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Anesth Analg 2001;93:1521-1525
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Small-Dose Pentobarbital Enhances Synaptic Transmission in Rat Hippocampus

David P. Archer, MD*, Naaznin Samanani, BSc*, and Sheldon H. Roth, PhD*{dagger}

Departments of *Anesthesia and {dagger}Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada

Address correspondence and reprint requests to David P. Archer, MD, Department of Anesthesia, Foothills Medical Centre, 1403 29th Street N.W., Calgary, Alberta, Canada T2N 2T9. Address e-mail to archerd{at}cadvision.com


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We investigated the contribution of bicarbonate ion, {gamma}-aminobutyric acid-A (GABAA) receptors, and N-methyl-D-aspartate (NMDA) receptors to pentobarbital-induced enhancement of excitatory synaptic transmission in the hippocampal slice. Transverse hippocampal slices (400 µm thick) were prepared from 20- to 30-day-old Sprague-Dawley rats and maintained in an interface chamber perfused with warmed (35°C) oxygenated artificial cerebrospinal fluid. Extracellular field potentials, evoked by orthodromic paired-pulse stimulation of the Schaffer collateral CA1 pathway, were analyzed for the population spike (PS) amplitude. Pentobarbital had a concentration-dependent, biphasic effect on PS amplitudes, which were increased approximately twofold (P < 0.001) when the slice was exposed to pentobarbital concentrations of 1 and 5 µM and depressed at drug concentrations larger than 10 µM. Pentobarbital (5 µM) did not increase the PS amplitude when stimulation was stopped during exposure to the drug. The enhancement of PS amplitude was suppressed in the presence of 10 µM acetazolamide, a nonselective carbonic anhydrase inhibitor, and when the slice was bathed in CO2/HCO3--free artificial cerebrospinal fluid. Pretreatment with 1 µM picrotoxin, a GABAA receptor antagonist, or 5 µM 2-amino-5-phosphopentanoic acid, a specific NMDA receptor antagonist, also suppressed enhancement of PS amplitude by 5 µM pentobarbital. The results suggest that small concentrations of pentobarbital (1 and 5 µM) enhance synaptic transmission through mechanisms involving GABAA and NMDA receptors and the HCO3- ion.

IMPLICATIONS: Enhanced hippocampal synaptic transmission after exposure to subanesthetic concentrations of pentobarbital persists during drug washout. This finding may help to explain why some patients experience excitation and enhanced pain during emergence from anesthesia.


   Introduction
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 Introduction
Methods
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 Discussion
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Results from recent studies (1–3) have confirmed earlier clinical observations that subanesthetic concentrations of both volatile and IV anesthetics enhance nociceptive reflexes (4–6). The neural mechanisms of nociceptive reflex enhancement and other manifestations of the excitatory state (7) that occur at light levels of anesthesia remain unknown; suppression of inhibitory neurotransmission (disinhibition) has been proposed as an explanation (8). We have reported that bicarbonate ion and nitric oxide are involved in nociceptive reflex enhancement by pentobarbital (9). When examined in the same subjects, the enhancement of nociceptive withdrawal reflexes by thiopental correlates with activation of the hippocampal electroencephalogram (hEEG), offering the possibility that similar mechanisms are involved (10).

We propose that enhancement of nociceptive reflexes and activation of hEEG may reflect enhanced synaptic transmission. The purpose of this study was to test the hypothesis that concentrations of pentobarbital previously shown to enhance nociceptive reflexes and to activate hEEG in vivo increase the effectiveness of synaptic transmission in hippocampal pathways in vitro. By using a hippocampal slice preparation, we measured field potentials in the pyramidal cell layer of the CA1 region. Responses in the CA1 region were evoked by orthodromic paired-pulse stimulation of the stratum radiatum pathway during bath exposure to pentobarbital in doses ranging from 0.1 to 100 µM. The roles of bicarbonate ion, {gamma}-aminobutyric acid-A (GABAA), and N-methyl-D-aspartate (NMDA) receptors were evaluated by the administration of pharmacologic inhibitors.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
Experimental procedures were approved by the Animal Care Committee of the Faculty of Medicine at the University of Calgary. We examined synaptic transmission in the stratum radiatum/CA1 pathway of rat hippocampal slices in vitro. As previously described (11), transverse slices 400 µm thick were prepared from male Sprague-Dawley rats (20–30 days old), placed into an interface tissue chamber perfused with oxygenated, prewarmed (35°C) artificial cerebrospinal fluid (ACSF), and bubbled with 95% oxygen/5% CO2, pH 7.4. The ACSF contained (in mM) NaCl, 124; KCl, 3; NaHCO3, 26; CaCl2, 2; MgSO4, 2; glucose, 10; and NaH2PO4, 1.25. In some experiments, slices were perfused with a nominally CO2/HCO3--free solution in which NaHCO3 was replaced with 10 mM HEPES buffer. The solution was buffered to pH 7.4 with NaOH and gassed with humidified oxygen.

A bipolar tungsten stimulating electrode was placed on the stratum radiatum to activate CA1 pyramidal neurons. Paired-pulse square-wave impulses (S1 and S2, 3–5 V) (11), generated by a Grass S88 stimulation and SIU5 isolation unit (Grass Corp., Quincy, MA), were delivered with varying interpulse interval delays (30–50 ms) adjusted to produce enhancement of the response to the second pulse (paired-pulse facilitation; PPF). Stimulus amplitude was set to elicit a half-maximal response to permit detection of synaptic potentiation. Stimuli were delivered at a frequency of 0.1 Hz. A glass microelectrode (1–4 M{Omega} resistance, filled with 2 M NaCl) was placed into the CA1 cell body region to record population spikes (PSs) in response to the first (PS1) and second stimuli (PS2). With this strategy, PS1 was not consistently recorded, and this analysis is based primarily on PS2. Field potentials were amplified with a Grass P15 amplifier (1- to 50-kHz filters) and digitally stored on videocassette tape by using a DR-384 analog-to-digital converter (Neuro Data Instruments Corp., New York, NY). After a 90-min recovery period without stimulation, control measurements were recorded for 20 min. The amplitude of PS2 was measured every 100 s with custom software (Labview®-based wave form analysis program; Advanced Measurements, Calgary, Canada).

For purposes of comparison (biological positive control), conventional long-term potentiation (LTP) of synaptic transmission was induced with high-frequency stimulation (four pulse trains, 3- to 5-V amplitude, at 100 Hz, with train durations of 1 s, presented at 20-s intervals) of the stratum radiatum pathway.

Pentobarbital was obtained from The British Drug House, Toronto, Canada; the carbonic anhydrase inhibitor, acetazolamide, the GABAA channel blocker, picrotoxin, and HEPES buffer were purchased from Sigma Chemical Co., St. Louis, MO. The NMDA receptor blocker, D(-)-2-amino-5-phosponopentanoic acid (AP-5), was purchased from Research Biochemicals International, Natick, MA. Acetazolamide and AP-5 were added to the ACSF after the 20-min control period at the same time that pentobarbital was added. Picrotoxin and HEPES were added to the ACSF at the beginning of the experiment, and control conditions were established in the presence of these agents before adding pentobarbital. Each slice was used for only one drug concentration. After 30 min of drug application, the slice was again perfused with drug-free ACSF (drug washout period).

Except where otherwise noted, each experiment was performed on at least five slices obtained from different rats. For data analysis, responses were gathered in sequences of six, averaged, and stored as a single record. The sequences for analysis were selected to represent the last 10 min of the control and drug washin periods and a 10-min period after 60 min of washout. Data sequences (control, washin, and washout) for each of the pentobarbital concentrations (0.1, 0.5, 1, 5, 10, 25, 50, and 100 µM) were compared by two-way repeated-measures analysis of variance (ANOVA) or Friedman’s repeated-measures ANOVA on ranks. Analyses were performed with Sigmastat® and plotted with SigmaPlot® software (both from SPSS, Chicago, IL). Statistical significance was inferred when P < 0.05. By using five slices, the experimental protocols had a power of greater than 0.8 to detect a 100% change in PS2 amplitude. Data, except where noted otherwise, are presented as mean ± SD.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Bath application of pentobarbital altered the amplitude of the PS responses to stratum radiatum stimulation in a biphasic fashion—small concentrations enhanced PS2 amplitude, and larger concentrations suppressed the response. A gradual increase in the PS2 amplitude was observed during exposure of the slice to concentrations of 1 and 5 µM pentobarbital (Fig. 1A) to maximal values more than twice the control value. The enhanced PS response remained stable during drug washout and did not return to baseline (Figs. 1A and 2A). The amplitudes of both PS1 and PS2 increased after exposure to pentobarbital, but the ratio PS2/PS1 decreased (Table 1). With pentobarbital concentrations exceeding 10 µM, suppression of evoked responses was observed (Fig. 1B), with recovery of the PS2 to control values during drug washout. The increase in PS2 amplitude after a 60-min washout of 5 µM pentobarbital (Fig. 2A) was similar to the stable enhanced response recorded 60 min after high-frequency stimulation (Fig. 2B) (P = 0.373). When paired-pulse stimulation was stopped during pentobarbital washin and for 60 min of washout, no increases in PS2 amplitude were observed (Fig. 2A).



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  		Figure 1. A, results from a representative single experiment show the population spike (PS2) response to the second stimuli during and after application of 5 µM pentobarbital. B, the biphasic effects of pentobarbital on PS2 amplitude. Pentobarbital concentrations of 1 and 5 µM increased the efficacy of synaptic transmission, whereas concentrations of 25 µM or larger depressed PS2. Black and gray bars represent mean responses, normalized with respect to the control values, after 30 min of drug application and after 60 min of drug washout, respectively. *P < 0.05 with respect to control values. For pentobarbital concentrations of 5 µM, n = 8 slices; for all other concentrations, n = 5 slices.

 

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  		Table 1. Pentobarbital Enhances the Amplitude of Responses to Paired-Pulse Stimulation
 


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  		Figure 2. A, the increased synaptic response after exposure to 5 µM pentobarbital (•, n = 8 slices) was not observed if paired-pulse stimulation of the stratum radiatum pathway was stopped during drug application and for 60 min of drug washout ({circ}, n = 5 slices). B, high-frequency stimulation (100 Hz) resulted in an immediate increase in the amplitude of the population spike after the second stimulus (PS2) that was similar to values after 60 min of drug washout in slices stimulated during exposure to 5 µM pentobarbital (n = 5 slices, P = 0.373).

 
Application of the antagonists or HEPES buffer did not have any independent effect on PS2 amplitude (Table 2). The increase in PS2 amplitude produced by stimulation in the presence of 5 µM pentobarbital (Fig. 1) did not occur during the coadministration and washout of 10 µM acetazolamide and when HEPES buffer was substituted for NaHCO3 in the ACSF bathing the slice (Table 3). Enhancement of synaptic transmission was also blocked by the coadministration of 1 µM picrotoxin and 5 µM AP-5 (Table 3).


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  		Table 2. Independent Effects of Acetazolamide, AP-5, Picrotoxin, HEPES Buffer, and Time on Population Spike (PS2) Amplitude
 

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  		Table 3. Coadministration of Drugs that Modulate Bicarbonate Ion, and GABAA and NMDA Receptors Blocks the Population Spike (PS2) Enhancement Seen During (washin) and After 5 µM Pentobarbital (washout)
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The increase in PS2 amplitudes induced by 1 µM and 5 µM pentobarbital is consistent with enhanced synaptic transmission in the stratum radiatum/CA1 pathway. The enhanced synaptic transmission required concomitant stimulation of the pathway and remained stable during drug washout. These observations suggest that the efficacy of synaptic transmission in the stratum radiatum/CA1 pathway was changed by stimulation of the pathway in the presence of small doses of pentobarbital. It is interesting that the amplitude of the LTP induced by high-frequency stimulation was similar to that induced by paired-pulse stimulation in the presence of 5 µM pentobarbital. Further studies directed at determining whether LTP can be induced by high-frequency stimulation once the PS2 has been enhanced with 5 µM pentobarbital (saturation studies) (12) would help to clarify the relationship between LTP and PS enhancement by pentobarbital.

The results from the studies with pharmacologic antagonists (Table 3) suggest that GABAA and NMDA receptors and bicarbonate ion are involved in PS enhancement by pentobarbital. These findings are consistent with previously described NMDA receptor-dependent excitation by GABA receptor activation (13,14). However, it is important to recognize that the mechanistic interpretations that can be derived from these extracellular studies are very limited, because it is impossible to determine which components of the synaptic pathway have been altered by the presence of pentobarbital. These findings could be explained by an increase in excitatory neurotransmitter release, a decrease in inhibitory neurotransmitter release, or postsynaptic effects. Further studies with intact-slice, whole-cell intracellular recording will be required to evaluate the neurophysiologic mechanisms involved.

Pentobarbital was chosen as a prototypical anesthetic in these preliminary electrophysiological studies because its molecular pharmacology has been extensively investigated. Pentobarbital has very limited clinical application, and it will be important to extend these studies to include other drugs, such as propofol and volatile anesthetics. Results suggest that enhancement of nociceptive withdrawal reflexes is a common feature of a wide variety of anesthetics, including propofol (2), volatile anesthetics (3), and alphathesin (4). We speculate that, as in the case of pentobarbital, concentrations of anesthetics that enhance nocifensive reflexes may also enhance synaptic transmission in hippocampal pathways.

Tohdoh et al. (15) examined single-pulse stimulation of the stratum radiatum/CA1 pathway and reported enhancement of PS amplitudes to 143% of control values by 50 µM pentobarbital, the smallest concentration that was included in their article. Similar to our findings (Figs. 1 and 2), Tohdoh et al. (15) noted that the PS enhancement by pentobarbital remained stable during reperfusion with ACSF, suggesting that the effect was not simply a pharmacologic effect of pentobarbital, because the inhibitory effects of larger concentrations of pentobarbital returned toward baseline values during drug washout.

The concentrations of pentobarbital examined in this study were smaller than those used by Tohdoh et al. (15). Our previous studies (2) in vivo showed that the hyperreflexia induced by pentobarbital was maximal at plasma drug concentrations of approximately 50 µM. In vitro, pentobarbital is preferentially distributed in the lipid phase, with a coefficient of approximately 10 (16), which is consistent with our observation that synaptic transmission is maximally enhanced at an aqueous concentration of 5 µM.

This study used paired-pulse stimulation, whereas Tohdoh et al. (15) used single stimuli. PPF of synaptic transmission is a form of short-term synaptic plasticity in which the second response to a pair of stimuli is enhanced when an appropriate interstimulus interval is selected (17). Paired-pulse stimulation has been used to examine how local stimulation can modify synapses in hippocampal neural networks (17). Activity-dependent mechanisms similar to those seen with PPF are proposed to be play a role in development, signal processing, learning, and memory (17). At least three factors are thought to contribute to PPF: increased presynaptic glutamate release (18), reduction in presynaptic GABA release (19,20), and activation of postsynaptic Ca2+/calmodulin-dependent protein kinase II (21). PPF decreases after the induction of LTP (22), a finding that is consistent with our observation that PS2/PS1 was decreased during the pentobarbital washout period when enhancement of synaptic transmission was greatest (Table 1).

In summary, we report a novel observation that paired-pulse stimulation of the stratum radiatum in the rat hippocampal slice in the presence of small concentrations of pentobarbital results in enhancement of the PS response. GABA and NMDA receptors and bicarbonate ion seem to be involved in the PS enhancement. These findings suggest that synaptic transmission in neural circuits thought to contribute to spatial memory in the rat (23) can be altered by stimulation in the presence of small concentrations of anesthetic. If these effects can be shown to occur in vivo, we speculate that they may have relevance for the long-term cognitive dysfunction that occurs in older patients after anesthesia (24).


   Acknowledgments
 
Supported in part by the Medical Research and the Canadian Anesthesiologists Society Burroughs-Wellcome Research Award.


   Footnotes
 
Presented in part at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, October, 2000.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  9. Archer DP, Roth SH. Acetazolamide and amiloride block pentobarbital-induced enhancement of nocifensive reflexes. Anesthesiology 1999; 90: 1158–64.[ISI][Medline]
  10. Archer DP, Roth SH. Pharmacodynamics of thiopentone: nocifensive reflex threshold changes correlate with hippocampal electroencephalography. Br J Anaesth 1997; 79: 744–9.[Abstract/Free Full Text]
  11. Hirota K, Roth SH. Sevoflurane modulates both GABAA and GABAB receptors in area CA1 of rat hippocampus. Br J Anaesth 1997; 78: 60–5.[Abstract/Free Full Text]
  12. Moser EI, Krobert KA, Moser M-B, Morris RGM. Impaired spatial learning after saturation of long-term potentiation. Science 1998; 281: 2038–42.[Abstract/Free Full Text]
  13. Smirnov S, Paalasmaa P, Uusisaari M, et al. Pharmacological isolation of the synaptic and nonsynaptic components of the GABA-mediated biphasic response in rat CA1 hippocampal pyramidal neurons. J Neurosci 1999; 19: 9252–60.[Abstract/Free Full Text]
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Accepted for publication July 24, 2001.




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