Effects Of Pentobarbital Research Articles

Pentobarbital induces thalamic oscillations in brain slices, modulated by GABA and glycine receptors

We studied the effects of pentobarbital and antagonists of glutamate, γ-aminobutyrate (GABA), and glycine receptors on extracellular activity in ventrobasal thalamic slices. Pentobarbital at sedative-hypnotic concentration (20 μM) reversibly induced 1–15 Hz oscillations. Sustained oscillations required electrical stimulation of internal capsule, but not elevated temperature or low [Mg 2+]. Anesthetic concentration (200 μM) of pentobarbital evoked only transient oscillations. Kynurenate-sensitive glutamate receptors were essential for oscillations. GABA A antagonism (bicuculline, 50 μM or gabazine, 20 μM) suppressed oscillations at 5–15 Hz. GABA B antagonism (CGP 35348, 100 nM), or antagonism of glycine receptors (strychnine, 1 μM) suppressed oscillations at 1–4 and 11–15 Hz. GABA and glycine receptors modulated oscillation frequency. For elimination, oscillations required GABA antagonists and strychnine. Receptors for glutamate and glycine mediated oscillations during GABA receptor blockade in ventrobasal nuclei, or on disconnection from nRT. Glycine receptors were critical for oscillations in dorsal thalamic network, divested of GABAergic inhibition. Glutamate and GABA receptors mediated pentobarbital-induced oscillations in nRT, disconnected from ventrobasal nuclei. Hence, pentobarbital oscillogenesis occurred in isolated networks of the ventrobasal and reticularis nuclei mediated by glutamate receptors, with frequency modulation by GABA A, GABA B, and glycine receptors. These stationary oscillations represent a model of sedation-hypnosis, amenable to pharmacological analysis.

Pentobarbital differentially modulates alpha1beta3delta and alpha1beta3gamma2L GABAA receptor currents.

GABAA receptors are modulated by a variety of compounds, including the neurosteroids and barbiturates. Although the effects of barbiturates on alphabetagamma isoforms, thought to dominate phasic (synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of alphabetadelta GABAA receptors, thought to mediate tonic (extra- or perisynaptic) inhibition, are unknown. Using ultrafast drug delivery and single channel recording techniques, we demonstrate isoform-specific pentobarbital modulation of low-efficacy, minimally desensitizing alpha1beta3 currents and high-efficacy, rapidly desensitizing alpha1beta3gamma2L currents. Specifically, with saturating concentrations of GABA, pentobarbital substantially potentiated peak alpha1beta3delta receptor currents but failed to potentiate peak alpha1beta3gamma2L receptor currents. Also, pentobarbital had opposite effects on the desensitization of alpha1beta3delta (increased) and alpha1beta3gamma2L (decreased) receptor currents evoked by saturating GABA. Pentobarbital increased steady-state alpha1beta3delta receptor single channel open duration primarily by introducing a longer duration open state, whereas for alpha1beta3gamma2L receptor channels, pentobarbital increased mean open duration by increasing the proportion and duration of the longest open state. The data support previous suggestions that GABA may be a partial agonist at alphabetadelta isoforms, which may render them particularly sensitive to allosteric modulation. The remarkable increase in gating efficacy of alpha1beta3delta receptors suggests that alphabetadelta isoforms, and by inference tonic forms of inhibition, may be important targets for barbiturates.

A role for neuropeptide Y in neurobiological responses to ethanol and drugs of abuse.

In recent years, evidence has emerged suggesting that neuropeptide Y (NPY) is involved with neurobiological responses to ethanol and other drugs of abuse. Here, we provide an overview of physiological, pharmacological, and genetic research showing that: (A) administration of ethanol, as well as ethanol withdrawal, alter central NPY expression, (B) NPY modulates ethanol consumption under certain conditions, and (C) NPY signaling modulates the sedative effects of several drugs, including ethanol, sodium pentobarbital, and ketamine. Evidence suggesting possible mechanism(s) by which NPY signaling modulates ethanol consumption are considered. It is suggested that NPY may influence ethanol consumption by regulating basal levels of anxiety, by modulating the sedative effects of ethanol, and/or by modulating ethanol's rewarding properties.

Single sodium channels from human skeletal muscle in planar lipid bilayers: characterization and response to pentobarbital.

To investigate the response to general anesthetics of different sodium-channel subtypes, we examined the effects of pentobarbital, a close thiopental analogue, on single sodium channels from human skeletal muscle and compared them to existing data from human brain and human ventricular muscle channels. Sodium channels from a preparation of human skeletal muscle were incorporated into planar lipid bilayers, and the steady-state behavior of single sodium channels and their response to pentobarbital was examined in the presence of batrachotoxin, a sodium-channel activator. Single-channel currents were recorded before and after the addition of pentobarbital (0.34-1.34 mM). In symmetrical 500 mM NaCl, human skeletal muscle sodium channels had an averaged single-channel conductance of 21.0 +/- 0.6 pS, and the channel fractional open time was 0.96 +/- 0.04. The activation midpoint potential was -96.2 +/- 1.6 mV. Extracellular tetrodotoxin blocked the channel with a half-maximal concentration (k1/2) of 60 nM at 0 mV. Pentobarbital reduced the time-averaged conductance of single skeletal muscle sodium channels in a concentration-dependent manner (inhibitory concentration 50% [IC50] = 0.66 mM). The steady-state activation was shifted to more hyperpolarized potentials (-16.7 mV at 0.67 mM pentobarbital). In the planar lipid bilayer system, skeletal muscle sodium channels have some electrophysiological properties that are significantly different compared with those of sodium channels from cardiac or from central nervous tissue. In contrast to the control data, these different human sodium channel subtypes showed the same qualitative and quantitative response to the general anesthetic pentobarbital. The implication of these effects for overall anesthesia will depend on the role the individual channels play within their neuronal networks, but suppression of both central nervous system and peripheral sodium channels may add to general anesthetic effects.

Effects of pregnanolone alone and in combination with other positive GABA A modulators on complex behavior in rats

Although positive modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors generally produce similar behavioral effects, regardless of which modulatory site on the GABA(A) receptor complex mediates these effects, some differences have been observed between the effects of neuroactive steroids and those of other positive GABA(A) modulators. The current study was designed to compare the behavioral effects of a neuroactive steroid to those of other positive GABA(A) modulators. Rats responded under a multiple schedule of repeated acquisition and performance of response chains, with responding maintained under a second-order fixed-ratio 2 schedule of food presentation. Pregnanolone, flunitrazepam, pentobarbital and ketamine, an antagonist at NMDA receptors, dose-dependently decreased response rates and increased the percentage of errors in both components of the multiple schedule. Although the rate-decreasing and error-increasing effects of pregnanolone, pentobarbital and ketamine were quantitatively similar to each other, flunitrazepam was less effective in decreasing response rates and more effective in increasing errors than the other three drugs. A dose of 3.2 mg/kg pregnanolone potentiated the effects of flunitrazepam and pentobarbital, producing 2- to 3-fold shifts to the left in the dose-effect curves. In contrast, pregnanolone did not alter the ketamine dose-effect curves. The disruptive effects of the neuroactive steroid pregnanolone are qualitatively similar to those of other positive GABA(A) modulators as well as ketamine; however, the potentiation of the effects of flunitrazepam and pentobarbital, and not ketamine, emphasizes the importance of GABA(A) receptors in the behavioral effects of pregnanolone.

Effects of pentobarbital on purinergic P2X receptors of rat dorsal root ganglion neurons.

Purinergic P2X receptors are ligand-gated ion channels that are activated by extracellular adenosine triphosphate (ATP) and are widely expressed not only in the central and peripheral nervous system but also in tissues throughout the body, playing an important role in the transfer of nociceptive information. Since the influence of barbiturates on P2X receptor subtypes is not known, we studied the effects of pentobarbital sodium (PB) on ATP responses in dorsal root ganglion (DRG) neurons. DRG neurons were dissected from 10- to 14-day-old rats and dissociated after enzyme treatment. Electrical measurements were performed using the nystatin-perforated patch recording mode under voltage-clamp conditions. Drugs were applied using the Y-tube method. ATP evoked three types of inward current at -60 mV: fast desensitizing, slow desensitizing, and mixed. The fast-type current was attributed to activation of P2X3 subtype and the slow type to the P2X2 subtype. PB suppressed the fast-type current in a concentration-dependent manner, while the slow type was slightly reduced. A noncompetitive inhibition was suggested by a downward shift of the ATP concentration-response curves. The current-voltage relationships showed inward rectification, and the extent of suppression was not affected by the holding potential. The reduction was greater in external solutions of higher pH. PB had subtype-specific effects on P2X receptors. The ionized form is likely to be responsible for the suppression of the P2X3 receptor current, which may result in a reduction of the excitability of central and peripheral neurons and may contribute to the anesthetic and analgesic actions of the agent.

Effects of pentobarbital on GABA-activated currents in acutely-isolated rat dentate gyrus granule neurons

Granule neurons from the rat dentate gyrus were acutely isolated and whole-cell currents recorded. Maximal enhancement of 7 μM γ-aminobutyric acid (GABA; EC 30) evoked currents was obtained with 100 μM pentobarbital where the peak-current was 2.1±0.2 of control. One hundred μM pentobarbital alone evoked no current response whereas 1 mM pentobarbital elicited a current response that was 0.4±0.2 of the 100 μM GABA-activated peak current. In 100 μM pentobarbital, the GABA EC 50 value shifted from 14 to 3 μM but the peak-saturating-current value was not altered. An off-current was recorded on removal of 100 μM and higher pentobarbital concentrations. Ten mM pentobarbital abolished the peak-current response to 7 and 100 μM GABA. The results show that in the granule neurons the drug potency differs for the different effects of pentobarbital at GABA A receptors with the modulatory and inhibitory effects requiring lower concentrations than the direct activation of the receptors.

Effects of stress and etifoxine on pentobarbital-induced loss of righting reflex in Balb/cByJ and C57BL/6J mice

We hypothesized that functional changes in the GABAergic system induced by stress would differ between two inbred mouse strains BALB/cByJ and C57BL/6J. We compared the effects of restraint stress and of the anxiolytic drug etifoxine (EFX) on the duration of pentobarbital-induced loss of righting reflex (hypnotic effect) in the two strains. Naive BALB/cByJ mice were less sensitive than naive C57BL/6J mice to the hypnotic effect of pentobarbital. C57BL/6J mice exhibited a shortening in the duration of pentobarbital-induced hypnosis following stress whereas stress had no effect in BALB/cByJ mice. EFX reversed the shortening of pentobarbital-induced hypnosis elicited by stress in C57BL/6J and shortened the duration of pentobarbital-induced hypnosis after stress in BALB/cByJ mice. Alterations in the GABAergic function in BALB/cByJ mice could be corrected by EFX, an enhancer of GABAergic transmission.

Pentobarbital modulates intrinsic and gaba-receptor conductances in thalamocortical inhibition

We investigated interactions of an anesthetic barbiturate, pentobarbital, with non-ligand gated channels and identified inhibitory synaptic transmission in thalamic neurons. Using whole cell voltage-clamp, current-clamp and single channel recording techniques in rat ventrobasal neurons of slices and dispersed preparations, we determined the mechanisms of pentobarbital actions on ionic currents and inhibitory postsynaptic currents (IPSCs), mediated by aminobutyric acid (GABA). We investigated pentobarbital effects on intrinsic currents using hyperpolarizing voltage commands from rest and tetrodotoxin blockade of action potentials. At concentrations near 8 μM, pentobarbital increased input conductance and induced net outward current, I PB , at potentials near action potential threshold. The reversal potential of I PB was −75 mV, implicating K + and other ions. Cs + (3 mM) which inhibits both K + currents and inward rectifier (I h ), completely blocked I PB , whereas the selective I h blocker, ZD-7288 (25 μM), or Ba 2+ (2 mM) which suppresses only K + currents, reduced I PB . Pentobarbital inhibited the I h , consistent with a ZD-7288-induced shift in reversal potential for I PB toward K + equilibrium potential. Pentobarbital increased the inward K + rectifier, I Kir , and leak current, I leak . We determined the susceptibility of IPSCs, evoked by reticular stimulation, to antagonism by bicuculline, picrotoxinin and 2-hydroxysaclofen and identified their receptor subclass components. At EC 50 =53 μM, pentobarbital increased the duration of IPSCs. The prolonged IPSC duration during pentobarbital was attributable to enhanced open probability of GABA A channels, because combined with GABA, pentobarbital application increased mean channel open time without affecting channel conductance. At concentrations up to 100 μM, pentobarbital did not directly activate GABA A receptors. The concentration-response relationships for pentobarbital effects on the intrinsic currents and IPSCs overlapped, implying multiple sites of action and possible redundancy in anesthetic mechanisms. This is the first study to show that an i.v. anesthetic modulates the intrinsic currents, I h , I Kir , and I leak , as well as IPSC time course in the same neurons. These effects likely underlie inhibition in thalamocortical neurons during pentobarbital anesthesia.

Pentobarbital modulates intrinsic and GABA-receptor conductances in thalamocortical inhibition

We investigated interactions of an anesthetic barbiturate, pentobarbital, with non-ligand gated channels and identified inhibitory synaptic transmission in thalamic neurons. Using whole cell voltage-clamp, current-clamp and single channel recording techniques in rat ventrobasal neurons of slices and dispersed preparations, we determined the mechanisms of pentobarbital actions on ionic currents and inhibitory postsynaptic currents (IPSCs), mediated by aminobutyric acid (GABA). We investigated pentobarbital effects on intrinsic currents using hyperpolarizing voltage commands from rest and tetrodotoxin blockade of action potentials. At concentrations near 8 μM, pentobarbital increased input conductance and induced net outward current, I PB, at potentials near action potential threshold. The reversal potential of I PB was −75 mV, implicating K + and other ions. Cs + (3 mM) which inhibits both K + currents and inward rectifier (I h), completely blocked I PB, whereas the selective I h blocker, ZD-7288 (25 μM), or Ba 2+ (2 mM) which suppresses only K + currents, reduced I PB. Pentobarbital inhibited the I h, consistent with a ZD-7288-induced shift in reversal potential for I PB toward K + equilibrium potential. Pentobarbital increased the inward K + rectifier, I Kir, and leak current, I leak. We determined the susceptibility of IPSCs, evoked by reticular stimulation, to antagonism by bicuculline, picrotoxinin and 2-hydroxysaclofen and identified their receptor subclass components. At EC 50=53 μM, pentobarbital increased the duration of IPSCs. The prolonged IPSC duration during pentobarbital was attributable to enhanced open probability of GABA A channels, because combined with GABA, pentobarbital application increased mean channel open time without affecting channel conductance. At concentrations up to 100 μM, pentobarbital did not directly activate GABA A receptors. The concentration-response relationships for pentobarbital effects on the intrinsic currents and IPSCs overlapped, implying multiple sites of action and possible redundancy in anesthetic mechanisms. This is the first study to show that an i.v. anesthetic modulates the intrinsic currents, I h, I Kir, and I leak, as well as IPSC time course in the same neurons. These effects likely underlie inhibition in thalamocortical neurons during pentobarbital anesthesia.

Involvement of brain lactate in neuronal metabolism

The involvement of brain lactate in neuronal metabolism was analyzed by ex vivo NMR spectroscopy with rats under the effects of pentobarbital, alphachloralose or morphine, which were infused with a solution of either [1-(13)C]glucose+lactate or glucose+[3-(13)C]lactate for 20 min. Electroencephalogram recordings indicated different brain electrical activity levels under the three drugs with a clear distinction between pentobarbital, on the one hand, and alphachloralose and morphine on the other. Labeling of metabolites in brain perchloric acid extracts and of blood glucose and lactate was determined by (13)C- and/or (1)H-observed/(13)C-edited-NMR spectroscopy. The following were found: (i) the ratio between glutamate C3 and C4 (13)C-enrichments increased from pentobarbital to alphachloralose and morphine whatever the labeled precursor, indicating a link between metabolic and electrical activity; (ii) under glucose+[3-(13)C]lactate infusion, alanine C3 and acetyl-CoA C2 enrichments were higher than that of lactate C3, revealing the occurrence of an isotopic dilution of the brain exogenous lactate (arising from blood) by lactate from brain (endogenous lactate); the latter was synthesized from glycolysis in a compartment other than the neurons; (iii) the contributions of labeled glucose and lactate to acetyl-CoA C2 enrichment indicated that the involvement of blood glucose relative to that of blood lactate to brain metabolism was correlated with brain activity. It can therefore be concluded that the brain electrical activity-dependent increase in the contribution of blood glucose relative to that of blood lactate to brain metabolism occurred partly via the increase in the metabolism of lactate generated from astrocytic glycolysis. This conclusion supports the hypothesis of an astrocyte-neuron lactate shuttle component in the coupling mechanism between cerebral activity and energy metabolism.

Sodium pentobarbital anesthesia transiently enhances the severity of infection following intragastric, but not intravenous, inoculation of Listeria monocytogenes in mice

In the present study we observed that mice anesthetized with sodium pentobarbital were far more susceptible to gastrointestinal challenge with Listeria monocytogenes than were unanaesthetized mice. The effect of pentobarbital anesthesia was transient (gone within 2 h) and did not alter the severity of infection following i.v. challenge with L. monocytogenes. Treatment with pharmacological inhibitors of gastric acidity (i.e. cimetidine and omeprazole), or intestinal motility (loperamide), did not duplicate the effect of pentobarbital on gastrointestinal listeriosis. These findings suggest that sodium pentobarbital anesthesia causes a short-lived but striking diminution in resistance to gastrointestinal listeriosis in mice, via an undefined mechanism.

The inhibitory effects of ketamine and pentobarbital on substance p receptors expressed in Xenopus oocytes.

Substance P receptors (SPR) modulate nociceptive transmission within the spinal cord. The effects of IV anesthetics on SPR are not clear. In this study, we investigated the effects of IV anesthetics on SPR expressed in Xenopus oocytes. We examined the effects of ketamine, pentobarbital, propofol, and tramadol on SP-induced Ca(2+)-activated Cl(-) currents mediated by SPR expressed in Xenopus oocytes using a whole-cell voltage clamp. Ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, but propofol and tramadol had little effect on the currents. We also studied the effects of ketamine and pentobarbital on [(3)H]-SP to SPR. Ketamine and pentobarbital inhibited the specific binding of [(3)H]-SP to SPR expressed in Xenopus oocytes. Scatchard analysis of [(3)H]-SP binding revealed that ketamine and pentobarbital decreased the apparent dissociation constant for binding and maximal binding, indicating noncompetitive inhibition. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ketamine and pentobarbital on SP-induced Ca(2+)-activated Cl(-) currents. The results suggest that ketamine and pentobarbital inhibit SPR function. The mechanism of their inhibition on SPR function could not be through activation of the PKC pathway and may be due to noncompetitive displacing the SP binding. We investigated the effects of IV anesthetics on substance P receptors (SPR) expressed in Xenopus oocytes. Ketamine and pentobarbital inhibit SPR function via noncompetitive displacing SP binding. The findings imply that the inhibition of SPR function by these compounds may play a role in the analgesic effects of these IV anesthetics.

Reinforcing versus anticonvulsant drugs: effects on intracranial self-stimulation rate–frequency M 50 indices

Drugs of abuse, such as amphetamine and morphine, produce reward-related shifts on intracranial self-stimulation (ICSS) thresholds. The facilitatory effects on ICSS thresholds of drugs that act through the GABAergic system, however, are reported to be attributed to their antiseizure and anticonvulsant effects, rather than their reinforcing effects. Using a rate–frequency ICSS paradigm, we examined the effects of amphetamine (a reinforcing drug of abuse that acts via the catecholaminergic system), pentobarbital (a GABA A receptor agonist and reinforcing barbiturate with anticonvulsant properties), and gabapentin (a nonspecific GABAergic agonist and anticonvulsant with low abuse potential) on ICSS M 50 indices. All three doses of amphetamine (0.5, 1.0, and 2.0 mg/kg) and pentobarbital (2.5, 5.0, and 10.0 mg/kg) significantly lowered rate–frequency M 50 values. Gabapentin, on the other hand, significantly raised rate–frequency M 50 values, albeit only at the highest dose administered (30 mg/kg). Our results indicate that shifts in ICSS M 50 values produced by pentobarbital are associated with the reinforcing, not the anticonvulsant, effect of pentobarbital. These results are consistent with the view that there is a common system underlying the reinforcing effects of drugs and ICSS reinforcement, and suggest that the reinforcing and anticonvulsant effects of GABA agonists are dissociable.

Deletion of GABAA receptor alpha 1 subunit-containing receptors alters responses to ethanol and other anesthetics.

GABA(A) receptors have been implicated in mediating several acute effects of ethanol including anxiolysis, ataxia, sedation/hypnosis, and anticonvulsant activity. Ethanol sensitivity of neurons has been associated with expression of alpha1 subunit-containing receptors. The objective of this study was to determine the contribution of alpha1 subunit containing receptors to ethanol responses in comparison to neurosteroids and other anesthetics using GABA(A) receptor alpha1 subunit knockout mice. Deletion of alpha1 subunit-containing receptors did not alter the anxiolytic, ataxic, anticonvulsant, or hypnotic effects of ethanol or acute functional tolerance to ethanol but did increase sensitivity to the locomotor-stimulating effects of ethanol. The ability of ethanol to potentiate muscimol-stimulated chloride uptake and ethanol clearance was also not altered following alpha1 subunit deletion. The anticonvulsant and hypnotic effects of neurosteroids as well as their potentiating effect on GABA-mediated Cl(-) uptake were unaltered in alpha1(-/-) mice. The hypnotic effect of pentobarbital, etomidate, and midazolam were reduced, whereas the effect of ketamine was enhanced in alpha1(-/-) mice. Thus, GABA(A) receptor alpha1 subunit-containing receptors appear to influence the motor-stimulating effect of ethanol and the sedative/hypnotic effects of some anesthetics, but not ethanol. These receptors do not appear to be necessary for most ethanol responses, suggesting involvement of other GABA(A) receptor subtypes or other targets altogether.

Pentobarbital Inhibits Ketamine-Induced Dopamine Release in the Rat Nucleus Accumbens: A Microdialysis Study

Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the actions of various psychotropic and addictive drugs. Ketamine and barbiturates have psychotropic effects and addictive properties, but barbiturates prevent ketamine’s psychotomimetic effects. We investigated the effects of ketamine and pentobarbital on dopamine release in the NAC. A microdialysis probe was implanted in the NAC in 35 rats, which were randomly assigned to seven groups: a normal saline intraperitoneal injection (ip) group, 50 and 100 mg/kg of ketamine ip groups, 25 and 50 mg/kg of pentobarbital ip groups, and a normal saline or 25 mg/kg of pentobarbital ip followed by 50 mg/kg of ketamine ip groups. Perfusate samples were collected every 20 min, and dopamine concentration was measured by high-performance liquid chromatography. Ketamine at doses of 50 mg/kg and 100 mg/kg significantly increased dopamine release in the NAC. Conversely, pentobarbital significantly decreased dopamine release in the NAC and inhibited the ketamine-induced dopamine release. These data suggest that the dopamine release in the NAC may be involved in ketamine-induced, but not barbiturate-induced, psychotropic effects and addiction. Inhibition of ketamine-induced dopamine release by barbiturates may be a mechanism by which they prevent ketamine emergence reactions.

Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: a microdialysis study.

Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the actions of various psychotropic and addictive drugs. Ketamine and barbiturates have psychotropic effects and addictive properties, but barbiturates prevent ketamine's psychotomimetic effects. We investigated the effects of ketamine and pentobarbital on dopamine release in the NAC. A microdialysis probe was implanted in the NAC in 35 rats, which were randomly assigned to seven groups: a normal saline intraperitoneal injection (ip) group, 50 and 100 mg/kg of ketamine ip groups, 25 and 50 mg/kg of pentobarbital ip groups, and a normal saline or 25 mg/kg of pentobarbital ip followed by 50 mg/kg of ketamine ip groups. Perfusate samples were collected every 20 min, and dopamine concentration was measured by high-performance liquid chromatography. Ketamine at doses of 50 mg/kg and 100 mg/kg significantly increased dopamine release in the NAC. Conversely, pentobarbital significantly decreased dopamine release in the NAC and inhibited the ketamine-induced dopamine release. These data suggest that the dopamine release in the NAC may be involved in ketamine-induced, but not barbiturate-induced, psychotropic effects and addiction. Inhibition of ketamine-induced dopamine release by barbiturates may be a mechanism by which they prevent ketamine emergence reactions. Ketamine increased dopamine release in the nucleus accumbens, which was inhibited by pentobarbital. The mesolimbic dopamine system may be involved in the psychotomimetic effects of ketamine, and the suppression of ketamine emergence reactions by barbiturates may be because of the inhibition of ketamine-induced dopamine release in the nucleus accumbens.

Convulsant and Anticonvulsant Effects on Spontaneous CA3 Population Bursts

This paper analyzes the effects of a convulsant and an anticonvulsant manipulation on spontaneous bursts in CA3 pyramidal cells in the in vitro slice preparation under conditions of low (3.3 mM [K(+)](o)) and high (8.5 mM [K(+)](o)) burst probability. When burst probability was low, the anticonvulsant, pentobarbital, produced the anticipated effects: the burst duration decreased and interburst interval increased. However, when burst probability was high, both anticonvulsant and convulsant manipulations decreased the interburst interval and the burst duration. To reconcile these findings, we utilized a model in which CA3 burst duration is limited by activity-dependent depression of CA3 excitatory recurrent collateral synapses and the interburst interval is determined by the time required to recover from this depression. We defined the burst end threshold as the level of synaptic depression at which bursts terminate, and the burst start threshold as the level of synaptic depression at which burst initiation is possible. Synapses were considered to oscillate between these thresholds. When average burst duration and interburst interval data were fit using this model, the paradoxically similar effects of the convulsant and anticonvulsant manipulations could be quantitatively interpreted. The convulsant maneuver decreased both the burst start and end thresholds. The start threshold decreased more than the end threshold, so that the thresholds were closer together. This decreased the time needed to transition from one threshold to the other, i.e., the interburst interval and burst duration. The anticonvulsant manipulation primarily increased the burst end threshold. This also decreased the difference between thresholds, decreasing both interburst interval and burst duration. This model resolves the paradoxical proconvulsant effects of pentobarbital in the CA3 preparation and provides insights into the effects of anticonvulsants on epileptiform discharges in the human EEG.

Pentobarbital depressant effects are independent of GABA receptors in auditory thalamic neurons.

Pentobarbital, a general anesthetic, has received extensive study for its ability to potentiate inhibition at GABA(A) subtype of receptors for GABA. Using whole cell current-clamp techniques and bath applications, we determined the effects of pentobarbital and GABA receptor antagonists on the membrane properties and tonic or burst firing of medial geniculate neurons in thalamic slices. Pentobarbital (0.01-200 microM) induced depressant effects in 50 of 66 neurons (76%). Pentobarbital hyperpolarized neurons by a mean of 3 mV and decreased the number of action potentials in tonic firing, evoked by current pulse injection from near the resting potential. Pentobarbital also decreased burst firing or low threshold Ca(2+)-spikes, evoked by current pulse injection into neurons at potentials hyperpolarized from rest. The blockade of tonic and burst firing, as well as low threshold Ca(2+)-spikes, was surmountable by increasing the amplitude of input current. The GABA(A) receptor antagonists, bicuculline (100 microM) and picrotoxinin (50-100 microM), did not block the depressant effects of pentobarbital (10 microM). The GABA(B) receptor antagonist, saclofen (200 microM), and GABA(C) receptor antagonist, (1,2,3,6-tetrahydropyridine-4-yl)methylphosphinate (10-50 microM), did not significantly alter the depressant effects. Pentobarbital produced excitatory effects (0.1-50 microM) on 11 neurons (17%) but had no effects on 5 neurons (7%). The excitation consisted of approximately 3 mV depolarization, increased tonic and burst firing and the rate of rise and amplitude of low threshold Ca(2+) spikes. These effects were associated with a increase in input resistance. In contrast, the depressant effects of pentobarbital correlated to a decreased input resistance measured with hyperpolarizing current pulse injection (IC(50) = 7.8 microM). Pentobarbital reduced Na(+)-dependent rectification on depolarization and lowered the slope resistance over a wide voltage range. Tetrodotoxin eliminated both Na(+)-dependent rectification and the pentobarbital-induced decrease in membrane resistance at depolarized voltages in two-thirds of the neurons. The pentobarbital-induced decrease in membrane resistance at voltages hyperpolarized from rest was not evident during co-application with Cs(+), known to block the hyperpolarization-activated rectifiers. In summary, the pentobarbital acted at low concentrations to depress thalamocortical neurons. The depression resulted from decreased rectification on depolarization, which no longer boosted potentials over threshold, and an increased conductance that shunted spike generation. The depressant effects of pentobarbital did not involve known types of GABA receptor interactions.

Reduction of spinal cord injury with pentobarbital and hypothermia in a rabbit model

Objectives: to evaluate the effects of hypothermia and pentobarbital on spinal cord ischaemia induced in a rabbit model. Materials and Methods: thirty-two rabbits, allocated into four equal groups, had the infrarenal aorta clamped distal to the left renal artery and above the iliac bifurcation for 40 min. Groups 3 and 4 had infusion of 15 mg/kg of pentobarbital intravenously for 5 min, 15 min before the cross-clamping. Groups 2 and 4 had infusion of 20 ml of Ringer's lactate (LR) solution at 3°C for 3 min during aortic cross clamp into the isolated aortic segment. Group 1 was untreated and served as control. Postoperative functions of spinal cord were assessed. Results: paraplegia occurred in all rabbits in Group 1, in one in each of Groups 2 and 3, whereas no paraplegia was observed in Group 4. In addition 2 and 3 animals of Groups 2 and 3, respectively revealed varying degree of neurological disturbances, whereas all animals of Group 4 had normal function. This difference between Groups 2, 3, and 4 vs Group 1 was significant (p < 0.002). So was the difference between Groups 2 and 4 (p = 0.03), whereas the difference between Groups 3 and 4 was not significant. Conclusions: hypothermia and pentobarbital was more effective than hypothermia alone for prevention of spinal cord ischaemia in a rabbit model.