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Article ; Online: An In Vitro Model for Identifying Cardiac Side Effects of Anesthetics.

Chang, Alex C Y / Chang, Andrew C H / Nicin, Luka / Weber, Gerhard J / Holbrook, Colin / Davies, M Frances / Blau, Helen M / Bertaccini, Edward J

Anesthesia and analgesia

2018 Volume 130, Issue 1, Page(s) e1–e4

Abstract: The understanding of anesthetic side effects on the heart has been hindered by the lack of sophisticated clinical models. Using micropatterned human-induced pluripotent stem cell-derived cardiomyocytes, we obtained cardiac muscle depressant profiles for ... ...

Abstract	The understanding of anesthetic side effects on the heart has been hindered by the lack of sophisticated clinical models. Using micropatterned human-induced pluripotent stem cell-derived cardiomyocytes, we obtained cardiac muscle depressant profiles for propofol, etomidate, and our newly identified anesthetic compound KSEB01-S2. Propofol was the strongest depressant among the 3 compounds tested, exhibiting the largest decrease in contraction velocity, depression rate, and beating frequency. Interestingly, KSEB01-S2 behaved similarly to etomidate, suggesting a better cardiac safety profile. Our results provide a proof-of-concept for using human-induced pluripotent stem cell-derived cardiomyocytes as an in vitro platform for future drug design.
MeSH term(s)	Adult ; Anesthetics, Intravenous/toxicity ; Cardiotoxicity ; Cell Line ; Etomidate/toxicity ; Female ; Heart Diseases/chemically induced ; Heart Diseases/pathology ; Heart Diseases/physiopathology ; Heart Rate/drug effects ; Humans ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/pathology ; Male ; Middle Aged ; Myocardial Contraction/drug effects ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/pathology ; Proof of Concept Study ; Propofol/toxicity ; Risk Assessment ; Time Factors ; Young Adult
Chemical Substances	Anesthetics, Intravenous ; Propofol (YI7VU623SF) ; Etomidate (Z22628B598)
Language	English
Publishing date	2018-08-31
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000003757
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Article ; Online: A newly developed anesthetic based on a unique chemical core.

Cayla, Noëlie S / Dagne, Beza A / Wu, Yun / Lu, Yao / Rodriguez, Larry / Davies, Daryl L / Gross, Eric R / Heifets, Boris D / Davies, M Frances / MacIver, M Bruce / Bertaccini, Edward J

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 31, Page(s) 15706–15715

Abstract: Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that ... ...

Abstract	Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that is highly selective for the slow type of γ-aminobutyric acid type A receptor (GABA
MeSH term(s)	Anesthetics/chemistry ; Anesthetics/pharmacology ; Animals ; Drug Evaluation, Preclinical ; Etomidate/chemistry ; Etomidate/pharmacology ; GABA-A Receptor Agonists/chemistry ; GABA-A Receptor Agonists/pharmacology ; Humans ; Mice ; Pyrroles/chemistry ; Pyrroles/pharmacology ; Rats ; Receptors, GABA-A/genetics ; Receptors, GABA-A/metabolism ; Xenopus laevis
Chemical Substances	Anesthetics ; GABA-A Receptor Agonists ; Pyrroles ; Receptors, GABA-A ; Etomidate (Z22628B598)
Language	English
Publishing date	2019-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1822076116
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Article ; Online: External validation of simulation-based assessments with other performance measures of third-year anesthesiology residents.

Mudumbai, Seshadri C / Gaba, David M / Boulet, John R / Howard, Steven K / Davies, M Frances

Simulation in healthcare : journal of the Society for Simulation in Healthcare

2012 Volume 7, Issue 2, Page(s) 73–80

Abstract: Introduction: There has been interest in the use of high-fidelity medical simulation to evaluate performance. We hypothesized that technical and nontechnical performance in the simulated environment is related to other various criterion measures, ... ...

Abstract	Introduction: There has been interest in the use of high-fidelity medical simulation to evaluate performance. We hypothesized that technical and nontechnical performance in the simulated environment is related to other various criterion measures, providing evidence to support the validity of the scores from the performance-based assessment. Methods: Twelve third-year anesthesia residents participated in a series of 6 short 5-minute scenarios and 1 longer 30-minute scenario. The short scenarios measured technical skills, whereas the longer one focused on nontechnical skills. Two independent raters scored subjects using analytic and holistic ratings. Short scenarios involved acute hemorrhage, blocked endotracheal tube, bronchospasm, hyperkalemia, tension pneumothorax, and unstable ventricular tachycardia. The long scenario concerned management of myocardial ischemia/infarction leading to cardiac arrest. Scores from the simulations were correlated with (a) rankings generated from an Internet-based global ranking instrument that categorized residents based on overall clinical ability and (b) residency board scores. Results: There were moderate correlations between various participant scores from the simulation-based assessment and aggregate rankings based on the global ranking instrument and residency examination scores. Conclusions: The associations between simulator performance, both for technical and nontechnical skills, and other markers of ability provide some evidence to support the validity of simulation-based assessment scores. Replication studies with larger numbers of residents are warranted.
MeSH term(s)	Adult ; Anesthesiology/education ; Clinical Competence ; Education, Medical, Graduate/methods ; Educational Measurement/methods ; Educational Status ; Faculty, Medical ; Health Knowledge, Attitudes, Practice ; Humans ; Internship and Residency ; Learning ; Reproducibility of Results ; Statistics as Topic ; Teaching/methods ; Time Factors
Language	English
Publishing date	2012-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Validation Studies
ZDB-ID	2223429-9
ISSN	1559-713X ; 1559-2332
ISSN (online)	1559-713X
ISSN	1559-2332
DOI	10.1097/SIH.0b013e31823d018a
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Article ; Online: Feasibility of an internet-based global ranking instrument.

Mudumbai, Seshadri C / Gaba, David M / Boulet, John / Howard, Steven K / Davies, M Frances

Journal of graduate medical education

2011 Volume 3, Issue 1, Page(s) 67–74

Abstract: Background: Single-item global ratings are commonly used at the end of undergraduate clerkships and residency rotations to measure specific competencies and/or to compare the performances of individuals against their peers. We hypothesized that an ... ...

Abstract	Background: Single-item global ratings are commonly used at the end of undergraduate clerkships and residency rotations to measure specific competencies and/or to compare the performances of individuals against their peers. We hypothesized that an Internet-based instrument would be feasible to adequately distinguish high- and low-ability residents. Materials and methods: After receiving Institutional Review Board approval, we developed an Internet-based global ranking instrument to rank 42 third-year residents (21 in 2008 and 21 in 2009) in a major university teaching hospital's department of anesthesiology. Evaluators were anesthesia attendings and nonphysicians in 3 tertiary-referral hospitals. Evaluators were asked this ranking question: "When it comes to overall clinical ability, how does this individual compare to all their peers?" Results: For 2008, 111 evaluators completed the ranking exercise; for 2009, 79 completed it. Residents were rank-ordered using the median of evaluator categorizations and the frequency of ratings per assigned relative performance quintile. Across evaluator groups and study years, the summary evaluation data consistently distinguished the top and bottom resident cohorts. Discussion: An Internet-based instrument, using a single-item global ranking, demonstrated feasibility and can be used to differentiate top- and bottom-performing cohorts. Although ranking individuals yields norm-referenced measures of ability, successfully identifying poorly performing residents using online technologies is efficient and will be useful in developing and administering targeted evaluation and remediation programs.
Language	English
Publishing date	2011-01-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2578612-X
ISSN	1949-8357 ; 1949-8357
ISSN (online)	1949-8357
ISSN	1949-8357
DOI	10.4300/JGME-D-10-00162.1
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Article ; Online: Use of medical simulation to explore equipment failures and human-machine interactions in anesthesia machine pipeline supply crossover.

Mudumbai, Seshadri C / Fanning, Ruth / Howard, Steven K / Davies, M Frances / Gaba, David M

Anesthesia and analgesia

2010 Volume 110, Issue 5, Page(s) 1292–1296

Abstract: Background: High-fidelity medical simulation can be used to explore failure modes of technology and equipment and human-machine interactions. We present the use of an equipment malfunction simulation scenario, oxygen (O(2))/nitrous oxide (N(2)O) ... ...

Abstract	Background: High-fidelity medical simulation can be used to explore failure modes of technology and equipment and human-machine interactions. We present the use of an equipment malfunction simulation scenario, oxygen (O(2))/nitrous oxide (N(2)O) pipeline crossover, to probe residents' knowledge and their use of anesthetic equipment in a rapidly escalating crisis. Methods: In this descriptive study, 20 third-year anesthesia residents were paired into 10 two-member teams. The scenario involved an Ohmeda Modulus SE 7500 anesthetic machine with a Datex AS/3 monitor that provided vital signs and gas monitoring. Before the scenario started, we switched pipeline connections so that N(2)O entered through the O(2) pipeline and vice versa. Because of the switched pipeline, the auxiliary O(2) flowmeter delivered N(2)O instead of O(2). Two expert, independent raters reviewed videotaped scenarios and recorded the alarms explicitly noted by participants and methods of ventilation. Results: Nine pairs became aware of the low fraction of inspired O(2) (Fio(2)) alarm. Only 3 pairs recognized the high fraction of inspired N(2)O (Fin(2)o) alarm. One group failed to recognize both the low Fio(2) and the high Fin(2)o alarms. Nine groups took 3 or more steps before instigating a definitive route of oxygenation. Seven groups used the auxiliary O(2) flowmeter at some point during the management steps. Conclusions: The fact that so many participants used the auxiliary O(2) flowmeter may expose machine factors and related human-machine interactions during an equipment crisis. Use of the auxiliary O(2) flowmeter as a presumed external source of O(2) contributed to delays in definitive treatment. Many participants also failed to notice the presence of high N(2)O. This may have been, in part, attributable to 2 facts that we uncovered during our video review: (a) the transitory nature of the "high N(2)O" alert, and (b) the dominance of the low Fio(2) alarm, which many chose to mute. We suggest that the use of high-fidelity simulations may be a promising avenue to further examine hypotheses related to failure modes of equipment and possible management response strategies of clinicians.
MeSH term(s)	Administration, Inhalation ; Adult ; Anesthesia, Inhalation ; Anesthesiology/education ; Anesthesiology/instrumentation ; Anesthetics, Inhalation/administration & dosage ; Data Interpretation, Statistical ; Equipment Failure ; Hernia, Inguinal/surgery ; Humans ; Internship and Residency ; Male ; Nitrous Oxide/administration & dosage ; Operating Rooms ; Oxygen/administration & dosage ; Patient Simulation ; Respiration, Artificial
Chemical Substances	Anesthetics, Inhalation ; Nitrous Oxide (K50XQU1029) ; Oxygen (S88TT14065)
Language	English
Publishing date	2010-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0b013e3181d7e097
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Article: A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II.

Kingery, Wade S / Davies, M Frances / Clark, J David

Pain

2003 Volume 104, Issue 1-2, Page(s) 75–84

Abstract: Sciatic nerve section in rats evokes chronic hindlimb edema, pain behavior, and hyperalgesia, a syndrome resembling complex regional pain syndrome (CRPS II) in man. Furthermore, there is an increase in spontaneous protein extravasation in the hindpaw ... ...

Abstract	Sciatic nerve section in rats evokes chronic hindlimb edema, pain behavior, and hyperalgesia, a syndrome resembling complex regional pain syndrome (CRPS II) in man. Furthermore, there is an increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous limbs of CRPS patients. Now we demonstrate that sciatic nerve section also generates chronic hindlimb warmth, distal articular tenderness, allodynia, and periarticular osteoporosis, sequelae of nerve injury resembling those observed in CRPS. We postulated that facilitated substance P signaling may contribute to these vascular and nociceptive abnormalities and attempted to reverse these changes with the long acting substance P receptor (NK(1)) antagonist LY303870. Hindpaw spontaneous extravasation was inhibited by LY303870. Systemic administration of LY303870 also reversed hindpaw edema and cutaneous warmth. Intrathecal, but not systemic administration of LY303870 reversed soft tissue and articular mechanical hyperalgesia in the hindpaw. Collectively, these data further support the hypothesis that the sciatic nerve transection model closely resembles CRPS and that substance P contributes to the spontaneous extravasation, edema, warmth, and mechanical hyperalgesia observed in this model.
MeSH term(s)	Animals ; Causalgia/drug therapy ; Causalgia/physiopathology ; Disease Models, Animal ; Indoles/pharmacology ; Indoles/therapeutic use ; Male ; Neurokinin-1 Receptor Antagonists ; Pain Measurement/drug effects ; Pain Measurement/methods ; Piperidines/pharmacology ; Piperidines/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurokinin-1/physiology ; Sciatic Neuropathy/drug therapy ; Sciatic Neuropathy/physiopathology ; Vascular Diseases/drug therapy ; Vascular Diseases/physiopathology
Chemical Substances	1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane ; Indoles ; Neurokinin-1 Receptor Antagonists ; Piperidines ; Receptors, Neurokinin-1
Language	English
Publishing date	2003-07
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	193153-2
ISSN	1872-6623 ; 0304-3959
ISSN (online)	1872-6623
ISSN	0304-3959
DOI	10.1016/s0304-3959(02)00467-0
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Article ; Online: The role of the craniospinal nerves in mediating the antinociceptive effect of transcranial electrostimulation in the rat.

Nekhendzy, Vladimir / Davies, M Frances / Lemmens, Hendrikus J M / Maze, Mervyn

Anesthesia and analgesia

2006 Volume 102, Issue 6, Page(s) 1775–1780

Abstract: Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, but its mechanism of action has not been elucidated. In a recently introduced clinically relevant rat model of TES we have validated and characterized the TES ... ...

Abstract	Transcranial electrostimulation (TES) has been reported to elicit significant analgesia, but its mechanism of action has not been elucidated. In a recently introduced clinically relevant rat model of TES we have validated and characterized the TES antinociceptive effect, suggesting involvement of the sensory nerves of the rat's scalp in mediating that effect. In this study, we have further investigated the role of the craniospinal nerves by attempting to block the TES antinociceptive effect with local anesthetic injected under the TES electrodes. We also applied different transcutaneous electrical nerve stimulation modalities through the TES electrodes and compared the elicited antinociceptive effect to that of TES. The antinociceptive effect was assessed by measuring nociceptive thresholds in the tail-flick latency test in awake, unrestrained male rats. Data were analyzed by one-way analysis of variance followed by the Bonferroni t-test. The TES antinociceptive effect was significantly reduced after local anesthetic injection, and administration of 100 Hz transcutaneous electrical nerve stimulation was, over time, capable of eliciting the same degree of antinociceptive effect as TES. We conclude that sensory craniospinal nerves play a critical role in mediating the TES antinociceptive action and offer a hypothesis on the underlying mechanism(s) responsible for this action.
MeSH term(s)	Analgesia ; Animals ; Cranial Nerves/physiopathology ; Male ; Neurons, Afferent/physiology ; Pain/physiopathology ; Pain/prevention & control ; Pain Management ; Rats ; Rats, Sprague-Dawley ; Scalp/innervation ; Skin/blood supply ; Transcutaneous Electric Nerve Stimulation
Language	English
Publishing date	2006-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/01.ANE.0000219588.25375.36
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Article: Comparative analgesic and mental effects of increasing plasma concentrations of dexmedetomidine and alfentanil in humans.

Angst, Martin S / Ramaswamy, Bhamini / Davies, M Frances / Maze, Mervyn

Anesthesiology

2004 Volume 101, Issue 3, Page(s) 744–752

Abstract: Background: In animals, systemic and intrathecal administration of the alpha2 -adrenergic receptor agonist dexmedetomidine results in robust antinociceptive effects in models of heat pain. In humans, systemically administered dexmedetomidine is approved ...

Abstract	Background: In animals, systemic and intrathecal administration of the alpha2 -adrenergic receptor agonist dexmedetomidine results in robust antinociceptive effects in models of heat pain. In humans, systemically administered dexmedetomidine is approved for sedating patients in the intensive care unit. However, whether systemic administration of dexmedetomidine in humans produces significant analgesia at doses causing sedation but not unconsciousness remains controversial. Methods: This study in human volunteers used a placebo-controlled, double-blind, and randomized design to examine whether dexmedetomidine at doses causing mild to severe sedation produces analgesia in experimental models of heat and electrical pain. Results were compared to the effects of the mu-opioid receptor agonist alfentanil. A computer-controlled infusion provided four median step-up plasma concentrations of dexmedetomidine (0.09, 0.24, 0.54, and 1.23 ng/ml) and alfentanil (13.4, 33.8, 67.8, and 126.1 ng/ml). Results: Sedative and cognitive effects of dexmedetomidine were dose-dependent, resulting in a median sedation score of 95 of 100 and slowing of cognitive speed (reaction time, trail-making test) by a factor of about two at the highest plasma concentration. Dexmedetomidine did not attenuate heat or electrical pain. Alfentanil caused severe sedation (median sedation score 88 of 100) and slowed cognitive speed by a factor of approximately 1.4 at the highest plasma concentration. Alfentanil attenuated heat and electrical pain dose dependently. Conclusion: This study documents that systemic dexmedetomidine lacks analgesic efficacy for heat and electrical pain at doses causing mild to severe sedation. These results provide further evidence suggesting that systemic administration of dexmedetomidine lacks broad analgesic activity in models of acute pain at doses not rendering humans unconscious.
MeSH term(s)	Adrenergic alpha-Agonists/blood ; Adrenergic alpha-Agonists/pharmacology ; Adult ; Alfentanil/blood ; Alfentanil/pharmacology ; Analgesics, Non-Narcotic/blood ; Analgesics, Non-Narcotic/pharmacology ; Analgesics, Opioid/blood ; Analgesics, Opioid/pharmacology ; Dexmedetomidine/blood ; Dexmedetomidine/pharmacology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Electric Stimulation ; Female ; Gas Chromatography-Mass Spectrometry ; Hemodynamics/drug effects ; Hot Temperature ; Humans ; Hypnotics and Sedatives/pharmacology ; Infusions, Intravenous ; Male ; Mental Processes/drug effects ; Neuropsychological Tests ; Pain Measurement/drug effects ; Reaction Time/drug effects
Chemical Substances	Adrenergic alpha-Agonists ; Analgesics, Non-Narcotic ; Analgesics, Opioid ; Hypnotics and Sedatives ; Alfentanil (1N74HM2BS7) ; Dexmedetomidine (67VB76HONO)
Language	English
Publishing date	2004-07-14
Publishing country	United States
Document type	Clinical Trial ; Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	269-0
ISSN	0003-3022
ISSN	0003-3022
DOI	10.1097/00000542-200409000-00024
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Article ; Online: Association of admission hematocrit with 6-month and 1-year mortality in intensive care unit patients.

Mudumbai, Seshadri C / Cronkite, Ruth / Hu, Kirsten U / Wagner, Todd / Hayashi, Ko / Ozanne, Gerard M / Davies, M Frances / Heidenreich, Paul / Bertaccini, Edward

Transfusion

2011 Volume 51, Issue 10, Page(s) 2148–2159

Abstract: Background: This study examined the association of hematocrit (Hct) levels measured upon intensive care unit (ICU) admission and red blood cell transfusions to long-term (1-year or 180-day) mortality for both surgical and medical patients.: Study ... ...

Abstract	Background: This study examined the association of hematocrit (Hct) levels measured upon intensive care unit (ICU) admission and red blood cell transfusions to long-term (1-year or 180-day) mortality for both surgical and medical patients. Study design and methods: Administrative and laboratory data were collected retrospectively on 2393 consecutive medical and surgical male patients admitted to the ICU between 2003 and 2009. We stratified patients based on their median Hct level during the first 24 hours of their ICU stay (Hct < 25.0%, 25% ≤ Hct < 30%, 30% ≤ Hct < 39%, and 39.0% and higher). An extended Cox regression analysis was conducted to identify the time period after ICU admission (0 to <180, 180 to 365 days) when low Hct (<25.0) was most strongly associated with mortality. The unadjusted and adjusted relationship between admission Hct level, receipt of a transfusion, and 180-day mortality was assessed using Cox proportional hazards regression modeling. Results: Patients with an Hct level of less than 25% who were not transfused had the worst mortality risk overall (hazard ratio [HR], 6.26; 95% confidence interval [CI], 3.05-12.85; p < 0.001) during the 6 months after ICU admission than patients with a Hct level of 39.0% or more who were not transfused. Within the subgroup of patients with a Hct level of less than 25% only, receipt of a transfusion was associated with a significant reduction in the risk of mortality (HR, 0.40; 95% CI, 0.19-0.85; p = 0.017). Conclusion: Anemia of a Hct level of less than 25% upon admission to the ICU, in the absence of a transfusion, is associated with long-term mortality. Our study suggests that there may be Hct levels below which the transfusion risk-to-benefit imbalance reverses.
MeSH term(s)	Aged ; Aged, 80 and over ; Anemia/blood ; Anemia/mortality ; Anemia/therapy ; Cohort Studies ; Erythrocyte Transfusion/statistics & numerical data ; Hematocrit/statistics & numerical data ; Hospital Mortality ; Humans ; Intensive Care Units ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Outcome Assessment (Health Care) ; Patient Admission ; Proportional Hazards Models ; Retrospective Studies ; Risk ; Severity of Illness Index
Language	English
Publishing date	2011-10
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	208417-x
ISSN	1537-2995 ; 0041-1132
ISSN (online)	1537-2995
ISSN	0041-1132
DOI	10.1111/j.1537-2995.2011.03134.x
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Article: Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites.

Hashemi, Ezzat / Sahbaie, Peyman / Davies, M Frances / Clark, J David / DeLorey, Timothy M

Brain research

2007 Volume 1129, Issue 1, Page(s) 191–199

Abstract: Gabrb3 gene deficient (gabrb3(-/-)) mice, control littermates (gabrb3(+/+)) and their progenitor strains C57Bl/6J and 129/SvJ were assessed for changes in the morphology of the main noradrenergic nuclei, the locus coeruleus (LC) and LC-associated ... ...

Abstract	Gabrb3 gene deficient (gabrb3(-/-)) mice, control littermates (gabrb3(+/+)) and their progenitor strains C57Bl/6J and 129/SvJ were assessed for changes in the morphology of the main noradrenergic nuclei, the locus coeruleus (LC) and LC-associated behaviors including anxiety and muscle tone. While the area defined by the cell bodies of the LC was found not to differ between gabrb3(-/-) mice and controls, the pericoerulear dendritic zone of the LC was found to be significantly enlarged in gabrb3(-/-) mice. Relative to controls, gabrb3(-/-) mice were also found to be hypotonic, as was indicated by poor performance on the wire hanging task. Gabrb3(-/-) mice also exhibited a significant increase in stretch-attend posturing, a form of risk assessment behavior associated with anxiety. However, in the plus maze, a commonly used behavioral test for assessing anxiety, no significant difference was observed between gabrb3(-/-) and control mice. Lastly, relative to controls, gabrb3(-/-) mice exhibited significantly less marble burying behavior, a method commonly used to assess obsessive-compulsive behavior. However, the poor marble burying performance of the gabrb3(-/-) mice could be associated with the hypotonic condition exhibited by these mice. In conclusion, the results of this study indicate that the gabrb3 gene contributes to LC noradrenergic dendrite development with the disruption of this gene in mice resulting in an enlarged plexus of LC dendrites with a concurrent reduction in muscle tone and marble burying behavior, an increase in risk assessment behavior but no change in the plus maze parameters that are commonly used for assessing anxiety.
MeSH term(s)	Animals ; Anxiety Disorders/genetics ; Anxiety Disorders/metabolism ; Anxiety Disorders/physiopathology ; Behavior, Animal/physiology ; Dendrites/metabolism ; Dendrites/pathology ; Disease Models, Animal ; Female ; Gene Expression Regulation, Developmental/genetics ; Locus Coeruleus/abnormalities ; Locus Coeruleus/metabolism ; Locus Coeruleus/physiopathology ; Male ; Maze Learning/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle Hypotonia/genetics ; Muscle Hypotonia/metabolism ; Muscle Hypotonia/physiopathology ; Nervous System Malformations/genetics ; Nervous System Malformations/metabolism ; Nervous System Malformations/physiopathology ; Neural Inhibition/genetics ; Receptors, GABA-A/genetics ; Risk-Taking ; Synaptic Transmission/genetics ; gamma-Aminobutyric Acid/metabolism
Chemical Substances	Gabrb3 protein, mouse ; Receptors, GABA-A ; gamma-Aminobutyric Acid (56-12-2)
Language	English
Publishing date	2007-01-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2006.10.050
Database	MEDical Literature Analysis and Retrieval System OnLINE

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