Bio

Academic Appointments


Administrative Appointments


  • NIH SAT Study Section, NIH (2013 - 2017)
  • Faculty Senate, Stanford Medical School (2008 - 2014)
  • Committee on Graduate Studies, Stanford University (2008 - 2011)
  • Environmental Health & Safety, Stanford University (2006 - 2009)
  • Neuroscience Subcommittee, Amer Soc Anesthesiology (2006 - 2013)
  • NIH Study Section - Adjunct, NIH (2004 - 2012)
  • Neuroscience Admissions Panel, Stanford Medical School (2000 - 2005)
  • Neuroscience Program Executive, Stanford Medical School (1997 - 2005)

Honors & Awards


  • Top 5 % of Reviews, Faculty of 1000 (2010 - 2013)
  • Top 10 % Reveiwer, Anesthesiology (2010)
  • Top 10 % of Reviews, Faculty of 1000 (Medicine) (2009)
  • Top 100 Citations, Anesthesia & Analgesia (2005)
  • Allen V. Cox Medal, Stanford University (2004)

Boards, Advisory Committees, Professional Organizations


  • Subcommittee Member, American Society of Anesthesiology (2005 - 2013)
  • Member, Society for Neuroscience (1985 - Present)
  • Member, Association of University Anesthesiologists (1998 - Present)
  • Member, International Society for Anaesthetic Pharmacology (2013 - Present)

Professional Education


  • MSc PhD, University of Calgary, Neuroscience and Pharmacology (1987)

Community and International Work


  • Sierra Club since 1987

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Amnesty International since 1996

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Wilderness Foundation since 1991

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Neuropharmacology

Cellular, synaptic and molecular mechanisms of action of central nervous system drugs; especially barbiturates, opiates, anesthetics and other CNS depressants. We use electrophysiological recording techniques and selective pharmacological probes, in hippocampal and cortical brain slices, to investigate the sites and mechanisms of action for CNS active agents. The long-term goal of our studies is to provide physiological background information required for the rational design of safer and more effective anesthetics and analgesics. Our recent studies have focussed on anesthetic effects at glutamate and GABA-mediated synapses as important targets for the CNS depressant effects of these agents. Depressed glutamate-mediated excitatory neurotransmission appears to be a common effect produced by most general anesthetics. We are currently studying agent specific actions at AMPA and NMDA glutamate receptor subtypes. Enhanced GABA-mediated inhibitory neurotransmission also appears to play an important role for many anesthetics. Anesthetics appear to act at both pre- and post-synaptic sites to alter neurotransmission in higher brain centers. Thus, discrete synaptic targets could provide fruitful avenues for the development of safer and more effective therapeutic agents for analgesia and anesthesia.

Teaching

2013-14 Courses


Publications

Journal Articles


  • Teaching an Old GABA Receptor New Tricks ANESTHESIA AND ANALGESIA Trudell, J. R., Bertaccini, E., Maclver, M. B. 2012; 115 (2): 270-273

    Abstract

    The accompanying articles in this issue of the journal's special collection describe attempts to improve on the dynamics of distribution and reduce side effects of analogs of etomidate and benzodiazepines. Both classes of drugs have their principal sites of action on ?-aminobutyric acid type A receptors, although at very different binding sites and by different mechanisms of action. Herein, we review the structure of ?-aminobutyric acid type A receptors and describe the location of the 2 likely binding sites. In addition, we describe how these drugs can interact with the nervous system at a systems level. We leave it to other reviewers to discuss whether these new drugs offer true clinical improvements.

    View details for DOI 10.1213/ANE.0b013e31824a0b3c

    View details for Web of Science ID 000306769500012

    View details for PubMedID 22344244

  • Human Subthalamic Neuron Spiking Exhibits Subtle Responses to Sedatives ANESTHESIOLOGY MacIver, M. B., Bronte-Stewart, H. M., Henderson, J. M., Jaffe, R. A., Brock-Utne, J. G. 2011; 115 (2): 254-264

    Abstract

    During deep brain stimulation implant surgery, microelectrode recordings are used to map the location of targeted neurons. The effects produced by propofol or remifentanil on discharge activity of subthalamic neurons were studied intraoperatively to determine whether they alter neuronal activity.Microelectrode recordings from 11 neurons, each from individual patients, were discriminated and analyzed before and after administration of either propofol or remifentanil. Subthalamic neurons in rat brain slices were recorded in patch-clamp to investigate cellular level effects.Neurons discharged at 42 ± 9 spikes/s (mean ± SD) and showed a common pattern of inhibition that lasted 4.3 ms. Unique discharge profiles were evident for each neuron, seen using joint-interval analysis. Propofol (intravenous bolus 0.3 mg/kg) produced sedation, with minor effects on discharge activity (less than 2.0% change in frequency). A prolongation of recurrent inhibition was evident from joint-interval analysis, and propofol's effect peaked within 2 min, with recovery evident at 10 min. Subthalamic neurons recorded in rat brain slices exhibited inhibitory synaptic currents that were prolonged by propofol (155%) but appeared to lack tonic inhibitory currents. Propofol did not alter membrane potential, membrane resistance, current-evoked discharge, or holding current during voltage clamp. Remifentanil (0.05 mg/kg) had little effect on overall subthalamic neuron discharge activity and did not prolong recurrent inhibition.These results help to characterize the circuit properties and feedback inhibition of subthalamic neurons and demonstrate that both propofol and remifentanil produce only minor alterations of subthalamic neuron discharge activity that should not interfere with deep brain stimulation implant surgery.

    View details for Web of Science ID 000293168800006

    View details for PubMedID 21701380

  • Loss of Recall and the Hippocampal Circuit Effects Produced by Anesthetics SUPPRESSING THE MIND: ANESTHETIC MODULATION OF MEMORY AND CONSCIOUSNESS MacIver, M. B. 2010: 175-192
  • Abused Inhalants Enhance GABA-Mediated Synaptic Inhibition NEUROPSYCHOPHARMACOLOGY MacIver, M. B. 2009; 34 (10): 2296-2304

    Abstract

    Abused inhalants are widely used, especially among school-age children and teenagers, and are 'gateway' drugs leading to the abuse of alcohol and other addictive substances. In spite of this widespread use, little is known about the effects produced by inhalants on the central nervous system. The similarity in behavioral effects produced by inhalants and inhaled anesthetics, together with their common chemical features, prompted this study of inhalant actions on a well-characterized anesthetic target, GABA synapses. Whole-cell patch clamp recordings were conducted on CA1 pyramidal neurons in rat hippocampal brain slices to measure effects on resting membrane properties, action potential discharge, and GABA-mediated inhibitory responses. Toluene, 1,1,1-trichloroethane, and trichloroethylene depressed CA1 excitability in a concentration-dependent and reversible manner. This depression appeared to involve enhanced GABA-mediated inhibition, evident in its reversal by a GABA receptor antagonist. Consistent with this, the abused inhalants increased inhibitory postsynaptic potentials produced using minimal stimulation of stratum radiatum inputs to CA1 neurons, in the presence of CNQX and APV to block excitatory synaptic responses and GGP to block GABA(B) responses. The enhanced inhibition appeared to come about by a presynaptic action on GABA nerve terminals, because spontaneous inhibitory postsynaptic current (IPSC) frequency was increased with no change in the amplitude of postsynaptic currents, both in the presence and absence of tetrodotoxin used to block interneuron action potentials and cadmium used to block calcium influx into nerve terminals. The toluene-induced increase in mIPSC frequency was blocked by dantrolene or ryanodine, indicating that the abused inhalant acted to increase the release of calcium from intracellular nerve terminal stores. This presynaptic action produced by abused inhalants is shared by inhaled anesthetics and would contribute to the altered behavioral effects produced by both classes of drugs, and could be especially important in the context of a disruption of learning and memory by abused inhalants.

    View details for DOI 10.1038/npp.2009.57

    View details for Web of Science ID 000268919100010

    View details for PubMedID 19494804

  • Anesthetics Discriminate Between Tonic and Phasic gamma-Aminobutyric Acid Receptors on Hippocampal CA1 Neurons ANESTHESIA AND ANALGESIA Bieda, M. C., Su, H., Maclver, M. B. 2009; 108 (2): 484-490

    Abstract

    Anesthesia is produced by a depression of neuronal signaling in the central nervous system (CNS); however, the mechanism(s) of action underlying this depression remain unclear. Recent studies have indicated that anesthetics can enhance inhibition of CNS neurons by increasing current flow through tonic gamma-aminobutyric acid (GABA(A)) receptor gated chloride channels in their membranes. Enhanced tonic inhibition would contribute to CNS depression produced by anesthetics, but it remains to be determined to what extent anesthetic actions at these receptors contribute to CNS depression. In the present study, we compared and contrasted the involvement of tonic versus synaptic GABA(A) receptors in the functional depression of CNS neurons produced by isoflurane and thiopental.In rat hippocampal slices, whole cell patch clamp recordings were used to study anesthetic effects on CA1 neuron intrinsic excitability, and population spike recordings were used to investigate effects on synaptically evoked discharge. These responses were chosen to test whether anesthetic effects on GABA receptors alter single neuron discharge and/or circuit level synaptic functioning. Phasic (synaptic) GABA receptors were selectively blocked using the GABA(A) antagonist gabazine and tonic responses were blocked using the chloride channel blocker picrotoxin.Clinically relevant and equi-effective concentrations of thiopental and isoflurane depressed CA1 neuron synaptically evoked discharge. This depression was partially reversed by blocking synaptic GABA(A) receptors with gabazine (20 microM). The thiopental-induced depression was reversed by approximately 60%, but the isoflurane-induced depression was reversed by only approximately 20%. Blocking tonic GABA(A) receptors with the addition of 100 microM picrotoxin produced an additional 40% reversal of the thiopental-induced depression, but no additional reversal was seen for isoflurane-depressed responses. In response to direct DC current injection, CA1 neuron discharge was depressed by thiopental and membrane conductance was increased. Both of these effects were reversed by picrotoxin, but not by gabazine. Isoflurane, in contrast, neither depressed current-evoked discharge, nor altered the membrane conductance of CA1 neurons.These results indicate that general anesthetics discriminate between synaptic and tonic GABA(A) receptors. Effects on both phasic and tonic receptors combined to depress circuit responses produced by thiopental, whereas only effects on synaptic GABA receptors appeared to play an important role for isoflurane. Together with the other known sites of action for these two anesthetics, our results support a multisite, agent-specific mechanism for anesthetic actions.

    View details for DOI 10.1213/ane.0b013e3181904571

    View details for Web of Science ID 000262590000016

    View details for PubMedID 19151276

  • Slow GABA(A) mediated synaptic transmission in rat visual cortex BMC NEUROSCIENCE Sceniak, M. P., MacIver, M. B. 2008; 9

    Abstract

    Previous reports of inhibition in the neocortex suggest that inhibition is mediated predominantly through GABA(A) receptors exhibiting fast kinetics. Within the hippocampus, it has been shown that GABA(A) responses can take the form of either fast or slow response kinetics. Our findings indicate, for the first time, that the neocortex displays synaptic responses with slow GABA(A) receptor mediated inhibitory postsynaptic currents (IPSCs). These IPSCs are kinetically and pharmacologically similar to responses found in the hippocampus, although the anatomical specificity of evoked responses is unique from hippocampus. Spontaneous slow GABA(A) IPSCs were recorded from both pyramidal and inhibitory neurons in rat visual cortex.GABA(A) slow IPSCs were significantly different from fast responses with respect to rise times and decay time constants, but not amplitudes. Spontaneously occurring GABA(A) slow IPSCs were nearly 100 times less frequent than fast sIPSCs and both were completely abolished by the chloride channel blocker, picrotoxin. The GABA(A) subunit-specific antagonist, furosemide, depressed spontaneous and evoked GABA(A) fast IPSCs, but not slow GABA(A)-mediated IPSCs. Anatomical specificity was evident using minimal stimulation: IPSCs with slow kinetics were evoked predominantly through stimulation of layer 1/2 apical dendritic zones of layer 4 pyramidal neurons and across their basal dendrites, while GABA(A) fast IPSCs were evoked through stimulation throughout the dendritic arborization. Many evoked IPSCs were also composed of a combination of fast and slow IPSC components.GABA(A) slow IPSCs displayed durations that were approximately 4 fold longer than typical GABA(A)fast IPSCs, but shorter than GABA(B)-mediated inhibition. The anatomical and pharmacological specificity of evoked slow IPSCs suggests a unique origin of synaptic input. Incorporating GABA(A) slow IPSCs into computational models of cortical function will help improve our understanding of cortical information processing.

    View details for DOI 10.1186/1471-2202-9-8

    View details for Web of Science ID 000253536800002

    View details for PubMedID 18199338

  • Cellular actions of urethane on rat visual cortical neurons in vitro JOURNAL OF NEUROPHYSIOLOGY Sceniak, M. P., MacIver, M. B. 2006; 95 (6): 3865-3874

    Abstract

    Urethane is widely used in neurophysiological experiments to anesthetize animals, yet little is known about its actions at the cellular and synaptic levels. This limits our ability to model systems-level cortical function using results from urethane-anesthetized preparations. The present study found that action potential discharge of cortical neurons in vitro, in response to depolarizing current, was strongly depressed by urethane and this was accompanied by a significant decrease in membrane resistance. Voltage-clamp experiments suggest that the mechanism of this depression involves selective activation of a Ba2+-sensitive K+ leak conductance. Urethane did not alter excitatory glutamate-mediated or inhibitory (GABA(A)- or GABA(B)-mediated) synaptic transmission. Neither the amplitude nor decay time constant of GABA(A)- or GABA(B)-mediated monosynaptic inhibitory postsynaptic currents (IPSCs) were altered by urethane, nor was the frequency of spontaneous IPSCs. These results are consistent with observations seen in vivo during urethane anesthesia where urethane produced minimal disruption of signal transmission in the neocortex.

    View details for DOI 10.1152/jn.01196.2005

    View details for Web of Science ID 000237653900050

    View details for PubMedID 16510775

  • Anesthesia in silico ANESTHESIOLOGY Sceniak, M. P., MacIver, M. B. 2006; 104 (3): 400-402

    View details for Web of Science ID 000235766400003

    View details for PubMedID 16508384

  • Isoflurane depresses hippocampal CA1 glutamate nerve terminals without inhibiting fiber volleys BMC NEUROSCIENCE Winegar, B. D., MacIver, M. B. 2006; 7

    Abstract

    Anesthetic-induced CNS depression is thought to involve reduction of glutamate release from nerve terminals. Recent studies suggest that isoflurane reduces glutamate release by block of Na channels. To further investigate this question we examined the actions of isoflurane, TTX, extracellular Ca2+, CNQX and stimulus voltage (stim) on glutamate-mediated transmission at hippocampal excitatory synapses. EPSPs were recorded from CA1 neurons in rat hippocampal brain slices in response to Schaffer-collateral fiber stimulation.Isoflurane (350 microM; 1 MAC) reversibly depressed EPSP amplitudes by ~60% while facilitation increased approximately 20%. Consistent with previous studies, these results indicate a presynaptic site of action that involves reduced excitation-release coupling. EPSPs were depressed to comparable levels by TTX (60 nM) or lowered stim, but facilitation was not changed, indicating a simple failure of axonal conduction. Similarly, partial antagonism of postsynaptic glutamate receptors with CNQX (10 microM) depressed EPSP amplitudes with no change in facilitation. However, EPSP depression by low external Ca2+ (0.8 mM) was accompanied by an increase in facilitation comparable to isoflurane. Isoflurane depression of EPSP amplitudes could also be partly reversed by high external Ca2+ (4 mM) that also decreased facilitation. Isoflurane or low Ca2+ markedly reduced the slopes of fiber volley (FV)-EPSP input-output curves, consistent with little or no effect on FVs. By contrast, TTX didn't alter the FV-EPSP curve slope, indicating that EPSP depression resulted from FV depression. FVs were remarkably resistant to isoflurane. Somatic spike currents were unaffected by 350 microM (1 MAC) isoflurane as well. The EC50 for isoflurane depression of FVs was approximately 2.8 mM (12 vol. %; 8 MAC).Isoflurane appears to depress CA1 synapses at presynaptic sites downstream from Na channels, as evident by the increased facilitation that accompanies EPSP depression. Fiber volleys did not exhibit depression by isoflurane, as has been reported for other brain regions.

    View details for DOI 10.1186/1471-2202-7-5

    View details for Web of Science ID 000235339000001

    View details for PubMedID 16409641

  • Anesthetic-induced burst suppression EEG activity requires glutamate-mediated excitatory synaptic transmission CEREBRAL CORTEX Lukatch, H. S., Kiddoo, C. E., MacIver, M. B. 2005; 15 (9): 1322-1331

    Abstract

    Many anesthetics evoke electroencephalogram (EEG) burst suppression activity in humans and animals during anesthesia, and the mechanisms underlying this activity remain unclear. The present study used a rat neocortical brain slice EEG preparation to investigate excitatory synaptic mechanisms underlying anesthetic-induced burst suppression activity. Excitatory synaptic mechanisms associated with burst suppression activity were probed using glutamate receptor antagonists (CNQX and APV), GABA receptor antagonists, and simultaneous whole cell patch clamp and microelectrode EEG recordings. Clinically relevant concentrations of thiopental (50--70 microM), propofol (5--10 microM) or isoflurane (0.7--2.1 vol%, 0.5--1.5 rat minimum aveolar concentration (MAC), 200--700 microM) evoked delta slow wave activity and burst suppression EEG patterns similar to in vivo responses. These effects on EEG signals were blocked by glutamate receptor antagonists CNQX (8.6 microM) or APV (50 microM). Depolarizing intracellular bursts (amplitude=34.7+/-4.5 mV; half width=132+/-60 ms) always accompanied EEG bursts, and hyperpolarization increased intracellular burst amplitudes. Barrages of glutamate-mediated excitatory events initiated EEG bursting activity. Glutamate-mediated excitatory postsynaptic currents were significantly depressed by higher anesthetic concentrations that depressed burst suppression EEG activity. A GABA(A) agonist produced a similar EEG effect to the anesthetics. It appears that anesthetic effects at both glutamate and GABA synapses contribute to EEG patterns seen during anesthesia.

    View details for DOI 10.1093/cercor/bhi015

    View details for Web of Science ID 000231296900005

    View details for PubMedID 15647528

  • Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices BMC NEUROSCIENCE Pittson, S., Himmel, A. M., MacIver, M. B. 2004; 5

    Abstract

    Anesthesia is produced by a depression of central nervous system function, however, the sites and mechanisms of action underlying this depression remain poorly defined. The present study compared and contrasted effects produced by five general anesthetics on synaptic circuitry in the CA1 region of hippocampal slices.At clinically relevant and equi-effective concentrations, presynaptic and postsynaptic anesthetic actions were evident at glutamate-mediated excitatory synapses and at GABA-mediated inhibitory synapses. In addition, depressant effects on membrane excitability were observed for CA1 neuron discharge in response to direct current depolarization. Combined actions at several of these sites contributed to CA1 circuit depression, but the relative degree of effect at each site was different for each anesthetic studied. For example, most of propofol's depressant effect (> 70 %) was reversed with a GABA antagonist, but only a minor portion of isoflurane's depression was reversed (< 20 %). Differences were also apparent on glutamate synapses-pentobarbital depressed transmission by > 50 %, but thiopental by only < 25 %.These results, in as much as they may be relevant to anesthesia, indicate that general anesthetics act at several discrete sites, supporting a multi-site, agent specific theory for anesthetic actions. No single effect site (e.g. GABA synapses) or mechanism of action (e.g. depressed membrane excitability) could account for all of the effects produced for any anesthetic studied.

    View details for DOI 10.1186/1471-2202-5-52

    View details for Web of Science ID 000226606200004

    View details for PubMedID 15579203

  • Determination of diffusion and partition coefficients of propofol in rat brain tissue: implications for studies of drug action in vitro BRITISH JOURNAL OF ANAESTHESIA Gredell, J. A., Turnquist, P. A., MacIver, M. B., Pearce, R. A. 2004; 93 (6): 810-817

    Abstract

    Propofol (2,6-diisopropylphenol) is a widely used general anaesthetic that modulates gamma-aminobutyric acid type A (GABA(A)) receptors, the major inhibitory neurotransmitter receptor in the brain. Previous studies have found that the concentration of propofol that is required to affect synaptic inhibition in brain slices is much higher than the free concentration that is achieved clinically and that modulates isolated receptors. We tested whether this is accounted for by slow equilibration in brain tissue, and determined the concentration that must be applied to achieve appropriate brain levels.Rat brain slices 300-microm thick were placed in a solution of 100 microM propofol in artificial cerebrospinal fluid for times ranging from 7.5 to 480 min. Concentrations in these slices were measured by HPLC to determine diffusion and partition coefficients. Electrophysiological measurements of the rate at which effects of 5 microM propofol developed were compared with the calculated rate of increase in tissue concentration.The diffusion coefficient was approximately 0.02x10(-6) cm2 s(-1), and the brain:artificial cerebrospinal fluid partition coefficient was 36. Diffusion times in brain slices agreed well with time course measurements of propofol-induced depression of synaptic responses, which continued to increase over 5 h. This depression was reversed by blocking GABA inhibition with picrotoxin (100 microM).Propofol does enhance inhibition in brain slices at a concentration of 0.63 microM in the superfusate, which produces brain concentrations corresponding with those achieved in vivo, but equilibration requires several hours. It is likely that slow diffusion to GABA receptors accounts for the high concentrations (>10 microM) that were needed to depress evoked responses in previous investigations.

    View details for DOI 10.1093/bja/aeh272

    View details for Web of Science ID 000225250500012

    View details for PubMedID 15377586

  • Major role for tonic GABA(A) conductances in anesthetic suppression of intrinsic neuronal excitability JOURNAL OF NEUROPHYSIOLOGY Bieda, M. C., MacIver, M. B. 2004; 92 (3): 1658-1667

    Abstract

    Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABA(A) inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABA(A) but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABA(A)-mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABA(A)-mediated inhibition using the GABA(A) receptor antagonist SR95531 (gabazine). Gabazine (20 microM) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABA(A) inhibition. Glutamatergic synaptic responses were not altered by propofol (< or =30 microM). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABA(A) conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABA(A) conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

    View details for DOI 10.1152/jn.00223.2004

    View details for Web of Science ID 000223539400037

    View details for PubMedID 15140905

  • Anesthetic properties of 4-iodopropofol - Implications for mechanisms of anesthesia ANESTHESIOLOGY Lingamaneni, R., Krasowski, M. D., Jenkins, A., Truong, T., Giunta, A. L., Blackbeer, J., MacIver, M. B., Harrison, N. L., Hemmings, H. C. 2001; 94 (6): 1050-1057

    Abstract

    Positive modulation of gamma-aminobutyric acid type A (GABAA) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including propofol. The role for GABAA receptors as an essential site in the anesthetic actions of propofol was recently challenged by a report that the propofol analog 4-iodopropofol (4-iodo-2,6-diisopropylphenol) potentiated and directly activated GABAA receptors, yet was devoid of sedative-anesthetic effects in rats after intraperitoneal injection. Given the important implications of these findings for theories of anesthesia, the authors compared the effects of 4-iodopropofol with those of propofol using established in vivo and in vitro assays of both GABAA receptor-dependent and -independent anesthetic actions.The effects of propofol and 4-iodopropofol were analyzed on heterologously expressed recombinant human GABAA alpha1beta2gamma2 receptors, evoked population spike amplitudes in rat hippocampal slices, and glutamate release from rat cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in Xenopus laevis tadpoles, in mice after intraperitoneal injection, and in rats after intravenous injection.Like propofol, 4-iodopropofol enhanced GABA-induced currents in recombinant GABAA receptors, inhibited synaptic transmission in rat hippocampal slices, and inhibited sodium channel-mediated glutamate release from synaptosomes, but with reduced potency. After intraperitoneal injection, 4-iodopropofol did not produce anesthesia in mice, but it was not detected in serum or brain. However, 4-iodopropofol did produce anesthesia in tadpoles (EC50 = 2.5 +/- 0.5 microM) and in rats after intravenous injection (ED50 = 49 +/- 6.2 mg/kg).Propofol and 4-iodopropofol produced similar actions on several previously identified cellular and molecular targets of general anesthetic action, and both compounds induced anesthesia in tadpoles and rats. The failure of 4-iodopropofol to induce anesthesia in rodents after intraperitoneal injection is attributed to a pharmacokinetic difference from propofol rather than to major pharmacodynamic differences.

    View details for Web of Science ID 000169137700016

    View details for PubMedID 11465597

  • Agent-selective effects of volatile anesthetics on GABA(A) receptor-mediated synaptic inhibition in hippocampal interneurons ANESTHESIOLOGY Nishikawa, K., MacIver, M. B. 2001; 94 (2): 340-347

    Abstract

    A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal cells in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role for the maintenance of anesthesia. The aim of this study was to compare effects produced by volatile anesthetics on inhibitory postsynaptic currents (IPSCs) of rat hippocampal interneurons.Pharmacologically isolated gamma-aminobutyric acid type A (GABAA) receptor-mediated IPSCs were recorded with whole cell patch-clamp techniques in visually identified interneurons of rat hippocampal slices. Neurons located in the stratum radiatum-lacunosum moleculare of the CA1 region were studied. The effects of clinically relevant concentrations (1.0 rat minimum alveolar concentration) of halothane, enflurane, isoflurane, and sevoflurane were compared on kinetics of both stimulus-evoked and spontaneous GABAA receptor-mediated IPSCs in interneurons.Halothane (1.2 vol% approximately 0.35 mm), enflurane (2.2 vol% approximately 0.60 mm), isoflurane (1.4 vol% approximately 0.50 mm), and sevoflurane (2.7 vol% approximately 0.40 mm) preferentially depressed evoked IPSC amplitudes to 79.8 +/- 9.3% of control (n = 5), 38.2 +/- 8.6% (n = 6), 52.4 +/- 8.4% (n = 5), and 46.1 +/- 16.0% (n = 8), respectively. In addition, all anesthetics differentially prolonged the decay time constant of evoked IPSCs to 290.1 +/- 33.2% of control, 423.6 +/- 47.1, 277.0 +/- 32.2, and 529 +/- 48.5%, respectively. The frequencies of spontaneous IPSCs were increased by all anesthetics (twofold to threefold). Thus, the total negative charge transfer mediated by GABAA receptors between synaptically connected interneurons was enhanced by all anesthetics.Volatile anesthetics differentially enhanced GABAA receptor-mediated synaptic inhibition in rat hippocampal interneurons, suggesting that hippocampal interneuron circuits are depressed by these anesthetics in an agent-specific manner.

    View details for Web of Science ID 000166694900021

    View details for PubMedID 11176100

  • Membrane and synaptic actions of halothane on rat hippocampal pyramidal neurons and inhibitory interneurons JOURNAL OF NEUROSCIENCE Nishikawa, K., MacIver, M. B. 2000; 20 (16): 5915-5923

    Abstract

    A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal neurons in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role during anesthesia. The aim of this study was to investigate effects of a general anesthetic, halothane, on membrane and synaptic properties of rat hippocampal interneurons. GABA receptor-mediated IPSCs were recorded with whole-cell patch-clamp techniques in visually identified CA1 pyramidal cells and interneurons located at the border of stratum lacunosum-moleculare and stratum radiatum. Halothane (0.35 mm congruent with 1.2 vol%) depressed evoked IPSC amplitudes recorded from both pyramidal cells and inhibitory interneurons. Also, halothane considerably prolonged the decay time constant of evoked IPSCs in pyramidal cells and interneurons. The frequencies of miniature IPSCs were increased by halothane (two- to threefold) in both types of neuron. On the other hand, halothane effects on resting membrane potentials were variable but minimal in both types of neurons. In current-clamp recordings, halothane depressed EPSP amplitudes and increased IPSP amplitudes recorded from both types of neurons. In addition, halothane increased the failure rate of synaptically evoked action potentials. Taken together, these data provide evidence that halothane increases GABA(A) receptor-mediated synaptic inhibition between synaptically connected interneurons and depresses excitatory transmission, similar to effects observed in pyramidal neurons.

    View details for Web of Science ID 000088676400005

    View details for PubMedID 10934238

  • Volatile anesthetics depress glutamate transmission via presynaptic actions ANESTHESIOLOGY MacIver, M. B., Mikulec, A. A., Amagasu, S. M., Monroe, F. A. 1996; 85 (4): 823-834

    Abstract

    Recent evidence for a presynaptic depression of glutamate release produced by volatile anesthetics prompted the current study of isoflurane and halothane effects on glutamate-mediated transmission in the mammalian central nervous system.Electrophysiologic recordings from CA1 neurons in rat hippocampal brain slices were used to measure anesthetic effects on glutamate-mediated excitatory postsynaptic potential (EPSP) amplitudes and paired pulse facilitation. Paired pulse facilitation is known to be altered when the calcium-dependent release of glutamate is depressed, but not when EPSP amplitudes are depressed by postsynaptic mechanisms.Isoflurane depressed EPSP amplitudes over a concentration range of 0.35-2.8 vol %, with a 50% depression (EC50) occurring at 1.0 vol % (0.71 rat minimum alveolar concentration). This depression was accompanied by an increase in paired-pulse facilitation of approximately 30% at 1.7 vol %, using interpulse intervals of 120 ms. Halothane depressed EPSP amplitudes in a concentration-dependent manner (0.3-2.4 vol %, EC50 = 1.1 minimum alveolar concentration; 1.3 vol %) and also increased facilitation by approximately 20% at 1.2 vol %. These effects persisted in the presence of 10 microM bicuculline, indicating that enhanced gamma-aminobutyric acid-mediated inhibition was not involved. The anesthetic-induced increase in facilitation and EPSP depression was mimicked by lowering extracellular calcium, which is known to depress glutamate release at these synapses. The postsynaptic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione depressed EPSP amplitudes with no change in facilitation.Our results confirm earlier findings that clinically relevant concentrations of volatile anesthetics depress glutamate-mediated synaptic transmission. The observed increases in synaptic facilitation support recent findings from biochemical and electrophysiologic studies indicating presynaptic sites of action contribute to anesthetic-induced depression of excitatory transmission. This anesthetic-induced reduction in glutamate release would contribute to the central nervous system depression associated with anesthesia by adding to postsynaptic depressant actions on glutamate receptors.

    View details for Web of Science ID A1996VM09800020

    View details for PubMedID 8873553

  • STRUCTURAL AND FUNCTIONAL SPECIALIZATION OF A-DELTA-FIBER AND C-FIBER FREE NERVE-ENDINGS INNERVATING RABBIT CORNEAL EPITHELIUM JOURNAL OF NEUROSCIENCE MacIver, M. B., Tanelian, D. L. 1993; 13 (10): 4511-4524

    Abstract

    An in vitro preparation of rabbit cornea was used to compare anatomical specialization and electrophysiological responses of A delta and C fiber sensory afferents which terminate as free nerve endings. Living nerve endings were visualized using epifluorescence microscopy and the vital dye 4-di2-ASP, and response properties were determined using microstimulation and recording of fiber discharge activity. Fiber type was determined based on conduction velocity measurement and preferred stimulus energy (modality) of each fiber. Four modality-specific fiber populations were identified: (1) slowly adapting C fiber cold receptors (conduction velocity of 0.25-1.6 m/sec), (2) C fiber chemosensitive units with mixed phasic and tonic activity (1.1-1.8 m/sec), (3) rapidly adapting mechanosensitive A delta fibers (1.5-2.8 m/sec), and (4) high-threshold mechano/heat (> 350 dyne or > 40 degrees C) phasic A delta afferents (3.5-4.4 m/sec). In addition to these physiological differences, anatomical specialization was also noted. A delta fiber nerve endings were distinguished from those of C fibers by thin, elongated sensory endings that ran parallel to the corneal surface; C fiber endings formed short, branching clusters that ran mostly perpendicular to the surface. The elongated structure of A delta nerve endings was associated with directional selectivity for mechanical stimuli. These results substantiate previous suggestions that free nerve endings can exhibit both structural and functional specialization.

    View details for Web of Science ID A1993MB16400033

    View details for PubMedID 8410200

  • INHALATION ANESTHETICS EXHIBIT PATHWAY-SPECIFIC AND DIFFERENTIAL ACTIONS ON HIPPOCAMPAL SYNAPTIC RESPONSES INVITRO BRITISH JOURNAL OF ANAESTHESIA MacIver, M. B., Roth, S. H. 1988; 60 (6): 680-691

    Abstract

    The effects of halothane, isoflurane and enflurane were compared on three CNS excitatory synaptic pathways in vitro, to determine whether selective actions described in vivo result from differential effects on anatomically distinct cortical pathways and neurone populations. Halothane (0.25-1.25 vol%) depressed postsynaptic excitability of CA1 pyramidal neurones in response to activation of stratum radiatum synaptic inputs, and concentration-dependent excitatory (0.25-1.25 vol%) and depressant (1.5-2.0 vol%) actions were observed on dentate granule neurone excitability and perforant path evoked synaptic responses. In contrast, isoflurane increased CA1 neurone excitability (0.25-0.75 vol%) and produced postsynaptic depression of dentate neurones (0.5-4.0 vol%). Enflurane also increased CA1 excitability (0.5-4.0 vol%), but depressed synaptic responses at equivalent concentrations, and produced mixed excitatory (0.25-1.0 vol%) and depressant (1.0-4.0 vol%) effects on dentate synaptic responses. Differential actions were also observed for the three anaesthetics on stratum oriens excitatory inputs to CA1 neurones, and on antidromic responses. A good correlation (r = 0.992) exists between the membrane/buffer partition coefficients of these anaesthetics and their half-maximal concentrations for depression of synaptic responses; however, this correlation does not reflect the different, anaesthetic-specific actions observed. The results indicate that inhalation anaesthetics act at multiple and selective hydrophobic recognition sites which are heterogenously distributed on different synaptic pathways.

    View details for Web of Science ID A1988N301300015

    View details for PubMedID 2837263

  • CHOLINERGIC THETA RHYTHM IN TRANSECTED HIPPOCAMPAL SLICES - INDEPENDENT CA1 AND DENTATE GENERATORS BRAIN RESEARCH Konopacki, J., Bland, B. H., MacIver, M. B., Roth, S. H. 1987; 436 (2): 217-222

    Abstract

    The controversy concerning intrahippocampal theta (theta) generators, arising as a result of in vivo investigations, prompted us to record theta-activity from isolated populations of CA1 pyramidal or dentate granule neurons in vitro. In the present study, transected slices (trans-slices) of the hippocampal formation were used to isolate the CA1 area from the dentate gyrus, providing a method for testing the 'two generator' hypothesis. We demonstrated that neurons in both the CA1 area and dentate gyrus could independently generate carbachol-induced (type 2) electroencephalogram (EEG) theta-activity. This activity could be completely blocked by the muscarinic receptor antagonist atropine sulfate but was unaffected by the nicotinic blocker, (+)-tubocurarine. These in vitro results provide the first direct evidence for the two-generator hypothesis and confirm the cholinergic-muscarinic nature of type 2 slow wave theta.

    View details for Web of Science ID A1987L659500002

    View details for PubMedID 3435823

  • ANESTHETICS PRODUCE DIFFERENTIAL ACTIONS ON MEMBRANE RESPONSES OF THE CRAYFISH STRETCH-RECEPTOR NEURON EUROPEAN JOURNAL OF PHARMACOLOGY MacIver, M. B., Roth, S. H. 1987; 141 (1): 67-77

    Abstract

    The actions of ethanol, halothane and pentobarbital on the membrane electrical properties and synaptic transmission of isolated crayfish stretch receptor neurons were studied to determine possible sites of action contributing to differential effects previously described on physiological discharge activity. The three agents depressed GABA-mediated transmission and altered postsynaptic membrane electrical properties. Both pre- and postsynaptic sites of action appeared to contribute to the anesthetic-induced alteration of neuronal function. The agents studied produced different, concentration-dependent, membrane effects which included biphasic actions on membrane resistance and spike threshold. The results suggest that multiple-sites of action are involved and different anesthetics may not act via the same mechanism(s) at these sites.

    View details for Web of Science ID A1987J947800008

    View details for PubMedID 3666028

  • ANESTHETICS PRODUCE DIFFERENTIAL ACTIONS ON THE DISCHARGE ACTIVITY OF A SINGLE NEURON EUROPEAN JOURNAL OF PHARMACOLOGY MacIver, M. B., Roth, S. H. 1987; 139 (1): 43-52

    Abstract

    The effects of 26 anesthetic agents were studied on the rhythmical discharge activity of a single isolated neuron (crayfish stretch receptor). Many of these agents produced concentration-dependent biphasic responses (excitation and depression), and some also induced altered discharge patterns (burst activity). The dominant effect of a few of the anesthetics was excitation (e.g. alphaxolone); depression (e.g. decanol); or burst activity (e.g. benzocaine). A correlation was found to exist between equieffective concentrations in the perfusate and membrane/buffer partition coefficients; however, this general phenomenon does not provide an explanation for the biphasic or differential responses. These results demonstrate that selective interactions occur at the level of the single neuron, and suggest the existence of recognition sites in neuronal membranes which can discriminate structural differences of anesthetics.

    View details for Web of Science ID A1987J329000005

    View details for PubMedID 3653240

  • CARBACHOL-INDUCED EEG THETA-ACTIVITY IN HIPPOCAMPAL BRAIN-SLICES BRAIN RESEARCH Konopacki, J., MacIver, M. B., Bland, B. H., Roth, S. H. 1987; 405 (1): 196-198

    Abstract

    Application of the cholinergic agonist carbachol (50 microM) produced theta-like rhythmical waveforms, recorded in the stratum moleculare of the dentate gyrus. Atropine sulfate (50 microM) antagonized the carbachol-induced theta-like activity, consistent with this action of atropine in vivo. These results provide the first direct evidence that hippocampal neurons are capable of producing synchronized slow-wave activity when isolated from pulsed rhythmic inputs of the medial septum and other brain regions.

    View details for Web of Science ID A1987G499900026

    View details for PubMedID 3567594

  • ENFLURANE-INDUCED BURST FIRING OF HIPPOCAMPAL CA 1 NEURONS - INVITRO STUDIES USING A BRAIN SLICE PREPARATION BRITISH JOURNAL OF ANAESTHESIA MacIver, M. B., Roth, S. H. 1987; 59 (3): 369-378

    Abstract

    Enflurane can produce seizure activity in the cortical EEG, in vivo, at concentrations associated with surgical anaesthesia. The present study was designed to determine whether this seizure-like burst activity could occur in isolated cortical neurones. Enflurane altered synaptic transmission in the in vitro rat hippocampal slice preparation and produced seizure-like burst discharges of CA 1 neurones, at vapour concentrations equivalent to those obtained during anaesthesia (2-6 vol%; 0.5-1.5 mmol litre-1). Burst discharges occurred both spontaneously and in response to stimulation of stratum radiatum fibres in the CA 1 pyramidal region, but not in the dentate area. Low concentrations of enflurane (approx. 0.75 mmol litre-1), decreased the field potential responses of CA 1 neurones; however, dentate granule neurone responses were increased. Input/output analyses of field excitatory post-synaptic potential (EPSP) and population spike amplitudes revealed that the enflurane-induced depression of field potential responses was associated with decreases in synaptic input, whereas burst activity resulted from a decrease in the threshold of CA 1 neurones.

    View details for Web of Science ID A1987G223300019

    View details for PubMedID 3828186

  • BARBITURATE EFFECTS ON HIPPOCAMPAL EXCITATORY SYNAPTIC RESPONSES ARE SELECTIVE AND PATHWAY SPECIFIC CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY MacIver, M. B., Roth, S. H. 1987; 65 (3): 385-394

    Abstract

    Barbiturate actions on excitatory synaptic responses in CA 1 and dentate regions of hippocampal slices were studied to determine whether different effects occur on anatomically distinct synaptic pathways. Pentobarbital facilitated transmission between stratum radiatum inputs and CA 1 neurons at low concentrations (0.02-0.08 mM) and produced postsynaptic depression at higher concentrations. Only depression was observed for stratum oriens inputs to CA 1 and perforant path inputs to dentate granulae neurons. The (+) isomer of pentobarbital was approximately four times more potent than the (-) isomer of racemic mixture. Phenobarbital (0.04-0.12 mM) produced only depression of synaptic responses in CA 1 and dentate pathways. Comparison of effect on field excitatory postsynaptic potentials and population spike responses indicated that the barbiturates act at selective and pathway-specific sites. The results provide further evidence for specific cellular and membrane recognition sites for barbiturate action.

    View details for Web of Science ID A1987G610700017

    View details for PubMedID 3034390

  • THETA IN HIPPOCAMPAL SLICES - RELATION TO SYNAPTIC RESPONSES OF DENTATE NEURONS BRAIN RESEARCH BULLETIN Konopacki, J., MacIver, M. B., Bland, B. H., Roth, S. H. 1987; 18 (1): 25-27

    Abstract

    The effects of cholinergic agents on isolated dentate neurons were studied to characterize cellular mechanisms underlying carbachol-induced 'theta' EEG activity. Carbachol, eserine, and acetylcholine produced a synchronization of slow wave activity (theta) accompanied by depression of perforant path to dentate field potentials. These effects were antagonized by atropine but not d-tubocurarine. The results suggest that muscarinic receptors mediate theta activity resulting from a depolarization of dentate neurons.

    View details for Web of Science ID A1987F955800005

    View details for PubMedID 3030510

  • Carbachol induced rhythmical slow wave activity recorded from dentate granule neurons in vitro. Proceedings of the Western Pharmacology Society MacIver, M. B., Harris, D. P., Konopacki, J., Roth, S. H., Bland, B. H. 1986; 29: 159-161

    View details for PubMedID 3763603

  • Pathway specific and differential effects produced by halothane on hippocampal neurons in vitro. Proceedings of the Western Pharmacology Society Roth, S. H., MacIver, M. B. 1986; 29: 163-166

    View details for PubMedID 3763604

  • THE EFFECTS OF TEMPERATURE ON NEURONAL EXCITABILITY PROCEEDINGS OF THE WESTERN PHARMACOLOGY SOCIETY MacIver, M. B., Roth, S. H. 1982; 25: 427-431

    View details for Web of Science ID A1982NW33700100

    View details for PubMedID 7122534

  • A SIMPLE AND SENSITIVE FORCE TRANSDUCER SUITABLE FOR MEASURING TENSIONS IN SMALL MUSCLE-FIBERS JOURNAL OF PHARMACOLOGICAL METHODS MacIver, M. B., Damson, E., Tan, K. S., Roth, S. H. 1981; 5 (2): 93-98

    Abstract

    The design and fabrication of a simple tension force transducer, sensitive enough to measure tensions of individual and fine bundles of muscle fibers, is described. The transducer is capable of accurately measuring tensions as little as 0.5 dynes along the longitudinal axis of fibers. The response of the transducer is linear within the range of 0.5 to 500 dynes. Examples of its use and small crustacean striated and vertebrate cardiac muscle fibers are presented.

    View details for Web of Science ID A1981LG93100001

    View details for PubMedID 6971964

  • EFFECTS OF HALOTHANE ON THE NEURONAL OUTPUT, MEMBRANE-PROPERTIES AND SYNAPTIC TRANSMISSION OF AN ISOLATED NEURON PROCEEDINGS OF THE WESTERN PHARMACOLOGY SOCIETY MacIver, M. B., Roth, S. H. 1980; 23: 405-411

    View details for Web of Science ID A1980JW14800093

    View details for PubMedID 6250158

Presentations


  • Anesthsia for DBS surgery

    http://videos.med.wisc.edu/presenters/1279

    Time Period

    8/21/2010 - Present

    Presented To

    University of Wisconsin-Madison

    Location

    Madison Wisconsin

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