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In vivo effects of single and repeated interferon-alpha administrations on the dynamics of noradrenaline, dopamine and 5-hydroxytryptamine were investigated in the mouse brain. Single interferon-alpha administration (15, 30 and 60 X 10(6) U/kg i.p.) had no significant effect on the levels of monoamines and their metabolites or monoamine turnover. When interferon-alpha (15 X 10(6) U/kg i.p.) was administered once a day for 5 days, however, both dopamine and 3,4-dihydroxyphenylacetic acid levels were significantly decreased and alpha-methyl-p-tyrosine-induced dopamine depletion was significantly suppressed. These results suggest that repeated interferon-alpha administration inhibits dopaminergic neural activity. This inhibitory action of interferon-alpha in dopamine neurons may be involved in adverse central effects, such as parkinsonism and depression with suicidal potential.

Effects of histamine H1-receptor antagonists on L-dopa-induced behavioral excitement were examined in mice to confirm behaviorally the inhibition of dopamine uptake by these compounds. L-Dopa (100-300 mg/kg, s.c.) combined with pargyline hydrochloride (80 mg/kg, i.p.) caused a dose-dependent behavioral excitement. The marked excitement induced by L-dopa (300 mg/kg) plus pargyline was significantly inhibited by pimozide (0.1 - 1 mg/kg, s.c.), a selective dopamine antagonist. Tripelennamine (10 mg/kg, s.c.), d-chlorpheniramine (1 and 2 mg/kg, s.c.), homochlorcyclizine (2 and 5 mg/kg, s.c.), diphenhydramine (2 and 5 mg/kg, s.c.) and mepyramine (2 and 5 mg/kg, s.c.) each markedly enhanced the moderate behavioral excitement induced by L-dopa (150 mg/kg) plus pargyline. These findings are behavioral evidence for inhibition of dopamine uptake by H1 antagonists, which has been suggested by neurochemical studies.

Fluorescence polarization immunoassay (FPIA) is widely used to determine serum vancomycin concentrations, and it has been shown to over-estimate vancomycin concentrations in sera from renally impaired patients. This phenomenon has generally been thought to result from interference by vancomycin crystalline degradation products (CDP-1). In this study, we confirmed that serum vancomycin concentrations in various patients determined by FPIA were higher than those determined by high-performance liquid chromatography (HPLC) or enzyme multiplied immunoassay (EMIT). However, the quantitative differences in the serum vancomycin concentrations determined by FPIA versus HPLC were higher than the CDP-1 concentrations, even when the cross-reactivity of FPIA to CDP-1 is assumed to be 100%. When the vancomycin calibrators for FPIA were stored at 4 degrees C for 30 days, their concentrations determined by FPIA and HPLC decreased by 14 and 20%, respectively, and CDP-1 corresponding to 20% of primary vancomycin was formed. When stored at 25 degrees C, the degradation of vancomycin was more marked. We concluded that not only the cross-reactivity of FPIA to CDP-1 but also the instability of calibrators may cause the overestimation of serum vancomycin concentrations determined by FPIA.

Thiamylal, a widely used anesthetic drug, has two enantiomers. We developed a novel and simple method for measuring thiamylal enantiomers in human serum using reversed-phase high-performance liquid chromatography. R(+)- and S(-)-Thiamylal were separated using a chiral mobile phase containing beta-cyclodextrin, and detected at the range of 50 ng/ml-25 micrograms/ml in serum. The relative standard deviations of R(+)- and S(-)-thiamylal were 3.4-8.7% and 2.8-8.7% for the intra-day assay, and 2.8-12.0% and 2.8-13.0% for the inter-day assay. This method may be applied to enantioselective pharmacokinetic studies of thiamylal.

A 75-year-old woman attempted suicide by ingesting a large quantity of granular Di-Syston which is an organophosphate insecticide containing 5% disulfoton (ethylthiometon). On admission, the total plasma phosphorodithioate sulfone concentration (disulfoton and its metabolites, phosphorodithioate sulfoxide and its sulfone) determined by gas chromatography was 1095 ng/mL. After gastric lavage, the concentration gradually decreased to 505 ng/mL. However, it began to increase again 20 h after admission and reached the peak concentration (1322 ng/mL) at 56 h. It was concluded that the secondary elevation of the plasma concentration was due to the prolonged absorption of the organophosphate from the residual granules in the stomach, despite the early gastric lavage. Pralidoxime iodide administration temporarily restored erythrocyte cholinesterase activity to almost normal and inhibited the excessive, delayed reduction of cholinesterase activity. It is recommended that poisoning with the granular form of disulfoton should be treated with repetitive or prolonged gastric and intestinal lavage, charcoal, and a continuous intravenous infusion of pralidoxime iodide in addition to atropine sulfate.

To characterize the tail-tremor and locomotor hyperactivity induced by repeated nicotine administration, the effects of nicotinic, alpha-adrenergic and dopaminergic blockers were investigated in rats. Daily administration of nicotine (0.5 mg/kg, s.c.) induced tail-tremor from the 4th day, which became more marked in intensity by subsequent administration. Locomotor hyperactivity was also induced by nicotine, which was enhanced by daily administration. The tail-tremor and locomotor hyperactivity induced by repeated nicotine administration were inhibited by mecamylamine (0.1-1 mg/kg, i.p.) but not by hexamethonium (0.5 and 1 mg/kg, i.p.). Clonidine (0.02 and 0.04 mg/kg, i.p.) and prazosin (0.5 and 1 mg/kg, i.p.) reduced tail-tremor more markedly than hyperactivity. However, haloperidol (0.05-0.2 mg/kg, i.p.) and chlorpromazine (1-5 mg/kg, i.p.) reduced hyperactivity more markedly than tail-tremor. These results suggest that nicotine-induced tail-tremor and hyperactivity are due to an increased susceptibility of central nicotinic receptors of nicotine followed by catecholaminergic mechanisms, and that tail-tremor may be more associated with the noradrenergic system than the dopaminergic system.

To clarify the in vivo first-pass metabolism of omeprazole, the pharmacokinetics were examined after oral, intraduodenal (i.d.), intraportal venous (i.p.v), and intravenous (i.v.) administration at various doses to rats. Extraction ratios in the liver and intestinal tract were determined from the areas under the concentration-time curve (AUC) for i.p.v. and i.v. administration and from those for id and ipv administration, respectively. Assuming that the drug was absorbed from the gastrointestinal tract completely, the hepatic and intestinal extraction ratios were 0.80, 0.63, and 0.59 at doses of 2.5, 5, and 10 mg/kg and 0.70 and 0.73 at doses of 5 and 10 mg/kg, respectively. The bioavailability of orally administered omeprazole was 6.4, 9.6, and 12.6% at the doses of 10, 20, and 40 mg/kg, respectively. There were no differences in the distribution volume of steady state, total clearance, or elimination half-life at any doses. In addition, the AUC value after oral administration (20 mg/kg) in rats acutely intoxicated with CCl4 was 2.4 times larger than that in the control. These findings suggest that omeprazole undergoes a first-pass metabolism in the intestinal mucosa and/or lumen, as well as in the liver, and that the major contribution to the dose-dependent increase in bioavailability is a saturation of the first-pass metabolism in the liver.

Histamine (HA) turnover in the rat hypothalamus following insufficient energy supply due to glucoprivation was examined after administration of insulin or 2-deoxy-d-glucose (2-DG). HA turnover was assessed by accumulation of tele-methylhistamine (t-MH), a major metabolite of brain HA, following administration of pargyline. Intraperitoneal injection of 1, 2, and 4 U/kg of insulin, which had no influence on steady-state levels of HA and t-MH, increased pargyline-induced accumulation of t-MH. Accumulation of t-MH due to pargyline was inversely related to the concomitant plasma glucose concentration after different doses of insulin. The level of t-MH accumulated by pargyline did not change compared with that of controls, when a euglycemic condition was maintained or insulin at a dose of 6 mU per rat was infused into the third cerebroventricle. Intracerebroventricular infusion of 24 µmol per rat of 2-DG, which had no influence on steady-state levels of HA and t-MH, increased the level of t-MH enhanced by pargyline. The results indicate that an increase in hypothalamic HA turnover in response to glucoprivation may be involved in homeostatic regulation of energy metabolism in the brain.

To compare in vivo effects of eleven compounds of different classes of histamine H1-receptor antagonists (alcoholamines: diphenhydramine, carbinoxamine, and clemastine; ethylenediamines: mepyramine, tripelennamine, and clemizole; alkylamines: triprolidine and chlorpheniramine; piperazines: meclizine and homochlorcyclizine; phenothiazines: promethazine) on neuronal uptake of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT), the effects on the turnover of these monoamines were examined in the mouse brain, based on the alpha-methyl-p-tyrosine-induced depletion of DA and NA or probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The DA turnover was reduced remarkably by diphenhydramine, tripelennamine, and promethazine, and also significantly by chlorpheniramine, mepyramine, clemizole, and homochlorcyclizine, at doses used in the ordinary animal experiments. The 5-HT turnover was reduced markedly by mepyramine, tripelennamine, and chlorpheniramine. In contrast, the NA turnover was increased by promethazine and homochlorcyclizine, possibly due to their antagonistic effects on alpha-adrenoceptors. These results suggest that (1) the degree of inhibition of the uptake of DA and 5-HT by histamine H1-receptor antagonists is considerably different, (2) most H1-antagonists have little influence on NA uptake and some compounds enhance NA release, and that (3) carbinoxamine, clemastine, triprolidine, and meclizine have comparatively weak influences on monoamine metabolism. These effects on brain monoamine systems may be related to some central actions of histamine H1-receptor antagonists, such as an addiction to these compounds combined with opioids.

Background Tacrolimus is a substrate of P-glycoprotein (PGP) encoded by the multidrug resistant (MDR)1 gene (ABCB1). PGP, a multidrug efflux pump, restricts the distribution of tacrolimus in the brain. In this study, we investigate the correlation of ABCB1 gene polymorphism with tacrolimus-induced neurotoxicity in patients after liver transplantation. Methods. The genotype of 6 patients with neurotoxic events and 11 patients without neurotoxic events was analyzed by polymerase chain reaction (PCR), and 8 mutations were detected. In addition to laboratory findings and patient characteristics, the contribution of mutations in the ABCB1 gene was evaluated with stepwise discriminant function analysis. Results. High tacrolimus concentration, liver dysfunction, and mutation at position 2677 in exon 21 were demonstrated as positive predictors of tacrolimus-induced neurotoxicity. Conclusion. It is indicated that blood concentrations, liver function, graft weight, and polymorphism in the ABCB1 gene are important factors in tacrolimus-induced neurotoxicity.

The inhibitory effect of nicotine pretreatment on reserpine-induced depletion of monoamines in mouse brain was investigated. The depletion of brain monoamines by 24 h after intraperitoneal injection of reserpine (2 mg/kg) was dose-dependently inhibited by nicotine (0.3 – 10 mg/kg, s.c.) pretreatment 20 min before reserpine injection. This effect of nicotine was more marked on dopamine depletion than on noradrenaline or 5-hydroxytryptamine depletion. The nicotine pretreatment also inhibited the reserpine-induced hypothermia and decrease in the locomotor activity. When reserpine (2 mg/kg) was injected intraperitoneally, the inhibitory effect of nicotine (3 mg/kg, s.c.) on the reserpine-induced depletion of brain monoamines and heart noradrenaline was not antagonized by hexamethonium (8 mg/kg, s.c.) but rather potentiated by mecamylamine (2 mg/kg, s.c.). However, when reserpine (0.5 mg/kg) was injected intravenously, pretreatment with nicotine (3 mg/kg, s.c.) inhibited the reserpine-induced dopamine depletion only, and this effect of nicotine was completely blocked by mecamylamine but not by hexamethonium. These results suggest that inhibitory effect of nicotine on the intraperitoneal reserpine-induced depletion of brain monoamines is due to an inhibition of absorption of reserpine, and that central nicotinic action is also involved in the antagonism by nicotine of reserpine-induced dopamine depletion.

Delayed damage to hippocampal CA1 pyramidal cells was observed in rats subjected to cerebral ischemia caused by 10 min of 4-vessel occlusion. Animals pretreated with alpha-fluoromethylhistidine, a suicide inhibitor of histidine decarboxylase, showed significantly more necrotic cells than did control animals. Mepyramine (H1-antagonist) and (R) alpha-methylhistamine (H3-agonist), but not zolantidine (H2-antagonist), significantly aggravated the delayed neuronal death. These results suggest that histaminergic neurons have a protective role, probably via H1-receptors, in the development of delayed neuronal death caused by cerebral ischemia.

The effects of 5-hydroxytryptamine (5-HT) receptor agonists on histamine turnover in mouse and rat brains were examined. The histamine turnover rate was estimated from the accumulation of tele-methylhistamine 90 min after i.p. injection of pargyline (65 mg/kg). In whole mouse brains, the histamine turnover was significantly inhibited by the 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (greater than 0.5 mg/kg) and buspirone (greater than 2 mg/kg) injected s.c. 10 min before pargyline treatment. 5-hydroxytryptophan (20 mg/kg) also significantly inhibited histamine turnover. Injections of the 5-HT1B agonist m-trifluoromethylphenylpiperazine (10 and 20 mg/kg) or the 5-HT2 agonist (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1, 2 and 5 mg/kg), however, did not affect histamine turnover. The inhibitory effect of 8-OH-DPAT (1 mg/kg) on histamine turnover was significantly antagonized (by 40%) by pindolol (20 mg/kg) and slightly antagonized (by 29%) by spiperone (10 mg/kg), while methysergide (20 mg/kg) and ketanserin (10 mg/kg) demonstrated no antagonistic effects. 8-OH-DPAT (0.3 and 1 mg/kg) also showed an inhibiting effect on histamine turnover in various regions of rat brains. Although the extent of inhibition was slightly larger in the striatum and cerebral cortex, there was no marked regional difference. These results suggest that histaminergic activity in the brain is regulated by 5-HT1A receptors.

Rats were chronically exposed to cigarette smoke for 20 min twice daily using a smoking machine. On days 1, 4, and 14, locomotor activity and rearing were measured for 15 min in an open-field apparatus. On day 1, exposure to cigarette smoke increased locomotor activity and rearing in the latter half of the observation period. This effect became more pronounced on days 4 and 14. Chronic cigarette smoke exposures for 21 days significantly decreased the norepinephrine levels in the hypothalamus, thalamus, and pons-medulla, but not the levels of dopamine, 5-hydroxytryptamine, or their metabolites. These results suggest that repeated cigarette smoke exposure increasingly stimulates locomotor activity and rearing and affects norepinephrine metabolism, especially in the brainstem.

A simple and highly sensitive method for the determination of histamine (HA) was developed using ion-pair, reversed-phase HPLC coupled with postcolumn o-phthalaldehyde derivatization fluorometry, and it was applied to the unpurified extracts of human and rat plasma, and brains of rats and mice. The HA concentrations both in the plasma and brains determined by the present method were well consistent with the values obtained by cation-exchange HPLC with postcolumn fluorescent derivatization currently in use. The present method was more advantageous than the assay using cation-exchange HPLC: (1) it was three to four times more sensitive (the detection limit was 0.5 pg of HA), and (2) it enabled the measurement of HA in samples containing (R)alpha-methylhistamine, a potent and specific H3-receptor agonist, which could not be separated from HA by cation-exchange chromatography. Using the present method coupled with intracerebral microdialysis, we found in the rat hypothalamus that (R)alpha-methylhistamine (5 mg/kg i.p.) markedly decreased the extracellular concentration of HA with a maximal effect (83% reduction) during 30-60 min after injection, suggesting that most of HA in the microdialysate fraction is neuronal in origin.

The effect of cigarette smoke exposure on the pharmacokinetics of indomethacin administered orally, intravenously or intrarectally was investigated in rats. When cirgarette smoke exposure was performed for 10 min using a Hamburg II smoking machine immediately after the oral administration of indomethacin (5 mg/kg), the plasma indomethacin concentration was significantly lowered during the first 2 h after administration. However, there was no significant difference in plasma indomethacin concentration between the cigarette smoke-exposed and nonexposed control rats thereafter. Cigarette smoke exposure caused a significant decrease in the area under the concentration-time curve from 0 to 4 h (AUC0–4) and a prolongation of the time to reach the maximum concentration (tmax). The plasma level of O-desmethyl-indomethacin (a major metabolite) was not significantly changed by cigarette smoke. When indomethacin (5 mg/kg) was administered to rats intravenously or intrarectally, cigarette smoke exposure did not have any influence on the pharmacokinetics of indomethacin or 0-desmethyl-indomethacin. The pharmacokinetic effect of cigarette smoke on orally administered indomethacin was mimicked by the subcutaneous injection of nicotine at 0.3 mg/kg but not at 0.1 mg/kg. These results suggest that acute exposure to cigarette smoke decreases the plasma concentration of indomethacin when it is administered orally but not intrarectally or intravenously.

Changes in the levels of histamine, monoamines, and their metabolites in the cerebral cortex and striatum after occlusion of the middle cerebral artery in rats were examined. The water content of the ipsilateral brain regions gradually increased after occlusion. In the ischemic side, 1 h after occlusion, the cortical norepinephrine and striatal 5-hydroxy-tryptamine levels significantly decreased, and striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid levels markedly increased. In contrast, the levels of histamine and tele-methylhistamine in either brain region gradually increased and the changes became pronounced and statistically significant 6-12 h after induction of ischemia. The striatal histamine and tele-methylhistamine reached levels three- and twofold higher, respectively, than those of the contralateral side. In rats treated with alpha-fluoromethylhistidine 1 h before induction of ischemia, elevation of histamine and tele-methylhistamine was not observed. The elevated histamine level in the ipsilateral straitum at 9 h after occlusion was further significantly increased by the treatment with metoprine, an inhibitor of histamine-N-methyltransferase. These results suggest that the histaminergic activity in the brain is gradually enhanced by cerebral ischemia.

The extracellular concentration of histamine (HA) in the hypothalamus of conscious and freely moving rats was measured by in vivo microdialysis and the effects of fasting and feeding on the HA concentration were examined. In non-fasted rats, the basal HA concentration was almost constant from 11.00 to 17.00 h on the day following implantation of the dialysis probe, the mean value being 11.1 pg 30 min . No significant change in the HA concentration was observed in rats deprived of food for 24 h. In 24-h fasted rats, feeding for 15 min produced a transient and significant increase in the HA concentration. These results suggest that histaminergic activity in the rat hypothalamus increases during feeding.

The in vivo effects of four H1-antagonists, diphenhydramine, chlorpheniramine, mepyramine, and promethazine, on the metabolism of noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) were investigated in the whole mouse brain. Diphenhydramine and chlorpheniramine had no significant effect on levels of NA, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), DA, and 5-HT, but they significantly decreased levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). In particular chlorpheniramine markedly decreased 5-HIAA levels at doses as low as 1 mg/kg, i.p. Mepyramine significantly decreased 5-HIAA levels but not those of other substances. High doses of promethazine significantly decreased NA levels but markedly increased those of MHPG, DOPAC, HVA, 5-HT, and 5-HIAA. The DA reduction induced by alpha-methyl-p-tyrosine (alpha-MT) was significantly inhibited by diphenhydramine, chlorpheniramine, and promethazine, but the alpha-MT-induced NA decrease was significantly enhanced by promethazine. The 5-HIAA accumulations induced by probenecid were significantly inhibited by chlorpheniramine and mepyramine. These results suggest: (1) Diphenhydramine and chlorpheniramine inhibit the turnover of both DA and 5-HT by blocking their neuronal uptake. (2) Promethazine and mepyramine inhibit DA and 5-HT turnover, respectively, as a result of the inhibition of the uptake mechanism. (3) Promethazine increases NA turnover by enhancing NA release. The discriminative effects of these drugs on the monoamine systems may be related to some differences in their CNS actions.

In a study of exogenous particulate contamination during angiography, the effect of injection speed of four kinds of radiographic contrast media (RCM) was investigated. The particle count (> or = 10 microns) in all RCM increased in a speed-dependent manner and the increase was especially dramatic at 3 ml s-1. The extent of increase in particulate matter was higher for ioxaglate than for the other three RCM. As particulate matter is unwanted and unnecessary, to prevent the harmful effects in patients much attention should be paid to various factors generating particulate matters, such as characteristics of RCM and plastic syringe.

The effects of lithium chloride and other antimanic drugs on locomotor hyperactivity induced by a mixture of methamphetamine (MAMP) and chlordiazepoxide (CDZP) were examined in mice, using an Animex activity meter. CDZP (12.5 mg/kg) given SC in combination with MAMP (1 mg/kg) caused a marked increase in locomotor activity, as compared with that in mice treated with MAMP alone. However, when CDZP (12.5 mg/kg) was administered together with 0.5 or 2.0 mg/kg of MAMP, no significant enhancement was observed. Lithium (2 and 3 mEq/kg, IP) and carbamazepine (4 and 8 mg/kg, IP) inhibited the hyperactivity induced by the MAMP (1 mg/kg)-CDZP (12.5 mg/kg) mixture to the level of activity in animals treated with MAMP (1 mg/kg) alone. Lithium and carbamazepine alone at these doses caused no significant inhibition of locomotor activity in saline- or MAMP-treated mice. Haloperidol (0.1 mg/kg, IP) and chlorpromazine (0.5 mg/kg, IP) decreased the MAMP-CDZP mixture-induced hyperactivity without significantly inhibiting locomotor activity in the saline- or MAMP-treated group. However, haloperidol (0.2 mg/kg) and chlorpromazine (1 mg/kg) alone significantly inhibited locomotor activity in all of the saline-, MAMP- and MAMP-CDZP mixture-treated groups. These results indicate that antimanic drugs selectively inhibit the hyperactivity induced by the MAMP-CDZP mixture, but that neuroleptics are less selective in inhibiting the hyperactivity.

The turnover rate of histamine (HA) and the half-life of neuronal HA were estimated in 9 regions of the rat brain following pargyline-induced accumulation of tele-methylhistamine (t-MH). The turnover rate was the highest in the hypothalamus (108.7 ng/g/hr). The striatum also showed a high turnover rate (80.2 ng/g/hr) despite much lower levels of HA and t-MH, as compared with the levels in the hypothalamus. The turnover rate was relatively high in the thalamus, cerebral cortex, amygdala and midbrain, but it was very low in the cerebellum. t-MH accumulation in the spinal cord was nil. The HA levels were reduced to various degrees (from nil to less than 40 % of the control) by (S)-α-fluoromethylhistidine, depending on the regions studied. The neuronal HA content of each brain region was subsequently estimated, and the half-life of neuronal HA in each region was calculated. The half-life of neuronal HA was the shortest (7.7 min) in the striatum, while it was long (about 50 min) in the hypothalamus and thalamus. Half-life values of about 20 min were obtained in other regions. These results show the high levels of histaminergic activity in some parts of the telencephalon, thalamus and midbrain as well as the hypothalamus.

The effects of halothane, enflurane, ketamine and pentobarbital on brain histamine dynamics were examined in mice. Brain histamine and tele-methylhistamine, a predominant metabolite of brain histamine, were simultaneously measured by high-performance liquid chromatography with fluorescence detection. Anaesthesia with the four agents had no effect on brain histamine content. The tele-methylhistamine content significantly increased during 1 h and 2 h anaesthesia with halothane (0.051 mmol/l or 0.76 mol/l) and 2 h anaesthesia with enflurane (0.11 mol/l or 0.16 mol/l). Enflurane and pentobarbital significantly inhibited the histamine depletion induced by alpha-fluoromethylhistidine (50 mg/kg, intraperitoneally), a specific inhibitor of histidine decarboxylase, suggesting that these agents decrease the histamine turnover. However, halothane and ketamine were ineffective in this respect. These results emphasize that various anaesthetics have different influences on brain histamine dynamics. Since there have been findings suggesting that brain histaminergic systems are involved in physiological functions such as regulation of blood pressure, body temperature and hormone secretion, changes in the brain histamine turnover should be given due attention with regard to physiological changes during anaesthesia.

The role of the central norepinephrine (NE) system, especially the locus coeruleus (LC), in the occurence of decapitation convulsions was investigated in rats. Intraspinal injection of 6-hydroxydopamine (6-OHDA) caused a significant inhibition of decapitation convulsions as shown by prolongation of the latency and shortening of the convulsion's duration, as well as decreasing the NE content of the spinal cord to 35% of the control value without affecting the NE content of the various regions in the brain. Chemical lesion of the descending bundle from the LC by treatment with 6-OHDA significantly inhibited decapitation convulsions in a similar manner. Moreover, there was a decrease in the NE content of the spinal cord and hypothalamus to 24% and 47% of the control value, respectively. Bilateral electrolytic lesion of the LC also significantly inhibited decapitation convulsions and decreased the NE content of the cortex and spinal cord to 15% and 74% of the control value, respectively. However, lesions of the dorsal and ventral NE bundle by treatment with 6-OHDA, which caused a marked decrease in the NE content of the cortex and hypothalamus, respectively, did not affect the decapitation convulsion. Intraspinal injection of 5,6-dihydroxytryptamine resulted in a decrease in the 5-hydroxytryptamine content of the spinal cord only; moreover, it did not change the decapitation convulsion. These results suggest that coeruleospinal NE neurons play an important role in the occurence of decapitation convulsions.