bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of α2B-Adrenoceptors Mediates the Cardiovascular Effects of Etomidate
Authors: Paris Andrea , Philipp Melanie , Tonner Peter H. , Steinfath Markus , Lohse Martin , Scholz Jens , Hein Lutz
Published: November 2003

Background

The intravenous anesthetic etomidate exhibits structural similarities to specific alpha2-adrenoceptor agonists of the type such as dexmedetomidine. The current study was performed to elucidate the possible interaction of etomidate with alpha2-adrenoceptors in mice lacking individual alpha2-adrenoceptor subtypes (alpha2-KO).

Methods

Sedative and cardiovascular responses to etomidate and the alpha2-agonist, dexmedetomidine, were determined in mice deficient in alpha2-receptor subtypes. Inhibition of binding of the alpha2-receptor antagonist [3H]RX821002 to recombinant alpha2-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro.

Results

In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha2A-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha2A-receptor subtype. Intravenous injection of etomidate resulted in a transient increase (duration 2.4 +/- 0.2 min) in arterial blood pressure in wild-type mice (17 +/- 3 mmHg). Etomidate did not affect blood pressure in alpha2B-KO or alpha2AB-KO mice. In membranes from HEK293 cells transfected with alpha2-receptors, etomidate inhibited binding of the alpha2-antagonist, [3H]RX821002, with higher potency from alpha2B- and alpha2C-receptors than from alpha2A-receptors (Ki alpha2A 208 microm, alpha2B 26 microm, alpha2C 56 microm). In alpha2B-receptor-expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2.

Conclusions

These results indicate that etomidate acts as an agonist at alpha2-adrenoceptors, which appears in vivo primarily as an alpha2B-receptor-mediated increase in blood pressure. This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.
Effects of Antidepressants on G Protein–coupled Receptor Signaling and Viability in Xenopus laevis Oocytes
Authors: Strümper Danja , Durieux Marcel E. , Tröster Barbara , Hahnenkamp Klaus , Vitan Cristina , den Bakker Christel G. , Hollmann Markus W.
Published: November 2003

Background

Tricyclic antidepressants are structurally related to local anesthetics, suggesting that part of their analgesic action may result from properties shared with local anesthetics. Because local anesthetics block G protein-coupled receptor signaling (which explains, in part, their inflammatory modulating properties), the authors studied whether antidepressants have similar effects.

Methods

Peak Ca-activated Cl currents induced in Xenopus laevis oocytes by lysophosphatidic acid (10(-4) m) were measured using a voltage clamp. The effects of a 30-, 120-, or 240-min incubation in amitriptyline, nortriptyline, imipramine, or fluoxetine were determined.

Results

After a 30-min incubation, low concentrations (10(-7)-10(-5) m) of antidepressants had no effect on lysophosphatidic acid-induced currents. After prolonged incubation, only amitriptyline or nortriptyline inhibited lysophosphatidic acid signaling (each to 58% of the control response at 10(-7) m after 240 min). At low concentrations, none of the compounds induced membrane damage (defined as a holding current of > 1 microA, 2% in control cells). Imipramine at 10(-3) m induced damage in 100% of oocytes, and fluoxetine at 10(-4) m induced damage in 71% of oocytes (P < 0.05 vs. control). Amitriptyline and nortriptyline had no effect.

Conclusions

These findings are in part different from those obtained with local anesthetics and suggest that interference with G protein-coupled signaling might explain, in part, the analgesic properties of some antidepressants. However, use of antidepressants in high concentrations may be associated with cellular toxicity.
Brain Stem Opioidergic and GABAergic Neurons Mediate the Antinociceptive Effect of Nitrous Oxide in Fischer Rats
Authors: Ohashi Yoko , Guo Tianzhi , Orii Ryo , Maze Mervyn , Fujinaga Masahiko
Published: November 2003

Background

Recent studies have revealed that N2O exerts its antinociceptive effect by inducing opioid peptide release in the brain stem, thereby activating the descending noradrenergic inhibitory neurons, which modulate pain processing in the spinal cord. However, the precise neuronal pathways that mediate these events remain to be determined.

Methods

Using immunohistochemical and behavioral techniques in adult male Fischer rats, the authors studied the involvement of brain stem opioidergic and gamma-aminobutyric acid-mediated (GABAergic) neurons in the N2O-induced antinociceptive effect using discrete microinjections of an opioid receptor antagonist or GABAergic activator into the periaqueductal gray area and pontine noradrenergic nuclei. They used c-Fos expression as an immunohistochemical mark of neuronal activation induced by N2O and the plantar test as the behavioral paradigm for nociception.

Results

Microinjection of either naloxone (an opioid receptor antagonist) or muscimol (a gamma-aminobutyric acid receptor type A agonist) into the ventrolateral periaqueductal gray area inhibited N2O-induced c-Fos expression in the spinal cord and pontine noradrenergic nuclei, particularly in the A7. Microinjection of either naloxone or muscimol into the A7 nuclei also inhibited N2O-induced c-Fos expression in the spinal cord and the N2O-induced antinociceptive effect by the plantar test.

Conclusions

These results support the hypothesis that both opioidergic and GABAergic neurons mediate the antinociceptive effect of N2O at the periaqueductal gray area and A7 in the brain stem. The authors postulate that N2O-induced opioid peptide release leads to inhibition of GABAergic neurons via opioid receptors. The descending noradrenergic inhibitory pathways, which are tonically inhibited by these gamma-aminobutyric acid neurons, are thereby activated (disinhibited) and modulate pain processing in the spinal cord.
Synergistic Antinociceptive Effects of Ketamine and Morphine in the Orofacial Capsaicin Test in the Rat
Authors: Alvarez Pedro , Saavedra Gloria , Hernández Alejandro , Paeile Carlos , Pelissier Teresa
Published: November 2003

Background

The clinical efficacy of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine for treating orofacial pain has already been reported. Side effects related to psychotomimetic disturbances, however, limit ketamine use as an analgesic. Theoretically, this limitation could be minimized by using low doses of ketamine in combination with other analgesics. In the present study, the potential synergistic antinociceptive interaction between ketamine and morphine in the orofacial capsaicin test in rats was investigated.

Methods

Male Sprague-Dawley rats were subcutaneously injected with solvent, ketamine, morphine, or combination of both drugs. Thirty minutes later, the orofacial capsaicin test was performed by injecting of 1.5 microg/25 microl of a capsaicin solution into the vibrissa pad. Animal behavior was recorded on videotape and analyzed off-line. The total time spent on rubbing-scratching nociceptive behavior during a period of 42 min was measured.

Results

Subcutaneously administered ketamine (0.4, 1.25, 4, 12.5 mg/kg), morphine (0.5, 1, 2, 4 mg/kg) and ketamine + morphine (0.20 + 0.12, 0.40 + 0.24, 0.80 + 0.49, 1.61 + 0.97, 3.21 + 1.94 mg/kg) reduced the rat facial rubbing-scratching behavior in a dose-dependent manner. Isobolographic analysis showed that the ketamine + morphine association inhibited the studied behavior in a superadditive manner.

Conclusions

These results indicate that ketamine and morphine have antinociceptive effects on the orofacial capsaicin test. Furthermore, their combination produces synergistic antinociception. It is therefore suggested that, used together, ketamine and morphine might be clinically efficient at lower doses than those currently used when administered separately. This could provide a useful strategy for the clinical management of orofacial pain.
Orally Administered Paracetamol Does Not Act Locally in the Rat Formalin Test
Authors: Bonnefont Jérôme , Alloui Abdelkrim , Chapuy Eric , Clottes Eric , Eschalier Alain
Published: November 2003

Background

The mechanism of action of paracetamol (acetaminophen) remains elusive because it is still under discussion as to whether it acts locally and/or centrally. The primary aim of this study was to clarify its site(s) of action (central and/or local) using the rat formalin test.

Methods

Spontaneous biting and licking of the injected paw following intraplantar injection of formalin 2.5% was monitored during the two phases of nociceptive behavior (0-5 and 20-40 min after injection), and the authors examined the antinociceptive activity of paracetamol following oral, intravenous, intraplantar, and intrathecal administrations as well as the reversion of this effect by an intrathecal injection of WAY 100,635, a selective 5-HT1A receptor antagonist.

Results

The oral administration of paracetamol (300, 400 mg/kg) reduced nociceptive behavior in both phases (400 mg/kg: 36.9 +/- 4.6% and 61.5 +/- 5.2% of inhibition in phases I and II, respectively, P <0.05), whereas lower doses reduced primarily the score of the second phase of the test. Only high doses of 10 to 20 mg/kg intraplantarly administered paracetamol, which were ineffective when administered subcutaneously, produced a significant but limited reduction in the early phase of the test and had no effect on the second phase or any antiinflammatory activity. Thus, this local effect did not seem to participate in the antinociceptive action of 400 mg/kg orally given paracetamol, which was totally blocked in both phases by an intrathecal injection of 40 microg WAY 100,635 per rat. Such an inhibition was not observed when paracetamol (200 microg per rat) was intrathecally coinjected with WAY 100,635, whereas the antinociceptive action of 5-HT (50 microg per rat, intrathecally) during both phases of pain was inhibited by WAY 100,635 (intrathecally).

Conclusions

Orally administered paracetamol does not seem to exert any relevant local action in the formalin model of tonic pain in rats, but it might activate the serotonergic bulbospinal pathways via a supraspinal site of action that remains to be elucidated.
Optimal Dose of Succinylcholine Revisited
Authors: Naguib Mohamed , Samarkandi Abdulhamid , Riad Waleed , Alharby Saleh W.
Published: November 2003

Background

The authors reappraised the conventional wisdom that the intubating dose of succinylcholine must be 1.0 mg/kg and attempted to define the lower range of succinylcholine doses that provide acceptable intubation conditions in 95% of patients within 60 s.

Methods

This prospective, randomized, double-blind study involved 200 patients. Anesthesia was induced with 2 mug/kg fentanyl and 2 mg/kg propofol. After loss of consciousness, patients were randomly allocated to receive 0.3, 0.5, or 1.0 mg/kg succinylcholine or saline (control group). Tracheal intubation was performed 60 s later. A blinded investigator performed all laryngoscopies and also graded intubating conditions.

Results

Intubating conditions were acceptable (excellent plus good grade combined) in 30%, 92%, 94%, and 98% of patients after 0.0, 0.3, 0.5, and 1.0 mg/kg succinylcholine, respectively. The incidence of acceptable intubating conditions was significantly greater (P < 0.05) in patients receiving succinylcholine compared with those in the control group but was not different among the different succinylcholine dose groups. The calculated doses of succinylcholine (and their 95% confidence intervals) that were required to achieve acceptable intubating conditions in 90% and 95% of patients at 60 s were 0.24 (0.19-0.31) mg/kg and 0.56 (0.43-0.73) mg/kg, respectively.

Conclusions

The use of 1.0 mg/kg of succinylcholine may be excessive if the goal is to achieve acceptable intubating conditions within 60 s. Comparable intubating conditions were achieved after 0.3, 0.5, or 1.0 mg/kg succinylcholine. In a rapid-sequence induction, 95% of patients with normal airway anatomy anesthetized with 2 mug/kg fentanyl and 2 mg/kg propofol should have acceptable intubating conditions at 60 s after 0.56 mg/kg succinylcholine. Reducing the dose of succinylcholine should allow a more rapid return of spontaneous respiration and airway reflexes.
Influence of Nitrous Oxide on Minimum Alveolar Concentration of Sevoflurane for Laryngeal Mask Insertion in Children
Authors: Kihara Shinichi , Yaguchi Yuichi , Inomata Shinichi , Watanabe Seiji , Brimacombe Joseph R. , Taguchi Noriko , Komatsuzaki Tetsuya
Published: November 2003

Background

Inhalational induction with sevoflurane and nitrous oxide is frequently used for Laryngeal Mask Airway (LMA; Laryngeal Mask Company, Henley-on-Thames, United Kingdom) insertion in children. The authors determined the influence of nitrous oxide on the minimum alveolar concentration (MAC) of sevoflurane for LMA insertion.

Methods

One hundred twenty unpremedicated children (age, 1-9 yr; American Society of Anesthesiologists physical status I) were randomly assigned to receive 1 of 15 end-tidal concentrations of nitrous oxide and sevoflurane for inhalational induction via a facemask: 0% nitrous oxide with 1.2, 1.4, 1.6, 1.8, or 2.0% sevoflurane; 33% nitrous oxide with 0.8, 1.0, 1.2, 1.4, or 1.6% sevoflurane; or 67% nitrous oxide with 0.4, 0.6, 0.8, 1.0, or 1.2% sevoflurane. The LMA was inserted after steady state end-tidal anesthetic concentrations had been maintained for 15 min. The response to insertion was recorded by three independent blinded observers. The interaction between nitrous oxide and sevoflurane was determined using logistic regression analysis.

Results

The MAC of sevoflurane for LMA insertion (95% confidence limit) was 1.57% (1.42-1.72%), and the concentration of sevoflurane required to prevent movement in 95% of children was 1.99% (1.81-2.57%). The addition of 33% and 67% nitrous oxide linearly decreased the MAC of sevoflurane for LMA insertion by 22% and 49%, respectively (P < 0.001). The interaction coefficient between nitrous oxide and sevoflurane did not differ from zero (P = 0.7843), indicating that the relation was additive.

Conclusions

Nitrous oxide and sevoflurane suppress the responses to LMA insertion in a linear and additive fashion in children.
Women Appear to Have the Same Minimum Alveolar Concentration as Men
Authors: Eger Edmond I , Laster Michael J. , Gregory George A. , Katoh Takasumi , Sonner James M.
Published: November 2003

Background

A recent report finds that elderly Japanese women given xenon have a significantly smaller (26% less) MAC (minimum alveolar concentration required to eliminate movement in response to surgical incision in 50% of patients) than Japanese men of the same age. The authors assessed whether this finding applied to other/all anesthetics.

Methods

The authors reviewed data obtained previously for 258 patients (127 women and 131 men) anesthetized with desflurane, diethyl ether, halothane, methoxyflurane, sevoflurane, or xenon. Data were normalized to the MAC for the anesthetic as determined by logistic regression (i.e., MAC would equal a value of 1.000).

Results

The MAC for the normalized combined (all) data for women (1.013 +/- 0.017; mean +/- SEM) did not differ significantly from the normalized combined data for men (1.005 +/- 0.009), and neither differed significantly from 1.000. However, a significantly smaller MAC value was found for women in two studies of sevoflurane (subsets of the above studies) given to Japanese patients: 12% in one study and 16% in the other.

Conclusions

Overall, no difference in MAC was found for women versus men. Whether women (particularly older Japanese women) have a smaller MAC than men remains to be confirmed by prospective studies.
Narcotrend® and Bispectral Index® Monitor Are Superior to Classic Electroencephalographic Parameters for the Assessment of Anesthetic States during Propofol-Remifentanil Anesthesia
Authors: Schmidt Gunter N. , Bischoff Petra , Standl Thomas , Jensen Kai , Voigt Moritz , Schulte am Esch Jochen
Published: November 2003

Background

A new electroencephalogram monitor, the Narcotrend, was developed to measure anesthetic depth. The authors compared the Narcotrend, the Bispectral Index, and classic electroencephalographic and hemodynamic parameters during anesthesia with propofol and remifentanil.

Methods

The authors investigated 25 patients undergoing laminectomy at different anesthetic states: awake, steady state anesthesia, first reaction during emergence, and extubation. Narcotrend value; BIS; relative power (percent) in delta, theta, alpha, and beta; median frequency; spectral edge frequency; and hemodynamic parameters were recorded simultaneously. The ability of the classic and processed electroencephalographic and hemodynamic parameters to predict the clinically relevant anesthetic states of awake, steady state anesthesia, first reaction, and extubation was tested using prediction probability.

Results

Only the Narcotrend was able to differentiate between awake versus steady state anesthesia and steady state anesthesia versus first reaction/extubation with a prediction probability value of more than 0.90.

Conclusions

Modern electroencephalographic parameters, especially Narcotrend, are more reliable indicators for the clinical assessment of anesthetic states than classic parameters.
Lidocaine Enhances GαiProtein Function
Authors: Benkwitz Claudia , Garrison James C. , Linden Joel , Durieux Marcel E. , Hollmann Markus W.
Published: November 2003

Background

Local anesthetics inhibit several G protein-coupled receptors by interaction with the Galphaq protein subunit. It is not known whether this effect on G protein function can be extrapolated to other classes of G proteins. The authors investigated interactions of lidocaine with the human adenosine 1 receptor (hA1R)-coupled signaling pathway. Activated A1Rs couple to adenylate cyclase via the pertussis toxin sensitive Galphai protein, thereby decreasing cyclic adenosine monophosphate formation. A1Rs are widely expressed and abundant in the spinal cord, brain, and heart. Interactions of LAs with the hA1R-coupled transduction cascade therefore might produce a broad range of clinically relevant effects.

Methods

The function of hA1Rs stably expressed in Chinese hamster ovary cells was determined with assays of cyclic adenosine monophosphate, receptor binding, and guanosine diphosphate/guanosine triphosphate gamma35S exchange by using reconstituted defined G protein subunits. Involvement of phosphodiesterase and Galphai was characterized by using the phosphodiesterase inhibitor rolipram and pertussis toxin, respectively.

Results

Lidocaine (10-9-10-1 M) had no significant effects on agonist or antagonist binding to the hA1R or on receptor-G protein interactions. However, cyclic adenosine monophosphate levels were reduced significantly to 50% by the LAs, even in the absence of an A1R agonist or presence of an A1R antagonist. This effect was unaffected by rolipram (10 mum), but abolished completely by pretreatment with pertussis toxin, which inactivates the Galphai protein. Therefore, the main target site for LAs in this pathway is located upstream from adenylate cyclase.

Conclusions

Lidocaine potentiates Galphai-coupled A1R signaling by reducing cyclic adenosine monophosphate production. The study suggests an interaction site for LAs in a Galphai-coupled signaling pathway, with the Galphai protein representing the prime candidate. Taken together with previous results showing inhibitory LA interactions on the Galphaq protein subunit, the data in the current study support the hypothesis that specific G protein subunits represent alternative sites of LA action.
Induction of Malignant Hyperthermia in Susceptible Swine by 3,4-Methylenedioxymethamphetamine (“Ecstasy”)
Authors: Fiege Marko , Wappler Frank , Weisshorn Ralf , Gerbershagen Mark U. , Menge Melanie , Schulte am Esch Jochen
Published: November 2003

Background

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") can mediate acute toxic effects such as muscle rigidity, metabolic acidosis, and hyperthermia. Because of close clinical similarities, an association between MDMA intoxication and malignant hyperthermia (MH) was suggested. The aim of this study was to investigate whether MDMA is a trigger of MH in susceptible swine.

Methods

MH-nontriggering general anesthesia was performed in six MH-susceptible (MHS) and six MH-normal swine. The animals were exposed to MDMA in cumulative doses of 0.5, 1, 2, 4, 8, and 12 mg/kg. The clinical occurrence of MH was defined by achievement of two of three conditions: central venous Pco2 >/=75 mmHg, central venous pH </= 7.20, and increase of body core temperature >/= 2.0 degrees C. Once MH occurred, a standardized therapy with dantrolene, sodium bicarbonate, and hyperventilation with 100% oxygen was initialized.

Results

Administration of 8 mg/kg MDMA triggered MH in all MHS swine. The MH-normal swine also developed clinical signs of hypermetabolism, but even after administration of 12 mg/kg MDMA, changes were moderate compared with the MHS swine. Dantrolene therapy of MDMA-induced MH crisis in the MHS swine partially counteracted the clinical signs of MH immediately.

Conclusions

MDMA induces MH in genetically susceptible swine in relevant doses. Therefore, MHS patients should avoid use of MDMA or related drugs. Patients with a personal or family history of MDMA-induced hyperthermia should be tested for a diagnosis of MH susceptibility. Dantrolene is effective in therapy of MDMA-induced porcine MH.
Quality of Recovery from Anesthesia in Neurosurgical Patients
Authors: Leslie Kate , Troedel Sally , Irwin Kimberley , Pearce Frances , Ugoni Antony , Gillies Robyn , Pemberton Elizabeth , Dharmage Shyamali
Published: November 2003

Background

Factors influencing quality of recovery in cranial and spinal neurosurgical patients are not known, possibly because of lack of a suitable instrument. Therefore, the authors measured quality of recovery using the QoR-40 score (a 40-item questionnaire on quality of recovery from anesthesia).

Methods

With informed consent, 200 patients undergoing elective neurosurgery were recruited. The QoR-40 score, visual analog scores for pain and quality of recovery, and data on complications were collected over 90 days. The psychometrics of the QoR-40 were tested and regression models were developed to determine predictors of quality of recovery and postoperative pain.

Results

The QoR-40 score demonstrated significant responsiveness, validity, and reliability. In cranial surgery patients, QoR-40 scores were lower on days 1 and 2 than either preoperatively or on days 3, 30, and 90. In spinal surgery patients, QoR-40 scores were lower preoperatively and on days 1 and 2 than on days 3, 30, and 90. Longer duration of surgery, more complications, and higher visual analog scores for pain were predictors of poor quality of recovery on day 3. Cranial surgery patients had moderately severe pain on days 1 and 2, whereas spinal surgery patients reported moderate pain for the whole study period. Neurologic deficits were negatively correlated with QoR-40 scores in cranial and spinal surgery patients.

Conclusions

The QoR-40 score is a useful instrument with which to assess quality of recovery in cranial and spinal surgery patients. Postoperative pain and neurologic deficits correlate with poor quality of recovery in these patients.
Inhibition of Spinal Prostaglandin Synthesis Early after L5/L6 Nerve Ligation Prevents the Development of Prostaglandin-dependent and Prostaglandin-independent Allodynia in the Rat
Authors: Hefferan Michael P. , O'Rielly Darren D. , Loomis Christopher W.
Published: November 2003

Background

Prostaglandins, synthesized in the spinal cord in response to noxious stimuli, are known to facilitate nociceptive transmission, raising questions about their role in neuropathic pain. The current study tested the hypothesis that spinal nerve ligation-induced allodynia is composed of an early prostaglandin-dependent phase, the disruption of which prevents allodynia.

Methods

Male Sprague-Dawley rats, fitted with intrathecal drug delivery or microdialysis catheters, underwent left L5-L6 spinal nerve ligation or sham surgery. Paw withdrawal threshold, brush-evoked behavior, and the concentration of prostaglandin E2 (PGE2) in spinal cerebrospinal fluid ([PGE2]dialysate) were determined for up to 24 days. PGE2-evoked glutamate release from spinal slices was also determined.

Results

Paw withdrawal threshold decreased from at least 15 g (control) to less than 4 g, beginning 1 day after ligation. Brushing the affected hind paw evoked nociceptive-like behavior and increased [PGE2]dialysate (up to 257 +/- 62% of baseline). There was no detectable change in basal [PGE2]dialysate from preligation values. The EC50 of PGE2-evoked glutamate release (2.4 x 10-11 M, control) was significantly decreased in affected spinal segments of allodynic rats (8.9 x 10-15 M). Treatment with intrathecal S(+)-ibuprofen or SC-560, beginning 2 h after ligation, prevented the decrease in paw withdrawal threshold, the brush-evoked increase in [PGE2]dialysate, and the change in EC50 of PGE2-evoked glutamate release. R(-)-ibuprofen or SC-236 had no effect.

Conclusions

The results of this study provide solid evidence that spinal prostaglandins, synthesized by cyclooxygenase-1 in the first 4-8 h after ligation, are critical in the pathogenesis of prostaglandin-dependent and prostaglandin-independent allodynia and that their early pharmacologic disruption affords protection against this neuropathic state in the rat.
Diverse Research on Alcohol and Aggression in Humans: In Memory of John A. Carpenter
Authors: Giancola Peter R. , White Helene Raskin , Berman Mitchell E. , McCloskey Michael S. , Greer Tammy F. , Widom Cathy Spatz , Chermack Stephen T. , Leonard Kenneth E. , Collins R. Lorraine , Quigley Brian M.
Published: November 2003

This article summarizes the proceedings of a symposium, chaired and co‐organized by Helene Raskin White and co‐organized by Peter R. Giancola, that was presented at the 2002 RSA Meeting in San Francisco. The goal of this symposium was to integrate findings from methodologically divergent studies on the topic of alcohol‐related aggression in humans. The investigators focused on isolating mediators and moderators of the alcohol‐aggression relationship. Peter R. Giancola presented laboratory data demonstrating how alcohol's acute effects on aggression are moderated by individual difference and contextual factors. Mitchell E. Berman presented laboratory data on alcohol's acute effects on self‐induced aggression. Helene Raskin White reviewed prospective data on how alcohol affects the intergenerational transmission of family violence. Stephen Chermack reviewed data on the impact of a family history of alcoholism and a family history of violence on the development of childhood behavioral problems and adult problems with drugs, alcohol, and violence. Finally, Kenneth E. Leonard presented data on personal and contextual factors influencing alcohol‐related barroom violence.
Alcohol Metabolism: Role in Toxicity and Carcinogenesis
Authors: Badger Thomas M. , Ronis Martin J.J. , Seitz Helmut K. , Albano Emanuele , Ingelman‐Sundberg Magnus , Lieber Charles S.
Published: November 2003

This article contains the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, organized and co‐chaired by Thomas M. Badger, Paul Shih‐Jiun Yin, and Helmut Seitz. The presentations were (1) First‐pass metabolism of ethanol: Basic and clinical aspects, by Charles Lieber; (2) Intracellular CYP2E1 transport, oxidative stress, cytokine release, and ALD, by Magnus Ingelman‐Sundberg; (3) Pulsatile ethanol metabolism in intragastric infusion models: Potential role in toxic outcomes, by Thomas M. Badger and Martin J.J. Ronis; (4) Free radicals, adducts, and autoantibodies resulting from ethanol metabolism: Role in ethanol‐associated toxicity, by Emanuele Albano; and (5) Gastrointestinal metabolism of ethanol and its possible role in carcinogenesis, by Helmut Seitz.
Salsolinol Produces Reinforcing Effects in the Nucleus Accumbens Shell of Alcohol‐Preferring (P) Rats
Authors: Rodd Zachary A. , Bell Richard L. , Zhang Ying , Goldstein Avram , Zaffaroni Alejandro , McBride William J. , Li Ting‐Kai
Published: November 2003

Background: The formation of salsolinol (SAL) has been hypothesized to be a factor contributing to alcoholism and alcohol abuse. If SAL is formed under chronic alcohol‐drinking conditions, then it may contribute to alcohol addiction by being rewarding itself. Because SAL can be formed by the nonenzymatic condensation of acetaldehyde with dopamine, the reinforcing effects of SAL were tested in the nucleus accumbens shell, a dopamine‐rich site considered to be involved in regulating alcohol‐drinking behavior.

Methods: The intracranial self‐administration technique was used to test the reinforcing properties of SAL. Adult, female alcohol‐preferring (P) rats were stereotaxically implanted with guide cannulae aimed at the nucleus accumbens shell. After 7 to 10 days to allow recovery from surgery, P rats were attached to the electrolytic microinfusion transducer system, placed in two‐lever experimental chambers, and allowed to respond for the self‐infusion of 100 nl of modified artificial cerebrospinal fluid (aCSF) or 0.03, 0.3, 3.0, or 12.5 μM SAL (3–1250 fmol/100 nl). Sessions were 4 hr in duration and were conducted in the dark cycle every 48 hr. The effects of coinfusing 10 to 400 μM sulpiride (given in sessions 5 and 6 after four acquisition sessions) on the intracranial self‐administration of 3.0 μM SAL were tested in a separate experiment.

Results: P rats given 0.3 to 12.5 μM SAL received significantly more infusions per session than did the group given aCSF alone (e.g., 50 infusions for 3.0 μM SAL versus 10 or fewer infusions for the aCSF group) and responded significantly more on the active than inactive lever. Coinfusion of 100 or 400 μM sulpiride reduced the responding on the active lever (80–100 responses/session without sulpiride) to levels observed for the inactive lever (fewer than 10 responses/session with sulpiride). This effect was reversible because giving SAL alone in session 7 reinstated responding on the active lever.

Conclusions: SAL is reinforcing in the nucleus accumbens shell of P rats at concentrations that are pharmacologically possible, and these reinforcing actions are mediated in part by D2/D3‐like receptors.
Effect of Chronic Alcohol Consumption on the Activity of the Hypothalamic‐Pituitary‐Adrenal Axis and Pituitary β‐Endorphin as a Function of Alcohol Intake, Age, and Gender
Authors: Gianoulakis Christina , Dai Xing , Brown Thomas
Published: November 2003

Background: Experimental evidence indicates that components of the hypothalamic‐pituitary‐adrenal (HPA) axis and of the endogenous opioid system, such as β‐endorphin (β‐END), influence alcohol consumption, whereas chronic alcohol abuse alters the activity of both systems. Furthermore, gender and age differences have been reported in the activity of the HPA axis under basal conditions, in response to stress and acute alcohol challenge. The objective of the present studies was to investigate the hypothesis that chronic alcohol consumption alters the activity of the HPA axis and pituitary β‐END as a function of severity of alcohol abuse, gender, and age.

Methods: Three age groups of each gender (18–29, 30–44, and 45–60 years old) were recruited. Each age and gender group included four subgroups: (a) nondrinkers, (b) light drinkers, (c) heavy drinkers, and (d) alcoholics in treatment. Demographic characteristics, alcohol consumption, and presence of alcohol dependence were recorded by using a structured interview. Blood samples were taken on the day of the interview. The levels of plasma adrenal corticotropic hormone (ACTH), cortisol, and β‐END were estimated as an index of the activity of the HPA‐axis and pituitary β‐END.

Results: Plasma ACTH and β‐END levels were significantly lower in females than males of all age and drinking category groups. Plasma cortisol levels were higher in 18‐ to 29‐year‐old female subjects compared with the 18‐ to 29‐year‐old male subjects. The plasma ACTH and β‐END levels were lower whereas plasma cortisol levels were higher in heavy drinkers than nondrinkers. This decrease in plasma ACTH and β‐END levels with heavy drinking was more pronounced in female than male subjects of the 30–44 and 45–60 age groups.

Conclusions: Chronic drinking, gender, and age influence the activity of the HPA‐axis and pituitary β‐END, which in turn may influence drinking behavior.
Alcoholism: Allostasis and Beyond
Authors: Koob George F.
Published: November 2003

Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma‐aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin‐releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.
Intimate Partner Violence and Drinking: New Research on Methodological Issues, Stability and Change, and Treatment
Authors: Caetano Raul , Schafer John , Fals‐Stewart William , O'Farrell Timothy , Miller Brenda
Published: November 2003

This article represents the proceedings of a symposium at the 2002 RSA meeting in San Francisco, California. The presentations were (1) Assessing couples’ agreement about alcohol involvement in intimate partner violence, by John Schafer; (2) The occurrence of partner physical aggression on days of alcohol consumption: a longitudinal diary study, by Williams Fals‐Stewart; (3) The 5‐year stability of intimate partner violence and drinking among White, Black, and Hispanic couples, by Raul Caetano; (4) Partner violence before and after individually‐based alcoholism treatment for male alcoholic patients, by Timothy O'Farrell. The discussant was Brenda Miller.
ADH Genotype Does Not Modify the Effects of Alcohol on High‐Density Lipoprotein
Authors: Whitfield John B. , O'Brien Martin E. , Nightingale Brian N. , Zhu Gu , Heath Andrew C. , Martin Nicholas G.
Published: November 2003

Background: Alcohol consumption has beneficial effects on mortality which are mainly due to reduction in cardiovascular disease. These are believed to be due, at least in part, to the increase in plasma high‐density lipoprotein (HDL) which is associated with alcohol consumption. It has been proposed that ADH3 genotype modifies the relationships between alcohol intake and cardiovascular disease by altering the HDL response to alcohol. The aim of this paper was to test for effects of ADH2 and ADH3 genotypes on the response of HDL components to habitual alcohol consumption.

Methods: Adult male and female subjects were genotyped for ADH2 and ADH3; and plasma HDL cholesterol, apolipoprotein A‐I, and apolipoprotein A‐II were measured. Nine hundred one subjects had both ADH2 and ADH3 genotypes and HDL cholesterol results, while 753 had both genotypes and all three lipid results. The effect of alcohol intake on the three measured HDL components, and a factor score derived from them, was estimated for each of the ADH2 and ADH3 genotype groups.

Results: All the measured components of HDL increased with increasing alcohol consumption over the range of intakes studied, 0–4 drinks per day. There were no significant interactions between alcohol consumption and ADH2 or ADH3 genotypes.

Conclusions: The concept that alcohol dehydrogenase genotype and alcohol metabolic rate modify the effects of alcohol on plasma HDL concentration is not supported by our results.
Ethyl Glucuronide Discloses Recent Covert Alcohol Use Not Detected by Standard Testing in Forensic Psychiatric Inpatients
Authors: Wurst Friedrich Martin , Vogel Rüdiger , Jachau Katja , Varga Arthur , Alling Christer , Alt Andreas , Skipper Gregory E.
Published: November 2003

Background: Considerable lives and money could be saved if one could detect early stages of lapsing/relapsing behavior in addicted persons (e.g., in safety‐sensitive workplaces) and could disclose harmful drinking in social drinkers. Due to the serious public health problem of alcohol use and abuse worldwide, markers of alcohol use have been sought. Both ethyl glucuronide (EtG) and phosphatidyl ethanol (PEth) appear to have high sensitivity and specificity and a time frame of detection that may elucidate alcohol use not detected by standard testing. Our aim was to assess their potential for detecting recent covert alcohol use under controlled conditions.

Methods: Thirty‐five forensic psychiatric inpatients in a closed ward who had committed a substance‐related offense (§64 StGB), were followed for 12 months. The complete time spectrum of possible alcohol consumption was covered by the complementary use of breath and urinary ethanol (hours), urinary EtG (days), %carbohydrate‐deficient transferrin (CDT)/PEth (weeks), and γ‐glutamyltranspeptidase (GGT)/mean corpuscular volume (MCV) (weeks‐months).

Results: Fourteen of the 146 urine samples examined were positive for EtG. In all EtG‐positive cases, patients reported alcohol consumption of between 40 and 200 g of ethanol 12–60 hr prior to testing. Urinary and breath ethanol were positive in only one case. In the blood samples, PEth was not positive in any case and %CDT did not exceed the reference value. Isoelectric focusing showed no abnormal Tf subtypes.

Conclusions: The findings emphasize the diagnostic and therapeutic usefulness, specificity, and sensitivity of EtG as a marker of recent alcohol use. Such a test is needed in numerous settings, including alcohol and drug treatment (to detect lapse/relapse), in safety‐sensitive work settings where use is dangerous or in other settings where use may be inappropriate (e.g., such as driving, workplace, pregnancy, or monitoring physicians or other professionals who are in recovery and working), or for testing other groups (such as children or those with medical problems) where alcohol use would be unhealthy or unsafe. The health, social and socioeconomic benefits arising from the future use of these markers is hard to overestimate.
Reduced Olfactory Sensitivity, Discrimination, and Identification in Patients With Alcohol Dependence
Authors: Rupp Claudia I. , Kurz Martin , Kemmler Georg , Mair Dolores , Hausmann Armand , Hinterhuber Hartmann , Fleischhacker W. Wolfgang
Published: November 2003

Background: Various olfactory deficits have been reported in the alcohol‐induced amnestic syndrome (Korsakoff's syndrome). Less is known about olfactory functioning in nonamnesic and nondemented alcoholic patients.

Methods: Olfactory performance of 30 alcohol‐dependent patients was assessed unirhinally using the Sniffin’ Sticks (threshold, discrimination, identification, composite TDI score) and compared with that of 30 healthy controls, matched for sex, age, and smoking status.

Results: Patients showed significantly reduced olfactory sensitivity (higher threshold), discrimination, and identification compared with controls. No group differences were observed in laterality. Identification and discrimination group differences remained significant after controlling for differences in sensitivity. Olfactory deficits in patients were present independent of age, gender, and duration of abstinence (<3 months) and were not attributable to smoking or general cognitive abilities. More than half of the patients (56.7%) could be classified as hyposmic. Lower overall olfactory functioning (TDI) was associated with longer duration of a regular alcohol intake and higher values of γ‐glutamyltransferase (GGT).

Conclusions: Olfactory dysfunction is common in nonamnesic and nondemented patients with alcohol dependence. Results suggest a detrimental effect of alcohol on central olfactory processing.
Gene Expression in Brain: A Window on Ethanol Dependence, Neuroadaptation, and Preference
Authors: Hoffman Paula L. , Miles Michael , Edenberg Howard J. , Sommer Wolfgang , Tabakoff Boris , Wehner Jeanne M. , Lewohl Joanne
Published: November 2003

This article represents the proceedings of a symposium at the 2002 joint RSA/ISBRA Conference in San Francisco, California. The organizer was Paula L. Hoffman and the co‐chairs were Paula L. Hoffman and Michael Miles. The presentations were (1) Introduction and overview of the use of DNA microarrays, by Michael Miles; (2) DNA microarray analysis of gene expression in brains of P and NP rats, by Howard J. Edenberg; (3) Gene expression patterns in brain regions of AA and ANA rats, by Wolfgang Sommer; (4) Patterns of gene expression in brains of selected lines of mice that differ in ethanol tolerance, by Boris Tabakoff; (5) Gene expression profiling related to initial sensitivity and tolerance in gamma‐protein kinase C mutants, by Jeanne Wehner; and (6) Gene expression patterns in human alcoholic brain: from microarrays to protein profiles, by Joanne Lewohl.
Alcohol Affects Executive Cognitive Functioning Differentially on the Ascending Versus Descending Limb of the Blood Alcohol Concentration Curve
Authors: Pihl Robert O. , Paylan Sheila S. , Gentes‐Hawn Alyson , Hoaken Peter N. S.
Published: November 2003

Background: Executive cognitive functioning (ECF), a construct that includes cognitive abilities such as planning, abstract reasoning, and the capacity to govern self‐directed behavior, has been recently researched as an antecedent to many forms of psychopathology and has been implicated in alcohol‐related aggression. This study was designed to examine whether differential ECF impairments can be noted on the ascending versus the descending limbs of the blood alcohol concentration curve.

Methods: Forty‐one male university students participated in this study. Twenty‐one subjects were given 1.32 ml of 95% alcohol per kilogram of body weight, mixed with orange juice, and the remaining 20 were given a placebo. Participants were randomly assigned to either an ascending or descending blood alcohol group and were tested on six tests of ECF on their assigned limb. Subjective mood data were also collected.

Results: Intoxicated participants on both limbs demonstrated ECF impairment; the descending‐limb group showed greater impairment than their ascending‐limb counterparts. Intoxicated subjects were significantly more anxious at baseline than placebo subjects. The introduction of this covariate nullified any significant differences in subjective mood found on either limb of the blood alcohol concentration curve, but ECF impairments remained robust.

Conclusions: Our results support the conclusion that alcohol negatively affects cognitive performance and has a differential effect on the descending versus the ascending limb of the blood alcohol concentration curve. The latter finding may have important ramifications relating to the detrimental consequences of alcohol intoxication.
Mecamylamine Attenuates the Subjective Stimulant‐Like Effects of Alcohol in Social Drinkers
Authors: Chi Henry , de Wit Harriet
Published: November 2003

Background: Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant‐like subjective effects of alcohol (0.8 g/kg) and decrease the self‐reported desire to consume additional alcohol beverages.

Methods: Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double‐blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective‐effect measures were taken at 30‐min intervals for 2 hr after beverage consumption.

Results: Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self‐reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine.

Conclusions: These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant‐like effects of alcohol.