activation of NMDA receptors. In contrast, LTP induced by very-high-frequency stimulation (200 Hz) is independent of NMDA receptor activation. Delivery of a 200-Hz TBS induced a persistent increase in EPSPs in the presence of 1 μm MK-801, a noncompetitive NMDA receptor antagonist (EPSP slope: 190 ± 5%, n = 5; figs. 5 and 6). This NMDA receptor-independent LTP was inhibited by 30 μm propofol administered before and during the 200-Hz stimulation (EPSP slope: 115 ± 2%, n = 5, P  < 0.05 vs.  control; figs. 5 and 6).
Fig. 6. Propofol inhibits the induction of  N  -methyl-d-aspartate receptor–independent long-term potentiation. In the presence of 1 μm MK-801 (  dashed bar  ), 200-Hz θ-burst stimulation (TBS) induced long-term potentiation (  open circles  ). Long-term potentiation induction was inhibited (  filled circles  ) when 30 μm propofol (  solid bar  ) was administered before and during the delivery of the 200-Hz TBS (  arrow  ).  Traces to the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after TBS (  solid traces  ). TBS was administered in the presence or absence of propofol (  upper  and  lower traces  , respectively).  Scale bar  : 2 mV, 5 ms  .
Fig. 6. Propofol inhibits the induction of  N  -methyl-d-aspartate receptor–independent long-term potentiation. In the presence of 1 μm MK-801 (  dashed bar  ), 200-Hz θ-burst stimulation (TBS) induced long-term potentiation (  open circles  ). Long-term potentiation induction was inhibited (  filled circles  ) when 30 μm propofol (  solid bar  ) was administered before and during the delivery of the 200-Hz TBS (  arrow  ).  Traces to the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after TBS (  solid traces  ). TBS was administered in the presence or absence of propofol (  upper  and  lower traces  , respectively).  Scale bar  : 2 mV, 5 ms 
	.
Fig. 6. Propofol inhibits the induction of  N  -methyl-d-aspartate receptor–independent long-term potentiation. In the presence of 1 μm MK-801 (  dashed bar  ), 200-Hz θ-burst stimulation (TBS) induced long-term potentiation (  open circles  ). Long-term potentiation induction was inhibited (  filled circles  ) when 30 μm propofol (  solid bar  ) was administered before and during the delivery of the 200-Hz TBS (  arrow  ).  Traces to the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after TBS (  solid traces  ). TBS was administered in the presence or absence of propofol (  upper  and  lower traces  , respectively).  Scale bar  : 2 mV, 5 ms  .
×
To determine whether the effects of propofol on LTP involve GABAAreceptors, we examined the effects of propofol on LTP induction in the presence of picrotoxin. Because high concentrations of picrotoxin promote epileptiform activity in the CA1 region and make it difficult to measure EPSP slopes, we used 1 μm picrotoxin in the current study. Previously, we found that this concentration of picrotoxin diminishes GABAergic inhibition but does not alter baseline synaptic potentials.12 In control slices treated with picrotoxin, we observed robust TBS-induced LTP (EPSP slope: 180 ± 4%, n = 6; fig. 7A). Propofol did not alter the induction of LTP in the presence of picrotoxin (176 ± 3%, n = 6; fig. 7A). Similarly, propofol did not inhibit NMDA receptor–independent LTP in the presence of picrotoxin. Delivery of 200-Hz very-high-frequency stimulation induced LTP in the presence of 1 μm MK-801, 1 μm picrotoxin, and 30 μm propofol (EPSP slope: 146 ± 10% n = 5, P  = 0.34 vs.  control; fig. 7B).
Fig. 7. Effects of propofol on  N  -methyl-d-aspartate receptor–dependent and independent long-term potentiation (LTP) in the presence of picrotoxin. (  A  ) In the presence of 1 μm picrotoxin (  dashed bar  ), 30 μm propofol (  solid bar  ) administered for 20 min before delivery of θ-burst stimulation (TBS;  arrow  ) did not inhibit LTP induction (  filled circles  ). Open circles show control LTP in the presence of picrotoxin induced by 100-Hz TBS (  arrow  ). (  B  ) Two hundred–hertz TBS (  arrow  ) induced LTP in the presence of 1 μm MK-801 (  open circles  ) and 1 μm picrotoxin (  dotted bar  ). In the presence of MK-801 and picrotoxin (  dotted bar  ), 30 μm propofol did not inhibit LTP induction (  filled circles  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) the delivery of 100-Hz TBS (  upper two sets of traces  ) or 200-Hz TBS in the presence of MK-801 (  lower two sets of traces  ). EPSP waves from control slices are shown in the  top  and  third from the top traces  , whereas slices treated with propofol are shown in the  second from the top  and  bottom traces  .  Scale bar  : 2 mV, 5 ms  .
Fig. 7. Effects of propofol on  N  -methyl-d-aspartate receptor–dependent and independent long-term potentiation (LTP) in the presence of picrotoxin. (  A  ) In the presence of 1 μm picrotoxin (  dashed bar  ), 30 μm propofol (  solid bar  ) administered for 20 min before delivery of θ-burst stimulation (TBS;  arrow  ) did not inhibit LTP induction (  filled circles  ). Open circles show control LTP in the presence of picrotoxin induced by 100-Hz TBS (  arrow  ). (  B  ) Two hundred–hertz TBS (  arrow  ) induced LTP in the presence of 1 μm MK-801 (  open circles  ) and 1 μm picrotoxin (  dotted bar  ). In the presence of MK-801 and picrotoxin (  dotted bar  ), 30 μm propofol did not inhibit LTP induction (  filled circles  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) the delivery of 100-Hz TBS (  upper two sets of traces  ) or 200-Hz TBS in the presence of MK-801 (  lower two sets of traces  ). EPSP waves from control slices are shown in the  top  and  third from the top traces  , whereas slices treated with propofol are shown in the  second from the top  and  bottom traces  .  Scale bar  : 2 mV, 5 ms 
	.
Fig. 7. Effects of propofol on  N  -methyl-d-aspartate receptor–dependent and independent long-term potentiation (LTP) in the presence of picrotoxin. (  A  ) In the presence of 1 μm picrotoxin (  dashed bar  ), 30 μm propofol (  solid bar  ) administered for 20 min before delivery of θ-burst stimulation (TBS;  arrow  ) did not inhibit LTP induction (  filled circles  ). Open circles show control LTP in the presence of picrotoxin induced by 100-Hz TBS (  arrow  ). (  B  ) Two hundred–hertz TBS (  arrow  ) induced LTP in the presence of 1 μm MK-801 (  open circles  ) and 1 μm picrotoxin (  dotted bar  ). In the presence of MK-801 and picrotoxin (  dotted bar  ), 30 μm propofol did not inhibit LTP induction (  filled circles  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) the delivery of 100-Hz TBS (  upper two sets of traces  ) or 200-Hz TBS in the presence of MK-801 (  lower two sets of traces  ). EPSP waves from control slices are shown in the  top  and  third from the top traces  , whereas slices treated with propofol are shown in the  second from the top  and  bottom traces  .  Scale bar  : 2 mV, 5 ms  .
×
The finding that picrotoxin overcomes the effects of propofol on LTP induction suggests that modulation of GABAAreceptors contributes to LTP inhibition. We examined this further using pentobarbital. At 30 μm, pentobarbital did not alter NMDA EPSPs (EPSP slopes in the presence of CNQX and low magnesium were 99 ± 5% of control, n = 5; fig. 8C) but did enhance PS paired pulse inhibition via  a GABAergic effect (fig. 1). Administration of pentobarbital before and during 100-Hz TBS did not completely suppress LTP induction, although the amplitude of LTP was less than control (EPSP slope: 135 ± 7%, n = 6, P  < 0.05 vs.  control; figs. 5 and 8A).
Fig. 8. Effects of pentobarbital on long-term potentiation (LTP) induction. (  A  ) Pentobarbital, 30 μm (  solid bar  ), did not completely inhibit the induction of  N  -methyl-d-aspartate receptor–dependent LTP (  filled circles  ) induced by 100-Hz θ-burst stimulation (TBS;  arrow  ).  Open circles  show LTP in control slices. (  B  ) Pentobarbital, 30 μm (  solid bar  ), did not completely block the induction of  N  -methyl-d-aspartate receptor–independent LTP (  filled circle  ) induced by 200-Hz TBS (  arrow  ) in the presence of 1 μm MK-801 (  dotted bar  ).  Open circles  show LTP in control slices.  Traces to the right of the graphs  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) delivery of 100-Hz TBS (  upper  ) in the presence of pentobarbital or 200-Hz TBS in the presence of MK-801 and pentobarbital (  lower traces  ). (  C  ) Pentobarbital did not alter  N  -methyl-d-aspartate–EPSPs.  Scale bar  : 2 mV, 5 ms  .
Fig. 8. Effects of pentobarbital on long-term potentiation (LTP) induction. (  A  ) Pentobarbital, 30 μm (  solid bar  ), did not completely inhibit the induction of  N  -methyl-d-aspartate receptor–dependent LTP (  filled circles  ) induced by 100-Hz θ-burst stimulation (TBS;  arrow  ).  Open circles  show LTP in control slices. (  B  ) Pentobarbital, 30 μm (  solid bar  ), did not completely block the induction of  N  -methyl-d-aspartate receptor–independent LTP (  filled circle  ) induced by 200-Hz TBS (  arrow  ) in the presence of 1 μm MK-801 (  dotted bar  ).  Open circles  show LTP in control slices.  Traces to the right of the graphs  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) delivery of 100-Hz TBS (  upper  ) in the presence of pentobarbital or 200-Hz TBS in the presence of MK-801 and pentobarbital (  lower traces  ). (  C  ) Pentobarbital did not alter  N  -methyl-d-aspartate–EPSPs.  Scale bar  : 2 mV, 5 ms 
	.
Fig. 8. Effects of pentobarbital on long-term potentiation (LTP) induction. (  A  ) Pentobarbital, 30 μm (  solid bar  ), did not completely inhibit the induction of  N  -methyl-d-aspartate receptor–dependent LTP (  filled circles  ) induced by 100-Hz θ-burst stimulation (TBS;  arrow  ).  Open circles  show LTP in control slices. (  B  ) Pentobarbital, 30 μm (  solid bar  ), did not completely block the induction of  N  -methyl-d-aspartate receptor–independent LTP (  filled circle  ) induced by 200-Hz TBS (  arrow  ) in the presence of 1 μm MK-801 (  dotted bar  ).  Open circles  show LTP in control slices.  Traces to the right of the graphs  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) delivery of 100-Hz TBS (  upper  ) in the presence of pentobarbital or 200-Hz TBS in the presence of MK-801 and pentobarbital (  lower traces  ). (  C  ) Pentobarbital did not alter  N  -methyl-d-aspartate–EPSPs.  Scale bar  : 2 mV, 5 ms  .
×
Because the effects of pentobarbital on TBS-LTP differed from those of propofol, we also examined whether pentobarbital inhibits NMDA receptor–independent LTP in the presence of 1 μm MK-801. Similar to effects on NMDA receptor–dependent LTP induced by TBS, administration of 30 μm pentobarbital for 20 min before and during the delivery of very-high-frequency stimulation diminished but did not completely block LTP induction (EPSP slope: 137 ± 10%, n = 5, P  = 0.15 vs.  control; fig. 8B). Given that 10–30 μm propofol completely blocks LTP, these results suggest that the effects of pentobarbital on LTP differ from those of propofol and that propofol has actions in addition to modulation of GABAAreceptors that contribute to its LTP inhibition.
We also examined the effects of propofol on the induction of homosynaptic LTD, a form of plasticity that requires activation of NMDA receptors in the CA1 region. In control slices, delivery of low-frequency stimulation consisting of 900 pulses delivered at 1 Hz (900-s stimulation) successfully induced LTD in control slices (EPSP slopes: 69 ± 3%, n = 7; fig. 9A). LTD induction was not blocked by administration of 30 μm propofol for 20 min before and during low frequency stimulation (66 ± 5%, n = 6; fig. 9A). Because propofol inhibits the induction of LTP but not LTD, it is possible that propofol shifts the frequency dependence of synaptic plasticity and thus would allow 10-Hz intermediate-frequency stimulation to induce LTD. In control slices, delivery of 900 pulses at 10 Hz (90-s stimulation) did not induce LTD (EPSP slopes: 92 ± 2%, n = 5; fig. 9B). Administration of 30 μm propofol for 20 min before and during delivery of 10 Hz stimulation had no significant effect (87 ± 3%, n = 5; fig. 9B), indicating that propofol did not shift the overall frequency dependence of synaptic plasticity towards LTD.
Fig. 9. Propofol does not inhibit the induction of long-term depression (LTD). (  A  ) Delivery of low-frequency stimulation consisting of 900 pulses at 1 Hz (  five arrows  ) induced LTD in the presence (  filled circles  ) or absence (  open circles  ) of 30 μm propofol (  solid bar  ). (  B  ) Delivery of 900 pulses at 10 Hz (  two arrows  ) did not induce long-term potentiation or LTD in control slices (  open circles  ). Administration of 30 μm propofol did not alter the effects of 10-Hz stimulation (  filled circles  ).  Traces on the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after (  solid traces  ) 1-Hz (  upper two sets  ) or 10-Hz stimulation (  lower two sets  ). EPSPs from control slices are shown in the  top  and  third set of traces  , whereas EPSPs from propofol-treated slices are shown in the  second  and  bottom traces  . Scale bar  : 2 mV, 5 ms  .
Fig. 9. Propofol does not inhibit the induction of long-term depression (LTD). (  A  ) Delivery of low-frequency stimulation consisting of 900 pulses at 1 Hz (  five arrows  ) induced LTD in the presence (  filled circles  ) or absence (  open circles  ) of 30 μm propofol (  solid bar  ). (  B  ) Delivery of 900 pulses at 10 Hz (  two arrows  ) did not induce long-term potentiation or LTD in control slices (  open circles  ). Administration of 30 μm propofol did not alter the effects of 10-Hz stimulation (  filled circles  ).  Traces on the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after (  solid traces  ) 1-Hz (  upper two sets  ) or 10-Hz stimulation (  lower two sets  ). EPSPs from control slices are shown in the  top  and  third set of traces  , whereas EPSPs from propofol-treated slices are shown in the  second  and  bottom traces  . Scale bar  : 2 mV, 5 ms 
	.
Fig. 9. Propofol does not inhibit the induction of long-term depression (LTD). (  A  ) Delivery of low-frequency stimulation consisting of 900 pulses at 1 Hz (  five arrows  ) induced LTD in the presence (  filled circles  ) or absence (  open circles  ) of 30 μm propofol (  solid bar  ). (  B  ) Delivery of 900 pulses at 10 Hz (  two arrows  ) did not induce long-term potentiation or LTD in control slices (  open circles  ). Administration of 30 μm propofol did not alter the effects of 10-Hz stimulation (  filled circles  ).  Traces on the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after (  solid traces  ) 1-Hz (  upper two sets  ) or 10-Hz stimulation (  lower two sets  ). EPSPs from control slices are shown in the  top  and  third set of traces  , whereas EPSPs from propofol-treated slices are shown in the  second  and  bottom traces  . Scale bar  : 2 mV, 5 ms  .
×
Discussion
Recent evidence indicates that propofol-induced anesthesia is not accompanied by recall of events occurring during the hypnotic state.13 This suggests that propofol disrupts memory formation during anesthesia and raises the possibility that anesthetically relevant concentrations of propofol also disrupt forms of synaptic plasticity thought to contribute to memory processing. Although we observed that propofol inhibits LTP in hippocampal slices, it is difficult to determine how the concentrations required for modulation of synaptic function and plasticity correlate with concentrations required for effective anesthesia. In humans, blood concentrations of propofol required for sedation range from 0.5 to 1 μg/ml (2.8–5.6 μm),14 whereas those for general anesthesia range from 2 to 6 μg/ml (11.2–33.6 μm).15 In rats, the blood concentrations obtained upon awakening are less than 3.5 μg/ml (19.6 μm), and additional doses are required to maintain hypnosis.16 These blood concentrations, however, may not exactly mirror the concentrations in extraneuronal spaces. It has been shown that concentrations of propofol in rat brain are greater than those in blood after intravenous infusion.17 Investigators have often used relatively high concentrations of propofol to demonstrate inhibitory effects on population spikes,11,18 presumably because of poor penetration of propofol into brain slices when administered by bath perfusion.19 Although the concentrations of propofol that inhibited LTP are greater than the concentrations in the cerebrospinal fluid calculated from doses used in clinical practice,20 the concentrations for LTP inhibition are similar to those required for paired pulse inhibition of population spikes. Therefore, the concentrations of propofol used in the current study seem to correlate with concentrations achieved during anesthesia, given that paired pulse inhibition in slices and clinical anesthesia are both thought to involve GABAergic actions. Considering that the IC50for propofol-mediated enhancement of paired pulse inhibition was 19 μm in hippocampal slices, it seems that the 10- to 30-μm concentrations associated with LTP inhibition are within a range that could be relevant for anesthesia.
To study possible mechanisms underlying memory disruption by propofol, we focused on examining 30 μm propofol, a concentration that completely inhibited LTP. We found that propofol inhibits LTP induction but has less effect on LTP maintenance in the CA1 region. A previous study found that intraperitoneal injections of propofol inhibit the maintenance but not the induction of LTP in vivo  .10 Reasons for this discrepancy are not clear but may involve differences in experimental conditions including drug administration methods.
Propofol is a partial inhibitor of NMDA receptors, and this partial inhibition in combination with GABAergic modulation may be critical for explaining effects on synaptic plasticity. When the effects of propofol are blocked by picrotoxin, the partial inhibitory effects of propofol on NMDA receptors are insufficient to block NMDA receptor–dependent LTP. Furthermore, propofol also blocks a form of LTP not dependent on NMDA receptors. These observations strongly suggest that there are several mechanisms contributing to the effects of propofol on synaptic plasticity.
Because activation of NMDA receptors plays a key role in LTP induction, we initially hypothesized that inhibition of NMDA receptors would account for propofol-mediated LTP inhibition. Previous studies have shown that propofol partially inhibits NMDA receptor–mediated responses in dissociated cultured neurons and in Xenopus  oocytes.21,22 Partial inhibition of NMDA receptor–mediated synaptic transmission, however, is typically not sufficient to inhibit LTP induction,23 unless there is relatively complete block of the component of transmission mediated by NR2A containing NMDA receptors.24 Our results indicate that propofol is not selective for specific subtypes of NMDA receptors, and thus, partial inhibition of NMDA receptors by propofol seems unlikely to account for the block of LTP.
Consistent with the idea that partial block of NMDA receptors does not account for the effects of propofol on LTP, we found that propofol also inhibits LTP induced by 200-Hz TBS that is independent of NMDA receptor activation.25 Previous studies have shown that LTP induced by 200-Hz stimulation involves activation of L-type calcium channels but not NMDA receptors.25 Therefore, 200-Hz stimulation induces LTP even in the presence of NMDA receptor block with MK-801 (fig. 6). Our observation that propofol inhibited the induction of NMDA receptor–independent LTP further supports the idea that effects on NMDA receptors cannot fully account for propofol-mediated inhibition of LTP.
We also found that propofol has GABAergic effects at concentrations that inhibit LTP. Several lines of evidence suggest that inhibition of GABAAreceptors enhances NMDA receptor activation and facilitates LTP.26 Loss of GABAergic inhibition may also act as a priming stimulus for the subsequent induction of LTP by increasing calcium influx through L-type calcium channels.27 In contrast, strong GABAA-mediated input suppresses calcium ion influx through calcium channels and NMDA receptor channels.28,29 Propofol is known to enhance the function of GABAAreceptors expressing a variety of GABAAreceptor subunits.30,31 Because picrotoxin overcomes the inhibitory effects of propofol on LTP induction, it seems that enhancement of GABAAreceptor function contributes significantly to the LTP inhibition mediated by propofol. Similarly, other anesthetics like midazolam and isoflurane also inhibit LTP.32,33 Because the inhibition of LTP by these agents is overcome by picrotoxin, it is likely that these agents share a common mechanism. Similar to propofol, ethanol partially inhibits NMDA receptors and depresses LTP induction. Schummers and Browning34 speculate that ethanol-mediated LTP inhibition results from the synergistic effects of partial NMDA receptor block and potentiation of GABAAreceptors. They showed that GABAAreceptor block with picrotoxin diminished the effects of ethanol on NMDA receptor–mediated EPSPs. In our experiments, the inhibitory effects of propofol on NMDA receptor–mediated EPSPs were not altered by picrotoxin.
To test whether modulation of GABAergic function is sufficient to suppress LTP induction, we examined pentobarbital, a barbiturate known to potentiate GABAAreceptors. Although pentobarbital does not inhibit LTP induction in vivo  ,35 effects of pentobarbital on LTP induction in vitro  have not been studied in detail. Because 100 μm pentobarbital depressed baseline synaptic responses, we focused our studies on 30 μm pentobarbital. Thirty micromolars is a concentration within the range found in rat CSF immediately after intravenous injection of pentobarbital (20–40 mg/kg).36 We chose to examine 30 μm pentobarbital based on the observation that pentobarbital enhanced paired pulse inhibition in a picrotoxin-sensitive fashion with an IC50of 29 μm. At 30 μm, pentobarbital had no effect on spike generation elicited by single stimuli and only partially suppressed LTP generation. Previous work has shown that LTP is difficult to induce under conditions where pentobarbital diminishes spike firing in slices.37 Because 30 μm pentobarbital did not alter NMDA EPSPs and 10–30 μm propofol produces a greater block of LTP with comparable GABAergic effects, it seems that additional factors are likely to contribute to propofol-mediated LTP inhibition. It is also possible that the modulation of GABAAreceptors by propofol differs from other modulators, resulting in unique effects on LTP induction. Pentobarbital prolongs the open time of GABA channels without affecting closed times,38 whereas propofol increases the channel open probability via  a decrease in closed times.39 Furthermore, pentobarbital does not block NMDA receptor–independent LTP, whereas propofol blocks this form of LTP. This result further suggests that the effects of propofol involve more than GABAergic enhancement. It is possible that effects on calcium channels, intracellular calcium homeostasis, or second messenger systems contribute to effects on synaptic plasticity. In particular, inhibition of L-type calcium channels by propofol40,41 coupled with GABAergic effects could account for the block of NMDA receptor–independent forms of LTP.
Long-term depression represents another form of synaptic plasticity in the hippocampus. Recent studies indicate that LTD induction may require a specific NMDA receptor subtype with selective inhibition of NMDA receptors containing NR2B subunits preventing the induction of LTD but not LTP in the CA1 region.24,42 We examined whether propofol mimics the effects of the NR2B antagonist ifenprodil on NMDA receptors. Because both ifenprodil-sensitive NMDA EPSPs and ifenprodil-insensitive NMDA EPSPs were inhibited by propofol, it seems that propofol does not block a specific subtype of NMDA receptors. The failure of propofol to inhibit LTD induction may reflect the only partial inhibitory effects of the drug on NR2B-containing NMDA receptors. However, Hendricson et al.  43 have shown that ifenprodil can facilitate the induction of LTD under some conditions, leaving some uncertainty about the role of NR2B receptors in LTD induction.
Taken together, our results indicate that propofol inhibits the induction of LTP with less effect on the maintenance of LTP and no effect on LTD. Although propofol is a partial inhibitor of NMDA receptors with actions that are distinct from subtype specific antagonists, the inhibition of LTP cannot be explained simply by partial inhibition of NMDA receptors. In addition, our results indicate that effects on GABAAreceptors contribute significantly to LTP inhibition, but these actions alone seem unlikely to account fully for the effects of propofol on synaptic plasticity.
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Fig. 1. Concentration–response curves for paired pulse inhibition of population spikes by propofol and pentobarbital. Each point represents six or more samples. Paired pulse stimulation was delivered to the Schaffer collateral pathway at an interval of 21 ms and an intensity sufficient to evoke maximal responses. Paired pulse inhibition of population spikes (PSs) was expressed as a change in the ratio of the second PS amplitude to the first PS amplitude after 20 min of drug administration. The IC50for propofol was 19 ± 12 μm, and the IC50for pentobarbital was 29 ± 1 μm. The  upper two traces on the right  depict PSs evoked by paired pulse stimulation before (  upper trace  ) and during (  second trace  ) administration of propofol. The  lower two traces  depict PSs evoked by paired pulse stimulation before (  third trace  ) and during (  bottom trace  ) administration of pentobarbital.  Scale bar  : 2.5 mV, 5 ms  .
Fig. 1. Concentration–response curves for paired pulse inhibition of population spikes by propofol and pentobarbital. Each point represents six or more samples. Paired pulse stimulation was delivered to the Schaffer collateral pathway at an interval of 21 ms and an intensity sufficient to evoke maximal responses. Paired pulse inhibition of population spikes (PSs) was expressed as a change in the ratio of the second PS amplitude to the first PS amplitude after 20 min of drug administration. The IC50for propofol was 19 ± 12 μm, and the IC50for pentobarbital was 29 ± 1 μm. The  upper two traces on the right  depict PSs evoked by paired pulse stimulation before (  upper trace  ) and during (  second trace  ) administration of propofol. The  lower two traces  depict PSs evoked by paired pulse stimulation before (  third trace  ) and during (  bottom trace  ) administration of pentobarbital.  Scale bar  : 2.5 mV, 5 ms 
	.
Fig. 1. Concentration–response curves for paired pulse inhibition of population spikes by propofol and pentobarbital. Each point represents six or more samples. Paired pulse stimulation was delivered to the Schaffer collateral pathway at an interval of 21 ms and an intensity sufficient to evoke maximal responses. Paired pulse inhibition of population spikes (PSs) was expressed as a change in the ratio of the second PS amplitude to the first PS amplitude after 20 min of drug administration. The IC50for propofol was 19 ± 12 μm, and the IC50for pentobarbital was 29 ± 1 μm. The  upper two traces on the right  depict PSs evoked by paired pulse stimulation before (  upper trace  ) and during (  second trace  ) administration of propofol. The  lower two traces  depict PSs evoked by paired pulse stimulation before (  third trace  ) and during (  bottom trace  ) administration of pentobarbital.  Scale bar  : 2.5 mV, 5 ms  .
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Fig. 2. Partial inhibition of  N  -methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic potentials (EPSPs) by propofol. (  A  ) Slopes of NMDA EPSPs, recorded in the presence of CNQX and low magnesium, were concentration-dependently inhibited by propofol with an IC50greater than 100 μm. Each point represents five or more samples.  Traces on the right  show NMDA EPSPs in the absence (  bold trace  ) and presence of 30 μm (  dotted trace  ) and 300 μm propofol (  thin trace  ). (  B  ) Ifenprodil-insensitive NMDA EPSPs were only partially depressed by propofol. After partial depression of NMDA receptor–mediated EPSPs by 10 μm ifenprodil (  open bar  ), 30 μm propofol (  filled bar  ) additively but only partially depressed the ifenprodil-insensitive NMDA receptor–mediated EPSPs.  Traces on the right  show representative EPSP waves recorded before ifenprodil (  bold trace  ) and before propofol (  dotted trace  ) and during propofol administration (  thin trace  ) in the presence of ifenprodil.  Scale bar  : 2 mV, 5 ms  .
Fig. 2. Partial inhibition of  N  -methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic potentials (EPSPs) by propofol. (  A  ) Slopes of NMDA EPSPs, recorded in the presence of CNQX and low magnesium, were concentration-dependently inhibited by propofol with an IC50greater than 100 μm. Each point represents five or more samples.  Traces on the right  show NMDA EPSPs in the absence (  bold trace  ) and presence of 30 μm (  dotted trace  ) and 300 μm propofol (  thin trace  ). (  B  ) Ifenprodil-insensitive NMDA EPSPs were only partially depressed by propofol. After partial depression of NMDA receptor–mediated EPSPs by 10 μm ifenprodil (  open bar  ), 30 μm propofol (  filled bar  ) additively but only partially depressed the ifenprodil-insensitive NMDA receptor–mediated EPSPs.  Traces on the right  show representative EPSP waves recorded before ifenprodil (  bold trace  ) and before propofol (  dotted trace  ) and during propofol administration (  thin trace  ) in the presence of ifenprodil.  Scale bar  : 2 mV, 5 ms 
	.
Fig. 2. Partial inhibition of  N  -methyl-d-aspartate (NMDA) receptor–mediated excitatory postsynaptic potentials (EPSPs) by propofol. (  A  ) Slopes of NMDA EPSPs, recorded in the presence of CNQX and low magnesium, were concentration-dependently inhibited by propofol with an IC50greater than 100 μm. Each point represents five or more samples.  Traces on the right  show NMDA EPSPs in the absence (  bold trace  ) and presence of 30 μm (  dotted trace  ) and 300 μm propofol (  thin trace  ). (  B  ) Ifenprodil-insensitive NMDA EPSPs were only partially depressed by propofol. After partial depression of NMDA receptor–mediated EPSPs by 10 μm ifenprodil (  open bar  ), 30 μm propofol (  filled bar  ) additively but only partially depressed the ifenprodil-insensitive NMDA receptor–mediated EPSPs.  Traces on the right  show representative EPSP waves recorded before ifenprodil (  bold trace  ) and before propofol (  dotted trace  ) and during propofol administration (  thin trace  ) in the presence of ifenprodil.  Scale bar  : 2 mV, 5 ms  .
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Fig. 3. Effects of various concentrations of propofol on long-term potentiation. Propofol was dissolved in dimethyl sulfoxide (DMSO) and continuously administered for the duration shown by the  solid bars  . One hundred–hertz θ-burst stimulation (TBS) was delivered at time 0 (  arrow  ). TBS induced long-term potentiation when 0.1% DMSO alone was administered (  A  ) or when 3 μm propofol was administered (  B  ). Administration of 10 μm propofol significantly depressed long-term potentiation production (  C  ), whereas 30 μm propofol completely blocked long-term potentiation (  D  ).  Traces to the right of the graphs  depict representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from slices treated with DMSO alone (  upper traces  ), 3 μm propofol (  second set of traces  ), 10 μm propofol (  third traces  ), and 30 μm propofol (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
Fig. 3. Effects of various concentrations of propofol on long-term potentiation. Propofol was dissolved in dimethyl sulfoxide (DMSO) and continuously administered for the duration shown by the  solid bars  . One hundred–hertz θ-burst stimulation (TBS) was delivered at time 0 (  arrow  ). TBS induced long-term potentiation when 0.1% DMSO alone was administered (  A  ) or when 3 μm propofol was administered (  B  ). Administration of 10 μm propofol significantly depressed long-term potentiation production (  C  ), whereas 30 μm propofol completely blocked long-term potentiation (  D  ).  Traces to the right of the graphs  depict representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from slices treated with DMSO alone (  upper traces  ), 3 μm propofol (  second set of traces  ), 10 μm propofol (  third traces  ), and 30 μm propofol (  bottom traces  ).  Scale bar  : 2 mV, 5 ms 
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Fig. 3. Effects of various concentrations of propofol on long-term potentiation. Propofol was dissolved in dimethyl sulfoxide (DMSO) and continuously administered for the duration shown by the  solid bars  . One hundred–hertz θ-burst stimulation (TBS) was delivered at time 0 (  arrow  ). TBS induced long-term potentiation when 0.1% DMSO alone was administered (  A  ) or when 3 μm propofol was administered (  B  ). Administration of 10 μm propofol significantly depressed long-term potentiation production (  C  ), whereas 30 μm propofol completely blocked long-term potentiation (  D  ).  Traces to the right of the graphs  depict representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from slices treated with DMSO alone (  upper traces  ), 3 μm propofol (  second set of traces  ), 10 μm propofol (  third traces  ), and 30 μm propofol (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
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Fig. 4. Effects of 30 μm propofol on long-term potentiation induction and maintenance. (  A  ) One hundred–hertz θ-burst stimulation (TBS;  arrow  ) induced long-term potentiation in control slices (  open circles  ). (  B  ) Administration of 30 μm propofol for 20 min before and during TBS (  solid bar  ) blocked long-term potentiation induction (  solid circles  ). (  C  ) TBS induced long-term potentiation in slices treated with 30 μm propofol (  filled circles  ) when propofol administration was begun 5 min after delivery of TBS (  solid bar  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from a control slice (  upper traces  ), a slice treated with propofol before and during the delivery of TBS (  middle set of traces  ), and a slice treated with propofol after TBS (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
Fig. 4. Effects of 30 μm propofol on long-term potentiation induction and maintenance. (  A  ) One hundred–hertz θ-burst stimulation (TBS;  arrow  ) induced long-term potentiation in control slices (  open circles  ). (  B  ) Administration of 30 μm propofol for 20 min before and during TBS (  solid bar  ) blocked long-term potentiation induction (  solid circles  ). (  C  ) TBS induced long-term potentiation in slices treated with 30 μm propofol (  filled circles  ) when propofol administration was begun 5 min after delivery of TBS (  solid bar  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from a control slice (  upper traces  ), a slice treated with propofol before and during the delivery of TBS (  middle set of traces  ), and a slice treated with propofol after TBS (  bottom traces  ).  Scale bar  : 2 mV, 5 ms 
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Fig. 4. Effects of 30 μm propofol on long-term potentiation induction and maintenance. (  A  ) One hundred–hertz θ-burst stimulation (TBS;  arrow  ) induced long-term potentiation in control slices (  open circles  ). (  B  ) Administration of 30 μm propofol for 20 min before and during TBS (  solid bar  ) blocked long-term potentiation induction (  solid circles  ). (  C  ) TBS induced long-term potentiation in slices treated with 30 μm propofol (  filled circles  ) when propofol administration was begun 5 min after delivery of TBS (  solid bar  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) obtained before (  dashed traces  ) and 60 min after TBS (  solid traces  ). EPSPs were obtained from a control slice (  upper traces  ), a slice treated with propofol before and during the delivery of TBS (  middle set of traces  ), and a slice treated with propofol after TBS (  bottom traces  ).  Scale bar  : 2 mV, 5 ms  .
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Fig. 5. Summary of the effects of propofol and pentobarbital on the induction of  N  -methyl-d-aspartate receptor–dependent long-term potentiation and  N  -methyl-d-aspartate receptor–independent long-term potentiation. One hundred–hertz or 200-Hz θ-burst stimulation was delivered in control slices (  open bars  ), in the presence of 30 μm propofol (  filled bars  ) or 30 μm pentobarbital (  hatched bars  )  . *P  < 0.05 by Student  t  test  .
Fig. 5. Summary of the effects of propofol and pentobarbital on the induction of  N  -methyl-d-aspartate receptor–dependent long-term potentiation and  N  -methyl-d-aspartate receptor–independent long-term potentiation. One hundred–hertz or 200-Hz θ-burst stimulation was delivered in control slices (  open bars  ), in the presence of 30 μm propofol (  filled bars  ) or 30 μm pentobarbital (  hatched bars  ) 
	. *P  < 0.05 by Student  t  test 
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Fig. 5. Summary of the effects of propofol and pentobarbital on the induction of  N  -methyl-d-aspartate receptor–dependent long-term potentiation and  N  -methyl-d-aspartate receptor–independent long-term potentiation. One hundred–hertz or 200-Hz θ-burst stimulation was delivered in control slices (  open bars  ), in the presence of 30 μm propofol (  filled bars  ) or 30 μm pentobarbital (  hatched bars  )  . *P  < 0.05 by Student  t  test  .
×
Fig. 6. Propofol inhibits the induction of  N  -methyl-d-aspartate receptor–independent long-term potentiation. In the presence of 1 μm MK-801 (  dashed bar  ), 200-Hz θ-burst stimulation (TBS) induced long-term potentiation (  open circles  ). Long-term potentiation induction was inhibited (  filled circles  ) when 30 μm propofol (  solid bar  ) was administered before and during the delivery of the 200-Hz TBS (  arrow  ).  Traces to the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after TBS (  solid traces  ). TBS was administered in the presence or absence of propofol (  upper  and  lower traces  , respectively).  Scale bar  : 2 mV, 5 ms  .
Fig. 6. Propofol inhibits the induction of  N  -methyl-d-aspartate receptor–independent long-term potentiation. In the presence of 1 μm MK-801 (  dashed bar  ), 200-Hz θ-burst stimulation (TBS) induced long-term potentiation (  open circles  ). Long-term potentiation induction was inhibited (  filled circles  ) when 30 μm propofol (  solid bar  ) was administered before and during the delivery of the 200-Hz TBS (  arrow  ).  Traces to the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after TBS (  solid traces  ). TBS was administered in the presence or absence of propofol (  upper  and  lower traces  , respectively).  Scale bar  : 2 mV, 5 ms 
	.
Fig. 6. Propofol inhibits the induction of  N  -methyl-d-aspartate receptor–independent long-term potentiation. In the presence of 1 μm MK-801 (  dashed bar  ), 200-Hz θ-burst stimulation (TBS) induced long-term potentiation (  open circles  ). Long-term potentiation induction was inhibited (  filled circles  ) when 30 μm propofol (  solid bar  ) was administered before and during the delivery of the 200-Hz TBS (  arrow  ).  Traces to the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after TBS (  solid traces  ). TBS was administered in the presence or absence of propofol (  upper  and  lower traces  , respectively).  Scale bar  : 2 mV, 5 ms  .
×
Fig. 7. Effects of propofol on  N  -methyl-d-aspartate receptor–dependent and independent long-term potentiation (LTP) in the presence of picrotoxin. (  A  ) In the presence of 1 μm picrotoxin (  dashed bar  ), 30 μm propofol (  solid bar  ) administered for 20 min before delivery of θ-burst stimulation (TBS;  arrow  ) did not inhibit LTP induction (  filled circles  ). Open circles show control LTP in the presence of picrotoxin induced by 100-Hz TBS (  arrow  ). (  B  ) Two hundred–hertz TBS (  arrow  ) induced LTP in the presence of 1 μm MK-801 (  open circles  ) and 1 μm picrotoxin (  dotted bar  ). In the presence of MK-801 and picrotoxin (  dotted bar  ), 30 μm propofol did not inhibit LTP induction (  filled circles  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) the delivery of 100-Hz TBS (  upper two sets of traces  ) or 200-Hz TBS in the presence of MK-801 (  lower two sets of traces  ). EPSP waves from control slices are shown in the  top  and  third from the top traces  , whereas slices treated with propofol are shown in the  second from the top  and  bottom traces  .  Scale bar  : 2 mV, 5 ms  .
Fig. 7. Effects of propofol on  N  -methyl-d-aspartate receptor–dependent and independent long-term potentiation (LTP) in the presence of picrotoxin. (  A  ) In the presence of 1 μm picrotoxin (  dashed bar  ), 30 μm propofol (  solid bar  ) administered for 20 min before delivery of θ-burst stimulation (TBS;  arrow  ) did not inhibit LTP induction (  filled circles  ). Open circles show control LTP in the presence of picrotoxin induced by 100-Hz TBS (  arrow  ). (  B  ) Two hundred–hertz TBS (  arrow  ) induced LTP in the presence of 1 μm MK-801 (  open circles  ) and 1 μm picrotoxin (  dotted bar  ). In the presence of MK-801 and picrotoxin (  dotted bar  ), 30 μm propofol did not inhibit LTP induction (  filled circles  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) the delivery of 100-Hz TBS (  upper two sets of traces  ) or 200-Hz TBS in the presence of MK-801 (  lower two sets of traces  ). EPSP waves from control slices are shown in the  top  and  third from the top traces  , whereas slices treated with propofol are shown in the  second from the top  and  bottom traces  .  Scale bar  : 2 mV, 5 ms 
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Fig. 7. Effects of propofol on  N  -methyl-d-aspartate receptor–dependent and independent long-term potentiation (LTP) in the presence of picrotoxin. (  A  ) In the presence of 1 μm picrotoxin (  dashed bar  ), 30 μm propofol (  solid bar  ) administered for 20 min before delivery of θ-burst stimulation (TBS;  arrow  ) did not inhibit LTP induction (  filled circles  ). Open circles show control LTP in the presence of picrotoxin induced by 100-Hz TBS (  arrow  ). (  B  ) Two hundred–hertz TBS (  arrow  ) induced LTP in the presence of 1 μm MK-801 (  open circles  ) and 1 μm picrotoxin (  dotted bar  ). In the presence of MK-801 and picrotoxin (  dotted bar  ), 30 μm propofol did not inhibit LTP induction (  filled circles  ).  Traces to the right of each graph  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) the delivery of 100-Hz TBS (  upper two sets of traces  ) or 200-Hz TBS in the presence of MK-801 (  lower two sets of traces  ). EPSP waves from control slices are shown in the  top  and  third from the top traces  , whereas slices treated with propofol are shown in the  second from the top  and  bottom traces  .  Scale bar  : 2 mV, 5 ms  .
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Fig. 8. Effects of pentobarbital on long-term potentiation (LTP) induction. (  A  ) Pentobarbital, 30 μm (  solid bar  ), did not completely inhibit the induction of  N  -methyl-d-aspartate receptor–dependent LTP (  filled circles  ) induced by 100-Hz θ-burst stimulation (TBS;  arrow  ).  Open circles  show LTP in control slices. (  B  ) Pentobarbital, 30 μm (  solid bar  ), did not completely block the induction of  N  -methyl-d-aspartate receptor–independent LTP (  filled circle  ) induced by 200-Hz TBS (  arrow  ) in the presence of 1 μm MK-801 (  dotted bar  ).  Open circles  show LTP in control slices.  Traces to the right of the graphs  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) delivery of 100-Hz TBS (  upper  ) in the presence of pentobarbital or 200-Hz TBS in the presence of MK-801 and pentobarbital (  lower traces  ). (  C  ) Pentobarbital did not alter  N  -methyl-d-aspartate–EPSPs.  Scale bar  : 2 mV, 5 ms  .
Fig. 8. Effects of pentobarbital on long-term potentiation (LTP) induction. (  A  ) Pentobarbital, 30 μm (  solid bar  ), did not completely inhibit the induction of  N  -methyl-d-aspartate receptor–dependent LTP (  filled circles  ) induced by 100-Hz θ-burst stimulation (TBS;  arrow  ).  Open circles  show LTP in control slices. (  B  ) Pentobarbital, 30 μm (  solid bar  ), did not completely block the induction of  N  -methyl-d-aspartate receptor–independent LTP (  filled circle  ) induced by 200-Hz TBS (  arrow  ) in the presence of 1 μm MK-801 (  dotted bar  ).  Open circles  show LTP in control slices.  Traces to the right of the graphs  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) delivery of 100-Hz TBS (  upper  ) in the presence of pentobarbital or 200-Hz TBS in the presence of MK-801 and pentobarbital (  lower traces  ). (  C  ) Pentobarbital did not alter  N  -methyl-d-aspartate–EPSPs.  Scale bar  : 2 mV, 5 ms 
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Fig. 8. Effects of pentobarbital on long-term potentiation (LTP) induction. (  A  ) Pentobarbital, 30 μm (  solid bar  ), did not completely inhibit the induction of  N  -methyl-d-aspartate receptor–dependent LTP (  filled circles  ) induced by 100-Hz θ-burst stimulation (TBS;  arrow  ).  Open circles  show LTP in control slices. (  B  ) Pentobarbital, 30 μm (  solid bar  ), did not completely block the induction of  N  -methyl-d-aspartate receptor–independent LTP (  filled circle  ) induced by 200-Hz TBS (  arrow  ) in the presence of 1 μm MK-801 (  dotted bar  ).  Open circles  show LTP in control slices.  Traces to the right of the graphs  show representative excitatory postsynaptic potentials (EPSPs) before (  dashed traces  ) and 60 min after (  solid traces  ) delivery of 100-Hz TBS (  upper  ) in the presence of pentobarbital or 200-Hz TBS in the presence of MK-801 and pentobarbital (  lower traces  ). (  C  ) Pentobarbital did not alter  N  -methyl-d-aspartate–EPSPs.  Scale bar  : 2 mV, 5 ms  .
×
Fig. 9. Propofol does not inhibit the induction of long-term depression (LTD). (  A  ) Delivery of low-frequency stimulation consisting of 900 pulses at 1 Hz (  five arrows  ) induced LTD in the presence (  filled circles  ) or absence (  open circles  ) of 30 μm propofol (  solid bar  ). (  B  ) Delivery of 900 pulses at 10 Hz (  two arrows  ) did not induce long-term potentiation or LTD in control slices (  open circles  ). Administration of 30 μm propofol did not alter the effects of 10-Hz stimulation (  filled circles  ).  Traces on the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after (  solid traces  ) 1-Hz (  upper two sets  ) or 10-Hz stimulation (  lower two sets  ). EPSPs from control slices are shown in the  top  and  third set of traces  , whereas EPSPs from propofol-treated slices are shown in the  second  and  bottom traces  . Scale bar  : 2 mV, 5 ms  .
Fig. 9. Propofol does not inhibit the induction of long-term depression (LTD). (  A  ) Delivery of low-frequency stimulation consisting of 900 pulses at 1 Hz (  five arrows  ) induced LTD in the presence (  filled circles  ) or absence (  open circles  ) of 30 μm propofol (  solid bar  ). (  B  ) Delivery of 900 pulses at 10 Hz (  two arrows  ) did not induce long-term potentiation or LTD in control slices (  open circles  ). Administration of 30 μm propofol did not alter the effects of 10-Hz stimulation (  filled circles  ).  Traces on the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after (  solid traces  ) 1-Hz (  upper two sets  ) or 10-Hz stimulation (  lower two sets  ). EPSPs from control slices are shown in the  top  and  third set of traces  , whereas EPSPs from propofol-treated slices are shown in the  second  and  bottom traces  . Scale bar  : 2 mV, 5 ms 
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Fig. 9. Propofol does not inhibit the induction of long-term depression (LTD). (  A  ) Delivery of low-frequency stimulation consisting of 900 pulses at 1 Hz (  five arrows  ) induced LTD in the presence (  filled circles  ) or absence (  open circles  ) of 30 μm propofol (  solid bar  ). (  B  ) Delivery of 900 pulses at 10 Hz (  two arrows  ) did not induce long-term potentiation or LTD in control slices (  open circles  ). Administration of 30 μm propofol did not alter the effects of 10-Hz stimulation (  filled circles  ).  Traces on the right  depict representative excitatory postsynaptic potentials (EPSPs) sampled before (  dashed traces  ) and 60 min after (  solid traces  ) 1-Hz (  upper two sets  ) or 10-Hz stimulation (  lower two sets  ). EPSPs from control slices are shown in the  top  and  third set of traces  , whereas EPSPs from propofol-treated slices are shown in the  second  and  bottom traces  . Scale bar  : 2 mV, 5 ms  .
×