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PubMed1988

Halothane: inhibition and activation of rat hepatic glutathione S-transferases.

Multiple halothane anesthesias (1.25 MAC for 1 hr on 3 alternate days) of male Long-Evans rats initially decreased by up to 30% and subsequently increased to up to 185% liver cytosolic glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene, 3,4-dichloro-1-nitrobenzene and trans-4-phenyl-3-buten-2-one and glutathione peroxidase activity. Halothane rapidly and reversibly activated hepatic cytosolic glutathione S-transferases and purified isoenzyme 1-2 but not isoenzymes 1-1 and 3-3. At high concentrations of halothane (ca. 22 mM), maximal activation was ca. 25%. Halothane, enflurane, isoflurane and methoxyflurane, but not the halothane metabolite 1-chloro-2,2-difluoroethylene, inhibited a mixture of liver cytosolic glutathione S-transferases with time (ca. 30% inhibition/15 min). The inhibition exhibited pseudo-first order kinetics (kobs = 0.13 min-1) and an I50 for halothane of greater than or equal to 15 mM. Halothane inhibited glutathione S-transferases 3-3, 3-4, and 4-4 by 50-60%, but did not affect isoenzymes 1-1 and 1-2. The ability of halothane to diminish hepatic glutathione S-transferase activity in vivo may in part reflect the time-dependent inhibition of glutathione S-transferase isoenzymes containing the 3- and 4-subunits.

Anesthesia↗

PubMed1994

Human hepatocytes express trifluoroacetylated neoantigens after in vitro exposure to halothane.

Biotransformation of anaesthetic halothane by cytochrome P450-dependent monooxygenases resulted in the production of reactive intermediate trifluoroacetyl (TFA) halide, capable of covalently binding to hepatocyte proteins. TFA-modified liver proteins can act as antigens and are implicated in the pathogenesis of halothane hepatitis in humans. The aim of this study was to investigate the formation of TFA-neoantigens in halothane-treated primary cultures of adult human hepatocytes and to evaluate the usefulness of this in vitro model for studying immune-mediated halothane hepatotoxicity. Cultured human hepatocytes were incubated with halothane under constant temperature, atmosphere and anaesthetic concentration conditions. The results obtained show that halothane-treated hepatocytes isolated from seven different donors produced TFA-antigens as detected by immunocytochemical and western immunoblot analysis using rabbit anti-TFA antiserum. TFA-adducts were localized mainly in the endoplasmic reticulum and in small amounts on the plasma membrane of parenchymal cells. By immunoblotting, several neoantigens, with molecular masses from 42 to 100 kDa, were detected in halothane-exposed hepatocytes. These observations are consistent with the formation of TFA-adducts through metabolism of the anaesthetic and suggest that primary cultures of human hepatocytes represent a suitable in vitro model to study the pathogenesis of immune-mediated halothane hepatotoxicity.

Antibody Specificity↗

PubMed1995

Effects of halothane on the nicotinic acetylcholine receptor from Torpedo californica.

To determine whether the binding of anesthetics to key membrane receptors is a plausible mode of action, we modeled the effect of the general anesthetic halothane in the nicotinic acetylcholine receptor membrane system isolated from Torpedo californica. Our results demonstrated that halothane inhibits the binding of [3H]phencyclidine ([3H]PCP) to the acetylcholine receptor. The inhibition was reversible, concentration dependent, and had an equilibrium dissociation constant (Kd) of 2.2% atm halothane at 25 degrees. Double-reciprocal plots of the halothane effects at various phencyclidine (PCP) concentrations imply that, under equilibrium conditions, halothane inhibits [3H]PCP binding competitively. In contrast, results from kinetic studies showed that the rate of PCP dissociation is highly sensitive to halothane with EC50 = 0.8% atm halothane in nitrogen. Several possible interpretations are discussed; however, the basic observation was that the kinetics of [3H]PCP binding to the nicotinic acetylcholine receptor was affected by halothane at low concentrations in this model system.

Animals↗

PubMed1993

Halothane's effects on GABA-gated chloride flux in mice selectively bred for sensitivity or resistance to diazepam.

The DS (diazepam-sensitive) and DR (diazepam-resistant) lines of mice, selected on the basis of their ataxic response to diazepam, also diverge in the physiologic response of their brain gamma-aminobutyric acidA (GABAA) receptors to benzodiazepines, as indicated by augmentation of GABA-mediated chloride flux. Cross-sensitivity and -resistance to other sedatives known to interact with the GABAA-receptor have also been demonstrated in DS and DR mice. Based on the finding that these mice also show cross-sensitivity and -resistance to obtundation by halothane, we predicted that their GABAA-receptors would also exhibit a differential response to halothane as assayed by an in vitro 36Cl- influx assay using purified brain microvesicles. Consistent with this prediction, therapeutic concentrations of halothane enhanced 1 mumol/l GABA-gated flux with significantly greater potency in DS than in DR mice (halothane EC50 336 +/- 64 mumol/l (S.E.M.) vs. 605 +/- 110 mumol/l, respectively, P = 0.03), but there was no difference in maximal flux enhancement between the two lines (DS 4.7 +/- 0.4 nmol.mg-1 x 3 s-1, vs. DR 4.7 +/- 0.5 nmol.mg-1 x 3 s-1). Halothane (500 mumol/l) also shifted the entire GABA concentration-flux relationship significantly to the left, decreasing the EC50 for GABA in both the DS and DR lines. Importantly, the shift in the GABA concentration-flux response in the presence of halothane was more pronounced in the DS mice (GABA EC50 1.8 +/- 0.4 mumol/l vs. 14.7 +/- 0.9 mumol/l without halothane) than in the DR mice (GABA EC50 4.7 +/- 0.6 mumol/l vs. 14.7 +/- 0.9 mumol/l without halothane).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1980

Interaction of halothane and aminophylline on the isolated hemidiaphragm of the rat.

Halothane itself (1--3 vol percent) produced no significant changes in either Td or dT/dt max of the isolated hemidiaphragm during direct electrical stimulation. On the other hand, halothane significantly potentiated the effect of aminophylline on the resting tension of the muscle, both in a resting non-stimulated muscle and during direct electrical stimulation. Diethyl-ether did not affect the action of aminophylline on the resting tension. The interaction between halothane and aminophylline can be taken as a model for malignant hyperpyrexia. Procaine regularly produced further potentiation of the halothane-aminophylline interaction. There was no halothane-aminophylline interaction in a calcium-free medium. Verapamil was found to potentiate the halothane-aminophylline interaction, whereas di-Na-EDTA depressed it. Halothane did not significantly affect the actions of isoprenaline and adrenaline on Td and dT/dt max during direct electrical stimulation. So far, there is no obvious molecular basis for the action of halothane, but the available evidence indicates that its action is taking place both on the cell membrane and inside the cell, probably by blocking the reaccumulation of calcium in the sarcoplasmic reticulum and thus increasing the amount of free calcium in the cell.

Aminophylline↗

PubMed1985

Effects of halothane on the development of rat brain: a golgi study of dendritic growth.

Dendritic growth was studied in rats exposed to halothane in utero for the entire gestation period and 60 days after birth. The exposure conditions were control, intermittent halothane (25 +/- 5 ppm or 100 +/- 5 ppm, 8 h/day, 5 days/week), or continuous halothane (25 +/- 5 ppm, 24 h/day, 7 days/week). Dendritic growth in terms of branch numbers and length was most advanced in the control groups, followed by those groups exposed to 25 +/- 5 ppm halothane intermittently, 25 +/- 5 ppm halothane continuously, and 100 +/- 5 ppm halothane intermittently. The latter two exposure conditions exerted identical effects on dendritic growth. The order of this dendritic growth level established at 5 postnatal days remained the same throughout the first 95 postnatal days in both the entorhinal cortex and subiculum. The effect of halothane on dendritic growth appeared to be enduring, and the delay in the initial dendritic growth caused by halothane was not compensated for by an increased rate of dendritic growth.

Animals↗

PubMed1984

An enzyme-linked immunosorbent assay for detection of antibodies against halothane-altered hepatocyte antigens.

Patients with massive liver cell necrosis that may follow halothane anaesthesia have a high incidence of circulating antibodies against halothane-induced hepatocyte antigens. In order to provide an objective and quantitative method for the detection of these antibodies, an enzyme-linked immunosorbent assay has been developed. Sera, after absorption with normal rabbit liver microsomal fraction, are tested for binding to microsomal fractions from control and halothane-pretreated rabbits. Those containing antibodies against halothane-induced determinants give significantly enhanced binding to halothane-altered fractions; this specificity was verified by absorption experiments. Using this method, halothane-related antibodies were detected in sera from 16/24 patients with halothane-associated liver failure, at titres ranging from 1:100 to 1:25600. Such antibodies were not detectable in sera from 26 normal blood donors, 5 healthy anaesthetists, 12 patients who had received multiple halothane anaesthetics but had normal liver function tests and 32 patients with a variety of other liver diseases. This rapid and reproducible assay should be of value for the detection of antibodies and for detailed investigation of patient antibody responses, and also for characterization of the route of production and metabolism of the antigen.

Absorption↗

PubMed1996

Effects of halothane and isoflurane on rat ventricular action potentials recorded in situ.

The effects of halothane and isoflurane on ventricular intracellular action potentials recorded in situ in pentobarbital anesthetized rats were studied. Halothane (0.5, 1 and 2 vol.%) and isoflurane (0.75, 1.5 and 3 vol.%) did not have identical effects on rat epicardial action potentials recorded by floating microelectrodes. However, over the concentration range tested, both anesthetics reduced blood pressure and heart rate to a similar extent. Isoflurane did not effect the maximum rate of rise of the action potential amplitude. However, 3 vol.% isoflurane reduced the resting membrane potential from -72+/-2 to -65+/-3 mV (mean+/-SEM, p<0.05) while the highest concentration of halothane had no effect. Halothane (2 vol.%) reduced action potential amplitude from 74+/-4 to 65+/-3 mV (p<0.05) and reduced the maximum rise rate of action potential from 175+/-21 to 133+/-8 V/s (p<0.05). Both isoflurane and halothane prolonged action potential duration at 10, 25 and 50% repolarization while only halothane significantly shortened action potential duration at 75% repolarization, Thus the effects of halothane and isoflurane on ventricular transmembrane action potentials were similar, but not identical. The relevance of such observations to the antiarrhythmic actions of halothane, but not isoflurane in this species is not clear.

Action Potentials↗

PubMed1990

Halothane impairs the bioenergetic functions of isolated rat liver mitochondria.

The effect of halothane, a potent and popular volatile anesthetic, on isolated rat liver mitochondria was examined. Halothane inhibited state 3 and dinitrophenol-induced uncoupled respiration with NAD(+)-linked substrates, but not with FAD-linked substrates, and did not affect the oxidation-reduction state of mitochondrial cytochromes. Moreover, halothane increased state 4 respiration and ATPase activity and decreased the extra-mitochrondrial pH change coupled to ATP synthesis. These results indicate that halothane impairs mitochondrial ATP production by interfering with both the electron transport from NAD+ to FAD and the coupling of oxidative phosphorylation. Halothane only slightly affected the membrane potential, which is commonly dissipated by typical classical uncouplers. Moreover, halothane inhibited both ATP-driven and respiration-driven Ca2+ accumulation in mitochondria and stimulated Ca2+ release from mitochondrial stores at concentrations higher than those at which it inhibited ATP production. These findings indicate that the uncoupling action of halothane is not classical. During halothane anesthesia, these mitochondrial abnormalities may contribute to hepatocyte dysfunctions.

Adenosine Triphosphatases↗

PubMed1995

Molecular mimicry in halothane hepatitis: biochemical and structural characterization of lipoylated autoantigens.

Exposure of human individuals to halothane causes, in about 20% of all cases, a mild transient form of hepatotoxicity. A small subset of exposed individuals, however, develops a potentially severe and life-threatening form of hepatic damage, coined halothane hepatitis. Halothane hepatitis is thought to have an immunological basis. Sera of afflicted individuals contain a wide variety of autoantibodies against hepatic proteins, in both trifluoroacetylated form (CF3CO-proteins) and, at least in part, in native form. CF3CO-proteins are elicited in the course of oxidative biotransformation of halothane, and include the trifluoroacetylated forms of protein disulfide isomerase, microsomal carboxylesterase, calreticulin, ERp72, GRP 78, and ERp99. Current evidence suggests that CF3CO-proteins arise in all halothane-exposed individuals; however, the vast majority of individuals appear to immunochemically tolerate CF3CO-proteins. The lack of immunological responsiveness of these individuals towards CF3CO-proteins might be due to tolerance, induced through the occurrence of structures in the repertoire of self-determinants, which immunochemically and structurally mimic CF3CO-proteins very closely. In fact, lipoic acid, the prosthetic group of the constitutively expressed E2 subunits of the family of mammalian 2-oxoacid dehydrogenase complexes and of protein X, was shown by immunochemical and molecular modelling analysis to be a perfect structural mimic of N6-trifluoroacetyl-L-lysine (CF3 CO-Lys), the major haptenic group of CF3CO-proteins. As a consequence of molecular mimicry, autoantibodies in patients' sera not only recognize CF3CO-proteins, but also the E2 subunit proteins of the 2-oxoacid dehydrogenase complexes and protein X, as autoantigens associated with halothane hepatitis. Furthermore, a fraction of patients with halothane hepatitis exhibit irregularities in the hepatic expression levels of these native, not trifluoroacetylated autoantigens. Collectively, these data suggest that molecular mimicry of CF3CO-Lys by lipoic acid, or the impairment thereof, might play a role in the susceptibility of individuals for the development of halothane hepatitis.

Autoantigens↗

PubMed2005

Cortical spreading depression (CSD)-induced tolerance to transient focal cerebral ischemia in halothane anesthetized rats is affected by anesthetic level but not ATP-sensitive potassium channels.

We investigated the participation of ATP-sensitive potassium (K(ATP)) channels, adenosine A1 receptors, and the effects of different levels of halothane anesthesia in the development of CSD-induced ischemic tolerance. To elicit CSD, 0.5 M KCl was applied for 2 h to the right hemisphere of halothane anesthetized male Wistar rats. The inhalation concentration of halothane during CSD was maintained at 0.5% (n = 8), 1.0% (n = 8), or 2.0% (n = 8). For control animals, saline was applied instead of KCl (n = 8). To inhibit K(ATP) channels or adenosine A1 receptors, glibenclamide (0.1 mg/kg icv; n = 8), 5-hydroxydeconaoate (5-HD; 100 mg/kg ip; n = 12), or 8-Cyclopentyl-1, 3-dipropylxanthine (DPCPX) (1.0 mg/kg ip; n = 8) was applied before preconditioning during 1.0% halothane anesthesia. Temporary occlusion (120 min) of the right middle cerebral artery was induced 4 days after preconditioning and the infarct volume was measured. Preconditioning elicited under 1.0% halothane reduced cortical infarct volume from 277 +/- 15 mm3 in the control group to 159 +/- 14 mm3 in the CSD group (mean +/- SEM, P < 0.05). In contrast, CSD induced during inhalation of 0.5% or 2.0% halothane did not confer ischemic tolerance. The reduction in infarct area with CSD during inhalation of 1% halothane was not changed in animals treated with glibenclamide or 5-HD or DPCPX. These results uncover a crucial role of halothane level but not of K(ATP) channels or adenosine A1 receptors in the preconditioning effects of CSD.

ATP-Binding Cassette Transporters↗

PubMed2004

Halothane augments event-related gamma oscillations in rat visual cortex.

Cortical gamma oscillations have been associated with neural processes supporting cognition and the state of consciousness but the effect of general anesthesia on gamma oscillations is controversial. Here we studied the concentration-dependent effect of halothane on gamma (20-60 Hz) power of event-related potentials (ERP) in rat primary visual cortex. ERP to light flashes repeated at 5-s intervals was recorded with chronically implanted, bipolar, intracortical electrodes at selected steady-state halothane concentrations between 0 and 2%. gamma-Band power was calculated for 0-1000, 0-300 and 300-1000 ms poststimulus periods and corresponding prestimulus (PS) periods. Multitaper power spectral analysis was used to estimate gamma power from both single-trial and average ERP in order to differentiate between phase-locked (evoked) and non-phase-locked (induced) gamma activities. Significant PS gamma power was present at all halothane concentrations. Flash elicited an increase in gamma power that lasted up to 1 s poststimulus at all halothane concentrations. Halothane at intermediate concentrations (0.5-1.2%) augmented both PS and ERP gamma power two to four times relative to the waking baseline. gamma Power was not different between waking and deeply anesthetized (2%) levels. gamma Power reached maximum, as predicted by a Gaussian fit of power-concentration data, at halothane concentration (0.86%) similar to the concentration (0.73%) that abolished the righting reflex, a behavioral index of loss of consciousness. Evoked, i.e. stimulus-locked, gamma power was present during the first 300 ms poststimulus but not later, and was approximately 50% of single-trial ERP gamma power. Single-trial gamma power was present also at 300-1000 ms poststimulus, reflecting ERP not phase-locked to the stimulus. In summary, these observations suggest that (1) gamma activity is present in states ranging from waking to deep halothane anesthesia, (2) halothane does not prevent the transfer of visual input to striate cortex even at surgical plane of anesthesia, and (3) anesthetic-induced loss of consciousness, as reflected by the loss of righting reflex, is not correlated with a reduction in gamma power. Variance with other studies may be due to an underestimation of gamma power by ERP signal averaging as compared with single-trial analysis.

Animals↗

PubMed2001

Differential effects of isoflurane and halothane on the induction of heat shock proteins.

Isoflurane is considered to be a less hepatotoxic volatile anesthetic than halothane since it not only undergoes quantitatively much less metabolism to form toxic reactive intermediates, but also preserves better hepatic blood flow. However, the biochemical basis for the reduced hepatotoxicity has not been elucidated. In this study, we examined the induction of two heat shock proteins, heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), in the livers of rats pretreated with or without phenobarbital, followed by exposure to isoflurane or halothane under hypoxic conditions. In the phenobarbital-pretreated rats, the maximal induction of HSP70 was observed by halothane-hypoxia treatment, followed by a half-maximal induction by isoflurane-hypoxia treatment, and less than 30% induction by hypoxia treatment alone. Serum alanine aminotransferase (ALT) activity, an indicator of hepatic dysfunction, which correlated well with the extent of centrilobular necrosis, showed similar changes with increases in HSP70 mRNA. In contrast, HO-1 mRNA was induced only by treatment with halothane-hypoxia. In addition, changes in the expression of HSP70 and HO-1 mRNAs were correlated with their protein expression in the liver. In non-pretreated rats, neither isoflurane-hypoxia exposure nor halothane-hypoxia exposure caused apparent hepatic injury. There was also no induction of HSP70 or HO-1 mRNA by these treatments in non-pretreated animals. These findings demonstrate that there is a significant difference in hepatic injury, and in the induction of HO-1 and HSP70 between halothane-hypoxia and isoflurane-hypoxia treatments. Isoflurane is known to be safer than halothane, which may, in part, be accounted for by the generation of less oxidative stress in the presence of isoflurane, as assessed by reduced induction of heat shock proteins compared with halothane treatment.

Anesthetics, Inhalation↗

PubMed1998

Spectroscopic analysis of halothane binding to the plasma membrane Ca2+-ATPase.

The intrinsic tryptophan (Trp) fluorescence of the plasma membrane Ca2+-ATPase (PMCA) is significantly quenched by halothane, a volatile anesthetic common in clinical practice. It has been proposed that halothane inhibition of the Ca2+-ATPase activity results from conformational changes following anesthetic binding in the enzyme. We have investigated whether the observed quenching reflects halothane binding to PMCA. We have shown that the quenching is dose dependent and saturable and can be fitted to a binding curve with an equilibrium constant K(Hal) = 2.1 mM, a concentration at which the anesthetic approximately half-maximally inhibits the Ca2+-ATPase activity. The relatively low sensitivity of halothane quenching of Trp fluorescence to the concentration of phosphatidylcholine and detergent in the PMCA preparation concurs with the quenching resulting from anesthetic binding in the PMCA molecule. Analysis of the Trp fluorescence quenching by acrylamide indicates that the Trp residues are not considerably exposed to the solvent (Stern-Volmer quenching constant of 2.9 M(-1)) and do not differ significantly in their accessibility to halothane. Other volatile anesthetics, diethyl ether and diisopropyl ether, reduce the quenching caused by halothane in a dose-dependent manner, suggesting halothane displacement from its binding site(s). These observations indicate that halothane quenching of intrinsic Trp fluorescence of PMCA results from anesthetic binding to the protein. The analysis, used as a complementary approach, provides new information to the still rudimentary understanding of the process of anesthetic interaction with membrane proteins.

Acrylamide↗

PubMed2002

Inhibitory action of halothane on rat masculine sexual behavior and sperm motility.

Adult male rats were exposed to inhale halothane in the following regime: 15 ppm/4 h/5 days/week/9 weeks. Sexual behavior observations and sperm motility test were made before halothane exposure (0 days) and at 15, 30, 45 and 60 days of exposure. Fifteen days after halothane exposure, this anesthetic inhibited the proportion of animals displaying ejaculation. In those animals ejaculating, halothane produced an inhibition of masculine sexual behavior reflected as an increase in the intromission latency, number of mounts and postejaculatory interval. At 30 days after exposure, only an increase in the intromission latency was observed. At 45 and 60 days, the inhibitory effect of halothane on sexual behavior disappeared. Similarly, at 15 and 30 days, but not at 45 or 60 days of halothane exposure, a reduced sperm motility was observed. Such transient effects of halothane suggest the development of tolerance to the inhibitory actions of this anesthetic on sexual behavior and sperm motility. These halothane effects are in line with an inhibition of masculine sexual behavior after stimulation of the GABAergic system.

Administration, Inhalation↗

PubMed1975

Controlled prospective study of the effect on liver function of multiple exposures to halothane.

Patients who had received halothane within a periof of one year and who required another anaesthetic were allocated at random to be given halothane or a control anaesthetic, the control being fiben using halothane-free apparatus. There were 76 patients entries in each group. Serum-glutamic-oxaloacetic-transaminase (S.G.O.T.) levels were measured before the anaesthetics and serially postoperatively for two to three weeks. The S.G.O.T. levels in the halothane group were significantly higher than in the controls. High levels were confined to patients who had had less than four previous halothane anaesthetics, increases above normal in the remainder and in the controls being rate. 1 patient in the halothane group had an S.G.O.T. of 440 I.U. per litre and hepatocellular necrosis on liver biopsy. 2 patients in the halothane group whose S.G.O.T.s rose to more than twice normal showed a similar reaction to re-exposure to halothane, although they had not shown a reaction to an intervening control anaesthetic.

Aged↗

PubMed1992

Effects of halothane on children's electroretinograms.

BACKGROUND: At times, anesthesia is necessary to test children's electroretinographic (ERG) responses. Halothane, an anesthetic commonly used for pediatric patients, affects some aspects of ERG responses, but it is unknown if halothane affects ERG parameters evaluated by contemporary clinical protocols. METHODS: Scotopic and photopic ERG responses were recorded from children when awake and then under halothane. RESULTS: Halothane has no effect on scotopic b-wave stimulus/response parameters, including amplitude, sensitivity, and implicit time. Scotopic a-wave amplitudes, implicit times, model parameters, and ratio of a- to b-wave amplitudes are unaffected by halothane. The amplitudes and implicit times of photopic responses to red flashes and 30 Hz flickering white light are not altered by halothane. Halothane causes no significant change in amplitudes and implicit times of the oscillatory potential wavelets. CONCLUSION: These results suggest that significant departures of ERG responses (studied with the protocol described herein) from a laboratory's normal values cannot be attributed to halothane.

Adolescent↗

PubMed2003

Halothane attenuated haloperidol and enhanced clozapine-induced dopamine release in the rat striatum.

The effect of halothane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by neuroleptics was studied using in vivo microdialysis techniques. Halothane attenuated haloperidol-induced dopamine release and enhanced clozapine-induced dopamine release in the rat striatum.A microdialysis probe was implanted into the right striatum of male SD rats. Rats were given saline or the same volume of 200 microg kg(-1) haloperidol (D(2) receptor antagonist), 10 mg kg(-1) sulpiride (D(2) and D(3) antagonist), or 10 mg kg(-1) clozapine (D(4) and 5-HT(2) antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or 1.5%). Halothane anesthesia did not change the extracellular concentration of DA, but increased the metabolite concentrations in a dose-dependent manner. The increased DA concentration induced by haloperidol was significantly attenuated by halothane anesthesia, whereas the metabolite concentrations were unaffected. Halothane had no effect on the changes in the concentrations of DA or its metabolites induced by sulpiride. The clozapine-induced increases in DA and its metabolites were enhanced by halothane anesthesia. Our results suggest that halothane anesthesia modifies the DA release modulated by antipsychotic drugs in different ways, depending on the effects of dopaminergic or serotonergic pathways.

3,4-Dihydroxyphenylacetic Acid↗