Effects Of Pentobarbital Research Articles

In vivo proton MRS to quantify anesthetic effects of pentobarbital on cerebral metabolism and brain activity in rat

To quantitatively investigate the effects of pentobarbital anesthesia on brain activity, brain metabolite concentrations and cerebral metabolic rate of glucose, in vivo proton MR spectra, and electroencephalography were measured in the rat brain with various doses of pentobarbital. The results show that (1) the resonances attributed to propylene glycol, a solvent in pentobarbital injection solution, can be robustly detected and quantified in the brain; (2) the concentration of most brain metabolites remained constant under the isoelectric state (silent electroencephalography) with a high dose of pentobarbital compared to mild isoflurane anesthesia condition, except for a reduction of 61% in the brain glucose level, which was associated with a 37% decrease in cerebral metabolic rate of glucose, suggesting a significant amount of "housekeeping" energy for maintaining brain cellular integrity under the isoelectric state; and (3) electroencephalography and cerebral metabolic activities were tightly coupled to the pentobarbital anesthesia depth and they can be indirectly quantified by the propylene glycol resonance signal at 1.13 ppm. This study indicates that in vivo proton MR spectroscopy can be used to measure changes in cerebral metabolite concentrations and cerebral metabolic rate of glucose under varied pentobarbital anesthesia states; moreover, the propylene glycol signal provides a sensitive biomarker for quantitatively monitoring these changes and anesthesia depth noninvasively.

State-dependent changes in high-frequency oscillations recorded in the rat nucleus accumbens

Among the local field potentials recorded in the rat nucleus accumbens (NAc) spontaneous high frequency oscillations (HFO) are typically represented by a small peak in the power spectra in the range of 140–180 Hz. These HFO are known to occur in the awake state, but their distribution over the sleep–wake cycle has not been investigated. To address this issue we firstly examined the power of HFO during periods of quiet waking, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Since general anesthesia resembles certain features of naturally occurring SWS we went on to examine the effect of pentobarbital, isoflurane or urethane anesthesia on spontaneous and ketamine-induced increases in HFO. With respect to waking, the power of spontaneous HFO decreased significantly during periods of SWS but did not differ during bouts of REM sleep. General anesthetics also reduced the power of spontaneous HFO recorded in the NAc and prevented the ketamine-induced increase. These findings suggest that behavioural states where the generation of mental activity is most intense are associated with the presence of HFO in the NAc. In line with this, states which lead to decreased mentation, such as naturally occurring SWS and general anesthesia are associated with reductions in the power of HFO. Our results also suggest that the awake state is necessary for NMDA antagonists to produce enhancement of HFO.

Effect of human chorionic gonadotropin on uterine blood flow in intact and ovariectomized gilts.

This experiment was designed to test the hypothesis that human chorionic gonadotropin (hCG) can directly influence uterine blood flow in pigs. In the study, 18 crossbred gilts (95-100 kg) which had exhibited at least one estrous cycle were used: 8 cyclic gilts in the luteal phase of the estrous cycle and 10 gilts ovariectomized (OVX) three weeks before the experiment began. The OVX animals received i.m. injections of 1 mg estradiol benzoate and 50 mg progesterone daily for five consecutive days before transducer implantation. Precalibrated electromagnetic blood flow transducers were surgically implanted around the uterine artery under general anaesthesia. Beginning at 120 min (0 h) following the placement of probes, i.e. after recording had stabilized, blood flow values were recorded at 10 min intervals for the next 360 min. At 0 h, cyclic (n = 4) and OVX (n = 5) gilts received a bolus injection (5 ml) of 1000 IU hCG intravenously through an indwelling catheter and then the same dose of hCG continuously during 4 hours in 40 ml of saline. The remaining cyclic (n = 4) and OVX (n = 5) gilts were infused with saline only and served as control. The mean (SEM) uterine blood flow at 0 h in cyclic (n = 8) and OVX (n = 10) gilts was 104.0 +/- 25.7 and 58.6 +/- 6.0 ml/min, respectively. Because of the variability of initial blood flow, especially in the cyclic gilts, hCG induced changes were expressed as a percent change from the initial flow and were compared to pretreatment period 0 (-30 - 0 h). hCG produced a significant increase in the uterine blood flow in both treated groups (p < 0.05) reaching at 70 min 110.2 +/- 3.4 vs 80.0 +/- 10.5 and 122.4 +/- 12.1 vs 90.6 +/- 3.8, and then at 230 min 116.7 +/- 9.3 vs 62.0 +/- 10.0 and 121.8 +/- 13.2 vs 85.4 +/- 2.3 percent of initial blood flow in cyclic and OVX gilts, respectively. A comparison of nine 30-min periods (periods 1-9) to period 0 showed a significant decrease of uterine blood flow in both (cyclic and ovariectomized) saline control groups in periods 2-9 (50-360 min). The comparison of the same periods in cyclic and ovariectomized hCG treated gilts revealed a significant increase during periods 7-9 (250-360 min) and in period 6, 9 (210-240 and 330-360 min), respectively. Serum estradiol levels increased significantly from 7.4 +/- 1.5 to 351.9 +/- 50.2 pg/ml in cyclic, and from 43.3 0 +/- 7.0 to 224.8 +/- 24.1 in OVX hCG treated gilts at 180 and 120 min, respectively, and returned to the levels of the control groups 240-300 min after the beginning of hCG infusion. Those results indicate that the early response in uterine blood flow is produced directly by hCG, which overcomes the inhibitory pharmacological effect of pentobarbital on uterine blood flow. The second phase of response to hCG could be caused by estradiol which significantly increased an hour earlier before uterine blood flow elevation. We have also shown a novel source of estradiol in castrated pigs which is released by hCG.

Pentobarbital Dose-dependently Increases Respiratory Genioglossus Muscle Activity while Impairing Diaphragmatic Function in Anesthetized Rats

Anesthetics depress both ventilatory and upper airway dilator muscle activity and thus put the upper airway at risk for collapse. However, these effects are agent-dependent and may involve upper airway and diaphragm muscles to varying degrees. The authors assessed the effects of pentobarbital on upper airway dilator and respiratory pump muscle function in rats and compared these results with the effects of normal sleep. Tracheostomized rats were given increasing doses of pentobarbital to produce deep sedation then light and deep anesthesia, and negative pressure airway stimuli were applied (n = 11). To compare the effects of pentobarbital with those of natural sleep, the authors chronically instrumented rats (n = 10) with genioglossus and neck electromyogram and electroencephalogram electrodes and compared genioglossus activity during wakefulness, sleep (rapid eye movement and non-rapid eye movement), and pentobarbital anesthesia. Pentobarbital caused a dose-dependent decrease in ventilation and in phasic diaphragmatic electromyogram by 11 +/- 0.1%, but it increased phasic genioglossus electromyogram by 23 +/- 0.2%. Natural non-rapid eye movement sleep and pentobarbital anesthesia (10 mg/kg intraperitoneally) decreased respiratory genioglossus electromyogram by 61 +/- 29% and 45 +/- 35%, respectively, and natural rapid eye movement sleep caused the greatest decrease in phasic genioglossus electromyogram (95 +/- 0.3%). Pentobarbital in rats impairs respiratory genioglossus activity compared to the awake state, but the decrease is no greater than seen during natural sleep. During anesthesia, in the absence of pharyngeal airflow, phasic genioglossus activity is increased in a dose-dependent fashion.

Anesthetic pentobarbital inhibits proliferation and migration of malignant glioma cells

Malignant gliomas are common and aggressive brain tumors in adults. The rapid proliferation and diffuse brain migration are main obstacles to successful treatment. Here we show that pentobarbital, a central depressant introduced clinically a century ago, is capable of suppressing proliferation and migration of C6 malignant glioma cells in a concentration-dependent manner. Pentobarbital also leads to a G1 phase cell cycle arrest accompanied by suppressed G1 cell cycle regulatory proteins Cyclin D1, Cyclin D3, CDK2 and phosphorylated Rb. In addition, noticeable morphological changes and interrupted α-tubulin microtubule assembly are induced by pentobarbital exposure. Intracellular signal pathways involved in the effect of pentobarbital is concerned with inactivation of ERK, c-Jun and Akt. Together, these findings suggest anti-proliferation and anti-migration effects of pentobarbital on malignant gliomas, most likely by arresting cell cycle and interfering microtubule. ERK, c-Jun MAPK and PI3K/Akt are possible signaling pathways involved.

A COMPARISON OF THE PHARMACOLOGICAL PROPERTIES OF RECOMBINANT HUMAN AND RAT α1β2γ2L GABAA RECEPTORS IN XENOPUS OOCYTES

In the present study, we compared the pharmacology, particularly neurosteroid modulation of the GABA(A) receptor, between human and rat alpha(1)beta(2)gamma(2)(L) GABA(A) receptors and between human receptors containing the long (L) and short (S) forms of the gamma(2)-subunit. We observed that maximum responses to GABA were significantly higher with the human alpha(1)beta(2)gamma(2)(L) receptor compared with the rat receptor. In terms of neurosteroid modulation, increases in the EC(15) response to GABA induced by 3alpha-OH-5beta-pregnan-20-one (3alpha5betaP), 5alpha-androstane-3alpha,17beta-diol (3alpha5alphaADL) and 5alpha-pregnane-3alpha,20beta-diol (3alpha5alpha-diol) were significantly greater for the rat compared with the human receptor. Responses to 30 micromol/L GABA were inhibited by 3beta-OH-5alpha-pregnan-20-one (UC1010) and 5beta-pregnan-3beta,20(R)-diol (UC1020) to a greater degree for human and rat receptors, respectively. Responses to GABA + 3alpha5alphaTHDOC were inhibited by 5alpha-pregnan-3beta,20(S)-diol (UC1019) and pregnenolone sulphate to a greater degree for human and rat receptors, respectively. The GABA dose-response curves for human alpha(1)beta(2)gamma(2)(S) and alpha(1)beta(2)gamma(2)(L) receptors were identical. However, the maximum GABA-evoked current, the direct gating effect of pentobarbital and the allosteric potentiation of the GABA EC(15) response by 3alpha5alphaTHDOC and 3alpha5betaP were significantly higher with alpha(1)beta(2)gamma(2)(S) than alpha(1)beta(2)gamma(2)(L) receptors. Inhibition of the response to 30 micromol/L GABA by UC1010 and UC1020 was greater for a(1)beta(2)gamma(2)(L) and alpha(1)beta(2)gamma(2)(S) receptors, respectively. Inhibition of responses to 3alpha5alphaTHDOC + GABA by UC1019 and UC1010 was significantly higher for alpha(1)beta(2)gamma(2)(L) receptors. In conclusion, the site of activation by GABA and neurosteroid modulation differ between human and rat alpha(1)beta(2)gamma(2)(L) receptors, as well as between human receptors containing the L and S splice variants of the gamma(2)-subunit.

Differential Effects of Thiopental and Pentobarbital on Spinal GABAA Receptors

General anesthetics thiopental and pentobarbital possess very similar chemical structures whereas their clinical potency is quite different. The underlying molecular mechanism is not fully understood. This study was designed to assess the differential effects of thiopental and pentobarbital on GABA(A) receptors of mechanically dissociated rat spinal dorsal horn neurons by using whole-cell patch-clamp technique. Pentobarbital, at a concentration of 30 microM, which markedly enhanced sub-saturated GABA-induced current (I(GABA)), had no effect on thiopental-induced maximal current. Similarly, the pentobarbital-induced maximal current was also not affected by 30 microM thiopental. Moreover, a linear summation of thiopental-induced maximal current and pentobarbital-induced sub-maximal current was observed. In addition, pentobarbital failed to further enhance I(GABA) in the presence of thiopental at a concentration with maximal modulatory effects on I(GABA), and vice versa. Our results thus suggest that thiopental and pentobarbital might exert the GABA mimetic effects independently, but share a common mechanism to produce the GABA modulatory effects.

Cyclopeptide alkaloid fraction from Zizyphi Spinosi Semen enhances pentobarbital-induced sleeping behaviors

This study aimed to investigate effects of cyclopeptide alkaloid fraction of ZSS (CAFZ) on pentobarbital-induced sleeping behaviors and to determine whether these effects were mediated by γ-aminobutyric acid (GABA) receptors Cl − channel activation, using a Western blot technique and Cl − sensitive fluorescence probe. GABA receptors subunits expression and Cl − influx were investigated in cultured cerebellar granule cells. CAFZ shortened sleeping onset and prolonged sleeping time induced by pentobarbital (42 mg/kg). It also significantly increased the falling asleep rate and duration of sleeping time at a sub-hypnotic dosage of pentobarbital (28 mg/kg). In addition, CAFZ in combination with GABA A receptors agonist, muscimol, synergistically prolonged pentobarbital-induced sleeping time. Both of CAFZ and pentobarbital treatment decreased GABA A receptors α-subunit expression, but did not change β- and γ-subunit expression. However, we found CAFZ and pentobarbital increased Cl − influx, CAFZ showed similar effects with muscimol in potentiating Cl − influx inducing effects of low-dose pentobarbital. In conclusion, it is suggested that the enhancement of Cl − influx by CAFZ may play an important role in the potentiation of pentobarbital-induced sleeping behaviors.

Anesthesia's Effects on Plasma Glucose and Insulin and Cardiac Hexokinase at Similar Hemodynamics and Without Major Surgical Stress in Fed Rats

Recent evidence suggests that hexokinase mitochondria association attenuates cell death, and that plasma glucose and insulin concentrations can influence clinical outcome. In the present study, we examined how different anesthetics per se affect these variables of glucose metabolism, i.e., under similar hemodynamic conditions and in the absence of major surgical stress. In fed rats, the effects of pentobarbital (PENTO), isoflurane (ISO), sevoflurane (SEVO), ketamine-medetomidine-atropine (KMA), and sufentanil-propofol-morphine (SPM) on the cardiac cellular localization of hexokinase (HK) and levels of plasma glucose and insulin were determined and compared with values obtained in nonanesthetized animals (control). The role of mitochondrial and sarcolemmal K(ATP)-channels and alpha2-adrenergic receptor in ISO-induced hyperglycemia was also evaluated. Mean arterial blood pressure was similar among the different anesthetic strategies. PENTO (5.3 +/- 0.2 mM) and SPM (5.1 +/- 0.2 mM) had no significant effect on plasma glucose when compared with control (5.6 +/- 0.1 mM). All other anesthetics induced hyperglycemia: 7.4 +/- 0.2 mM (SEVO), 9.9 +/- 0.3 mM (ISO), and 14.8 +/- 1.0 mM (KMA). Insulin concentrations were increased with PENTO (2.13 +/- 0.13 ng/mL) when compared with control (0.59 +/- 0.22 ng/mL), but were unaffected by the other anesthetics. Inhibition of the mitochondrial K(ATP) channel (5-hydroxydecanoate acid) or the alpha(2)-adrenergic receptor (yohimbine) did not prevent ISO-induced hyperglycemia. Only the nonspecific K(ATP) channel inhibitor glibenclamide was able to prevent hyperglycemia by ISO. Cytoslic HK relative to total HK increased in the following sequence: control (35.5% +/- 2.1%), SEVO (35.5% +/- 2.7%), ISO (36.6% +/- 1.7%), PENTO (41.2% +/- 2.0%; P = 0.082 versus control), SPM (43.0% +/- 1.8%; P = 0.039 versus control), and KMA (46.6 +/- 2.3%; P = 0.002 versus control). Volatile anesthetics and KMA induce hyperglycemia, which can be explained, at least partly, by impaired glucose-induced insulin release. The data indicate that the inhibition of insulin release by ISO is mediated by sarcolemmal K(ATP) channel activation. The use of PENTO and SPM is not associated with hyperglycemia. SPM and KMA reduce the antiapoptotic association of HK with mitochondria.

Relevance of anaesthesia for dofetilide‐induced torsades de pointes in α1‐adrenoceptor‐stimulated rabbits

No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or alpha-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in alpha(1)-adrenoceptor-stimulated rabbits. Rabbits anaesthetized intravenously with pentobarbital, propofol or alpha-chloralose were infused simultaneously with the alpha(1)-adrenoceptor agonist phenylephrine (15 microg kg(-1) min(-1), i.v.) and dofetilide (0.04 mg kg(-1) min(-1), i.v.). The electrocardiographic QT interval, the T (peak)-T (end) interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15-0.5 Hz to assess the sympathetic activity. Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with alpha-chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with alpha-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the alpha-chloralose and propofol anaesthesia groups. In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared.

Low Concentrations of Pentobarbital Enhance Excitability of Rat Hippocampal Neurons

Although the excitation phase observed during anesthetic induction and emergence is familiar to anesthesiologists, the cellular mechanisms of this phenomenon are not well understood. At anesthetic concentrations approximately one-tenth those required for surgical anesthesia, subjects demonstrate increased responsiveness to noxious stimulation. We previously estimated that the decrease in nociceptive reflex threshold is maximal at pentobarbital concentrations of approximately 5 microM. Here we used the rat hippocampal slice preparation to examine whether 5 microM pentobarbital increases the excitability of neurons. Intracellular recordings were obtained from CA1 neurons during stimulation of the Schaffer collateral pathway. We examined the effect of pentobarbital on resting intrinsic membrane properties and stimulus-response relationships. Excitability was evaluated with the relationship between the synaptic signal strength, as indicated by the excitatory postsynaptic potential slope, and the probability of spiking (E-S relationship). Pentobarbital increased the excitability of hippocampal neurons, as shown by an increased probability of spiking at any given synaptic signal strength (P = 0.002), an effect known as "E-S potentiation." Pentobarbital was associated with an increase in the input resistance of the neuron and a shift of the action potential threshold towards more negative values. Pentobarbital did not increase the excitatory postsynaptic potential slope at any given stimulus strength. At a 5 microM concentration, pentobarbital increased E-S coupling by enhancing the excitability of the postsynaptic neurons. Pentobarbital induced changes in intrinsic membrane properties that may contribute to increased excitability.

THE REDUCTION OF TUMOR NECROSIS FACTOR-α RELEASE AND TISSUE DAMAGE BY PENTOBARBITAL IN THE EXPERIMENTAL ENDOTOXEMIA MODEL

Sepsis is the leading cause of death for intensive care patients. Lipopolysaccharide (LPS) administration to animals under anesthesia is a strategy for the study of uncontrolled release of proinflammatory cytokines. Anesthetics have been indicated that they can specially affect immune responses, such as the inflammatory response. Pentobarbital is an anesthetic used mainly in animal studies. Thus, the effect of pentobarbital on tumor necrosis factor-alpha (TNF-alpha) release was determined. The results revealed that pentobarbital suppressed the expression of TNF-alpha mRNA and its proteins, which may result from the decrease in the activities of nuclear factor-kappaB and activator protein 1 and the reduction of the expression of p38 mitogen-activated protein kinase by pentobarbital. After the inhibitory activity of the pentobarbital for TNF-alpha release was proven in vivo, the cytotoxic effects of LPS were examined in vivo with or without pentobarbital treatments. In vivo results indicated that plasma levels of alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, creatine kinase, serum urea nitrogen, and amylase decreased dramatically in the anesthetic group with pentobarbital administration. Finally, the effect of pentobarbital on TNF-alpha-related cell death was monitored in vitro, and the results indicated the pentobarbital could directly enhance the viabilities of cells under the treatment of TNF-alpha and protected cells from apoptosis induced by deferoxamine mesylate-induced hypoxia. These results suggest that pentobarbital significantly influences the LPS-induced inflammatory response and protects cells from death directly and indirectly induced by TNF-alpha. The information provides a perspective to re-evaluate the results of the experiments in which animals were anesthetized with pentobarbital. The anti-inflammatory effects of the drugs may have been caused by the synergistic effect of pentobarbital.

Inhibition of human 5-HT3A and 5-HT3AB receptors by etomidate, propofol and pentobarbital

The actions of intravenous anaesthetics on 5-HT(3AB) receptors have not been studied. Using oocyte electrophysiology, the effects of etomidate, propofol, and pentobarbital on human 5-HT(3A) and 5-HT(3AB) receptors were studied and compared. Inhibition of peak currents by all three compounds in both receptor subtypes was anaesthetic concentration-dependant and non-competitive. Because the half-maximal inhibitory concentrations for etomidate, propofol and pentobarbital in 5-HT(3A) and 5-HT(3AB) receptors were all above their respective anaesthetic concentrations, the results of our study suggest that neither 5-HT(3) receptor subtype contributes to the anaesthetic actions of etomidate, propofol or pentobarbital.

The Effect of Isoflurane, Halothane and Pentobarbital on Noise-Induced Hearing Loss in Mice

Ear surgery using mastoid drills can lead to noise-induced hearing loss (NIHL). We investigated whether inhaled anesthetics or pentobarbital could have protective effects on NIHL in mice. Mice were exposed to broad band white noise for 3 h per day for 3 consecutive days, with or without anesthesia, using halothane, isoflurane, or pentobarbital. The hearing level of each mouse was analyzed before exposure, and 1 day, 1, 2, and 3 Wk, and 1 mo after noise exposure by measuring auditory brainstem response thresholds. At 1 Wk after noise exposure, the organ of Corti was stained with a fluorescent isothiocyanate-conjugated phalloidin probe and a TUNEL kit. In the unanesthetized control group, the hearing threshold increased to 77.5 +/- 8.0 dB hearing level (HL) after noise stimulation. In the pentobarbital, isoflurane, and halothane groups, hearing threshold increased to 62.5 +/- 6.3 dB HL, 45.5 +/- 9.8 dB HL, and 39.3 +/- 6.2 dB HL, respectively, with all anesthetized groups of mice showing significantly preserved hearing compared with the control group (P < 0.05). But, in mice anesthetized with pentobarbital, hearing loss was more severe than in those treated with the inhaled anesthetics (P < 0.05). Hair cell survival was reduced in unanesthetized control mice and somewhat reduced in pentobarbital-treated mice, but largely unaffected in mice treated with inhaled anesthetics. These findings indicate that, while halothane, isoflurane and pentobarbital could protect mice against NIHL and hair cell damage, inhaled anesthetics were more effective.

ENDOTOXIN‐INDUCED ACUTE LUNG INJURY AND ORGAN DYSFUNCTION ARE ATTENUATED BY PENTOBARBITAL ANAESTHESIA

1. Acute lung injury (ALI) as a result of sepsis is a major cause of mortality. Certain anaesthetic agents have been reported to suppress pro-inflammatory cytokines and inducible nitric oxide (NO) synthase (iNOS) activities. We investigated the effects of pentobarbital on ALI and organ functions after the administration of endotoxin. 2. Intravenous (i.v.) pentobarbital (20 or 40 mg/kg) was administered 5 min after lipopolysaccharide (LPS; 10 or 30 mg/kg via i.v. infusion). To avoid hypoxia and/or hypercapnia following anaesthesia, we installed a special chamber connected to a rodent ventilator to provide ventilation with 95% oxygen content and 5% nitrogen. The animal was kept at eucapnic conditions (arterial PCO2 at an average of 38 +/- 2 mmHg). 3. We monitored the arterial pressure (AP) and heart rate (HR). Acute lung injury was evaluated by lung weight changes, protein concentration in bronchoalveolar lavage, and Evans blue leakage. Plasma nitrate/nitrite, methyl guanidine and biochemical factors were determined. Pathological and immunofluorescent examinations were performed to observe the lung changes and to determine the activities of pro-inflammatory cytokines, nitrotyrosine and iNOS. 4. Lipopolysaccharide caused dose-dependent systemic hypotension with an increase in the extent of ALI. The lung pathology included oedema and inflammatory cell infiltration. Accompanying the ALI, LPS elevated plasma nitrate/nitrite, methyl guanidine, blood urea nitrogen, lactic dehydrogenase, creatinine phosphokinase, glutamic transaminase and amylase. The lung tissue content of tumour necrosis factor-alpha, interleukin-lbeta, iNOS and nitrotyrosine was increased following LPS administration. These changes were abrogated by pentobarbital anaesthesia. 5. Our results indicated that pentobarbital anaesthesia significantly augmented the LPS-induced systemic hypotension. However, it attenuated the LPS-induced ALI and organ dysfunctions. This agent also improved the survival rate following LPS at high and low doses. This mechanism may be related to the inhibitory effects on the increases in the production or activity of NO, free radicals, pro-inflammatory cytokines, nitrotyrosine and iNOS.

Pentobarbital Enhances γ-Aminobutyric Acid-Mediated Excitation Without Altering Synaptic Plasticity in Rat Hippocampus

Synaptic plasticity is thought to provide a molecular mechanism for learning and memory. N-methyl-d-aspartate receptor-mediated plasticity requires that N-methyl-d-aspartate receptor activation coincides with postsynaptic depolarizing potentials (DPSP(A)'s). Pentobarbital, in high concentrations, enhances DPSP(A)'s, but high concentrations suppress synaptic plasticity, probably by impairing glutamatergic transmission. Here we tested the hypothesis that low concentrations of pentobarbital can enhance DPSP(A)'s and modify the induction of synaptic plasticity. Studies were performed in vitro on rat hippocampal slices. With glutamate transmission blocked, intracellular recording from CA1 neurons was used to investigate the influence of 5 microM pentobarbital on DPSP(A)'s and neuron excitability evoked by high frequency (100 Hz) stimulation. With glutamate transmission intact, extracellular recording was used to examine the effect of 5 microM pentobarbital on the induction of long-term depression and long-term potentiation of synaptic transmission by conditioning stimuli applied to the Schaffer collateral pathway. High frequency stimulation generated typical DPSP(A)'s that were mediated by gamma-aminobutyric acid(A) receptors and dependent upon HCO3-. Pentobarbital (5 microM) increased the amplitude, but not the width, at half-maximal amplitude of DPSPA's (P < 0.01). Pentobarbital increased the probability of action potential generation during the DPSP(A)'s. Pentobarbital did not alter the induction of long-term depression or long-term potentiation. Despite increasing the amplitude of DPSP(A)'s, 5 microM pentobarbital did not alter the induction of synaptic plasticity by a range of conventional conditioning stimuli. These results do not support the hypothesis that excitatory effects of pentobarbital may alter synaptic plasticity.

Effect of pentobarbital on pH and electrolyte levels after induced seizure in rats

We studied the effects of high doses of pentobarbital (PB) and carbamazepine (CBZ) on electrolyte levels and pH in an epileptic animal model. Pentobarbital decreased Ca2+ and Na+ levels without pentylenetetrazole (PTZ). After this, Ca2+ and Na+ levels continued to decrease except when CBZ was used, which preserved the Ca2+ levels PTZ may have opposed effects on PB. Our results suggest that PB causes changes in electrolyte levels and pH, but these changes are diminished by CBZ.

The lack of CB1 receptors prevents neuroadapatations of both NMDA and GABAA receptors after chronic ethanol exposure

As the contribution of cannabinoid (CB1) receptors in the neuroadaptations following chronic alcohol exposure is unknown, we investigated the neuroadaptations induced by chronic alcohol exposure on both NMDA and GABA(A) receptors in CB1-/- mice. Our results show that basal levels of hippocampal [(3)H]MK-801 ((1)-5-methyl-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-imine) binding sites were decreased in CB1-/- mice and that these mice were also less sensitive to the locomotor effects of MK-801. Basal level of both hippocampal and cerebellar [(3)H]muscimol binding was lower and sensitivity to the hypothermic effects of diazepam and pentobarbital was increased in CB1-/- mice. GABA(A)alpha1, beta2, and gamma2 and NMDA receptor (NR) 1 and 2B subunit mRNA levels were altered in striatum of CB1-/- mice. Our results also showed that [(3)H]MK-801 binding sites were increased in cerebral cortex and hippocampus after chronic ethanol ingestion only in wild-type mice. Chronic ethanol ingestion did not modify the sensitivity to the locomotor effects of MK-801 in both genotypes. Similarly, chronic ethanol ingestion reduced the number of [(3)H]muscimol binding sites in cerebral cortex, but not in cerebellum, only in CB1+/+ mice. We conclude that lifelong deletion of CB1 receptors impairs neuroadaptations of both NMDA and GABA(A) receptors after chronic ethanol exposure and that the endocannabinoid/CB1 receptor system is involved in alcohol dependence.

Chronic swim stress alters sensitivity to acute behavioral effects of ethanol in mice

Epidemiological data support a strong link between stress, stress-related disorders and risk for alcoholism. However, precisely how stress might impact sensitivity to the intoxicating effects of ethanol or the willingness to voluntary consume ethanol remains unclear. The present study assessed the effects of daily exposure to forced swim stress on subsequent sensitivity to the sedative/hypnotic, hypothermic, ataxic (measured using accelerating rotarod), and anxiolytic-like (measured using elevated plus-maze) effects of ethanol, and ethanol consumption and preference in a two-bottle choice paradigm, in male C57BL/6J mice. Stress effects on the sedative/hypnotic effects of the barbiturate pentobarbital were also tested. Results showed that chronic (fourteen days) but not acute (one or three days) swim stress significantly potentiated the sedative/hypnotic and hypothermic effects of 4 g/kg, but not 3 g/kg, ethanol. The sedative/hypnotic effects of pentobarbital were attenuated by chronic swim stress. Irrespective of chronicity, swim stress did not alter the ataxic or anxiolytic-like effects of ethanol, or alter ethanol self-administration either during or after stress. These data provide further evidence that stress alters the intoxicating effects of high doses of ethanol in a behaviorally selective manner.

An investigation of the behavioral actions of ethanol across adolescence in mice

The transition from adolescence into adulthood is characterized by rapid maturation of brain systems mediating reward and by increasing experimentation with drugs of abuse including ethanol (EtOH). Previous studies have found marked differences in sensitivity to the behavioral effects of EtOH in adolescent rats as compared to adults, but relatively few studies have been conducted in mice. The present study examined sensitivity to various behavioral effects of EtOH in C57BL/6J mice at various stages of adolescence/adulthood (4, 6, 8 weeks old). Ages were compared for locomotor stimulant (open field), anxiolytic-like (elevated plus-maze), memory-impairing (Pavlovian fear conditioning) and ataxic (accelerating rotarod) effects of EtOH, and the sedative/hypnotic (sleep time) effects of EtOH and pentobarbital. EtOH self-administration was compared using a two-bottle choice paradigm. Measures of EtOH metabolism were also obtained. Early adolescent mice exhibited increased sensitivity to locomotor stimulant (1.5 g/kg), anxiolytic-like (1.5 g/kg) and ataxic (1.5-2.5 g/kg), but not memory impairing (2.0 g/kg), effects of EtOH relative to adults. Early adolescent, and to some extent peri-adolescent, mice were less sensitive than adults to the sedative/hypnotic effects of EtOH (3.5-4.5 g/kg), but not pentobarbital (40-50 mg/kg). Early adolescent mice showed lower EtOH preference, but not EtOH consumption, than adults. Blood EtOH concentrations were higher at early time points and lower at later time points after (3.0 g/kg) EtOH injection in early and peri-adolescents relative to adults. Present data demonstrate that sensitivity to the acute intoxicating effects of EtOH changes across mouse adolescent development in a behavior-dependent manner.