Accumulation of N,N-dimethyltryptamine in rat brain cortical slices.

14C-DMT accumulates in rat brain cortical slices incubated at 37 C. This process has many of the properties of an active uptake mechanism. It is temperature-sensitive, sodium-dependent, saturable, and is inhibited by metabolic inhibitors. Tryptamine derivatives were more effective than the catecholamines in competing for 14C-DMT accumulation. A number of psychotropic drugs were inhibitors of 14C-DMT accumulation. In general, irrespective of pharmacologic class, the tertiary amines were more potent than the secondary or primary amines, although there were some exceptions. Most of the accumulated 14C-DMT was associated with the cytoplasmic fraction. Of the portion associated with the crude mitochondrial fraction, 54.4% was associated with nerve-ending fraction.

Novel 3,7-diheterabicyclo[3.3.1]nonanes that possess predominant class III antiarrhythmic activity in 1-4 day post infarction dog models: X-ray diffraction analysis of 3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nona ne dihydroperchlorate.

Several 3,7-diheterabicyclo[3.3.1]nonanes (DHBCNs) were prepared and screened in the Harris dog model for their ability to abolish pace-induced and sustained ventricular tachycardia (SVT) or prevent induction of ventricular tachycardia. In addition, an electrophysiological examination was made in the infarcted hearts of each animal to determine if more than one class activity was present. The examples exhibited predominately class III antiarrhythmic activity via a prolongation of the ventricular effective refractory period (VERP) in the models, although there may well be an underlying class Ib action present as exemplified by the ability of several of the agents to slow conduction in the myocardial infarcted dog hearts. 3-[4-(1H-Imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonan e dihydroperchlorate displayed powerful class III activity in the model systems while several other DHBCNs exhibited various degrees of class III action. An X-ray diffraction analysis revealed that this compound has a 3,7-diazabicyclo[3.3.1]nonane bicyclic unit in a chair-chair conformation.

Rhythmic firing of Deiters' neurons and synchronization by cerebellar inhibition in lidocaine-treated cats.

Cerebellar inhibition of spontaneous or homocysteic acid-induced activity of dorsal Deiters' neurons was studied in cats anesthetized with chloralose-urethane. Following intravenous lidocaine (5-10 mg/kg), cerebellar inhibition was not reduced but postinhibitory peaks (PIPs) appeared in the poststimulus histograms. The number of PIPs increased as variability in firing rate decreased after lidocaine. The frequency of PIPs observed in the histograms approximated the monitored firing rates of the cells. The peaks observed in autocorrelograms constructed after lidocaine had the same frequency, structure and variability as the PIPs. In 'dot diagrams', only one spike per corresponding PIP was observed. Similar PIPs were observed in poststimulus histograms constructed during inhibition of crayfish stretch receptor neurons which fired regularly in the absence of lidocaine. These studies indicate that the postinhibitory peaks and silent periods were due to synchronized firing of Deiters' neurons induced by cerebellar inhibition, which was detectable only after lidocaine regularized the firing of Deiters' neurons.

Effect of a chronic tryptophan dietary deficiency on the rat's sleep-wake cycle.

The sleep-wake cycle of 12 tryptophan dietary deficient rats and their non-deficient paired controls were observed for a 8:00 a.m. to 8:00 p.m. period. EEG, EMG and body activity were continuously monitored on polygraphic recordings throughout the 12 hr observation period. The results indicate no significant difference between the tryptophan deficient and sufficient animals in time spent awake, slow-wave or parodoxical sleep. There was a non-significant trend among the tryptophan deficient animals to be less active and spend more time in both slow-wave and paradoxical sleep, which is in contrast to an expected insomnia effect. The results do not support the suggested relationship between reduced serotonin levels and the occurrence of insomnia, questioning the serotonergic theory of sleep.

Reduction of rapid eye movement (REM) sleep by glucose alone or glucose and insulin in rats.

Administration of a high dose of glucose (2.5 g/kg, i.p.) that is known to produce severe hyperglycemia in euglycemic rats suppressed rapid eye movement (REM) sleep time significantly during the first three hours of 8 hr total electroencephalogram (EEG) recording period. Co-administration of glucose (2.5 g/kg, i.p.) and a non-convulsive dose of insulin (1.0 I.U./kg, i.p.) produced a significant reduction in REM sleep time during 1st through 5th hour and an increase in slow-wave sleep (NREM) time in the 3rd and 4th hour of 8 hr total EEG recording period. However, awake, NREM and REM sleep time in the 8 hr total EEG recording period were unaffected by either glucose alone or glucose plus insulin treatments. These results strongly suggest that the insulin's effects on the sleep-awake cycle i.e. reduction in REM and a slight increase in NREM sleep times of rats is not due to indirect effects of insulin on the central nervous system via hypoglycemia as reported by us previously, but could possibly be due to its direct effects on brain chemistry of neurotransmitters such as serotonin, catecholamines and acetylcholine which are believed to modulate the sleep-awake cycle pattern in rats.

Sleep: sequential reduction of paradoxical (REM) and elevation of slow-wave (NREM) sleep by a non-convulsive dose of insulin in rats.

Administration of a single non-convulsive dose of insulin (1.0, I.U./kg., I.P.) which produced no observable gross behavioral changes in rats, reduced rapid eye movement (REM) sleep time 100% in the first 3 hrs. and 82% by the 4th hr., reaching control subject levels (saline-treated) by the 6th hr. In contrast, slow-wave sleep (NREM) time in insulin treated animals exceeded control subject levels by 49% by the end of the 2nd hr., returning to normal by the 5th hr. Although there was no difference between insulin and saline treated rats for the total 8 hr. post-injection recording period for total percentage of time awake, or slow-wave sleep time, a 44% reduction in REM sleep time was observed in insulin treated animals compared to that of a saline treated control. The significance of these findings are discussed in terms of known neurochemical changes i.e., an increase of both brain tryptophan and serotonin in rats, induced by a subconvulsive dose of exogenous insulin.

Failure of naloxone to attenuate fasting induced hyperphagia in broiler chicks.

Subcutaneous administration of naloxone at 1 to 10 mg/kg produced a dose-related decrease in feed intake of broiler chicks. Food deprivation for 3, 6, 12, and 24 hours produced a significant increase in feed intake compared to non-food deprived birds. Subcutaneous administration of naloxone at 1 to 10 mg/kg failed to attenuate hyperphagia of broiler chicks, deprived of food for 12 hrs. These data suggest that opiate receptors are involved in the regulation of spontaneous feeding behavior in broiler chicks. However, in contrast to other mammals and pigeons, a mechanism, other than endorphinergic system, not sensitive to naloxone blockade, might be involved in food deprivation induced hyperphagia in broiler chicks.

Feeding behavior and its responsiveness to naloxone differ in lean and obese sheep.

Feeding and its regulation by opioids were studied in lean sheep and sheep in the static phase of dietary obesity. Sheep were fasted 16 h and on separate days were injected IV with 0 (saline), 0.01, 0.1, 1, or 3 mg/kg naloxone 5 min before they were allowed ad lib intake for the ensuing 32 h. All sheep were in chronic zero energy balance when not fed ad lib during naloxone treatment. After 0 mg/kg naloxone, intake rate was at least twice as fast (p < 0.05) in lean than obese sheep through the first 4 h of ad lib feeding, but was similar (approximately 0.5 g/min) in both groups of sheep after 8 h of ad lib feeding. Dose-dependent inhibitory effects of naloxone on intake were observed in lean and obese sheep through the first 4 h of ad lib feeding with maximum inhibition at +2 h. Dose-response curve for naloxone inhibition of intake was shifted leftward in obese compared with lean sheep. Dose of naloxone needed to inhibit intake by 25% was less (p < 0.05) in obese (0.13 mg/kg) than lean (0.57 mg/kg) sheep when both groups experienced similar plasma concentrations of injected naloxone. Basal concentrations of immunoreactive beta-endorphin in fasted plasma were similar in lean (33 +/- 4 pg/ml) and obese (48 +/- 9 pg/ml) sheep. Dietary obesity in sheep was associated with reduced appetite and with enhanced responsiveness to the intake-inhibitory effects of naloxone.

Naltrexone fails to suppress spontaneous locomotor activity in hamsters.

The increased spontaneous locomotor activity (SLMA) of rats exposed to a novel environment is decreased by opiate antagonists. In the present study, naltrexone (1.0-40 mg/kg) failed to reduce the SLMA of hamsters exposed to the novel environment of activity cages. The SLMA of another group of untreated hamsters declined following 4 consecutive exposures to the activity cages. Thus, the novelty-induced increase in hamster SLMA is not sensitive to opiate antagonism. The differential sensitivity of rats and hamsters to opiate effects on activity and feeding may be due to the presence of an opiate-sensitive hibernation system in hamsters.

The acute and subchronic toxicity of BRB-I-28, a novel class Ib antiarrhythmic agent, in CD-1 mice.

The acute and subchronic toxic effects of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane HCl), a novel class Ib antiarrhythmic agent, were investigated in male and female mice. The estimated oral LD(50) for BRB-I-28 was 128 mg/kg (male mice) and 131 mg/kg (female mice). In subchronic oral studies, four groups of mice (15/sex/group/dose) were fed daily with diets containing BRB-I-28 for 90 consecutive days. The equivalent daily doses were approximately 0, 16, 32, 76 (male) and 0, 18, 37, 89 mg/kg (female). All mice survived. Food consumption per day was decreased, but water consumption per day was increased (in a non-dose-dependent manner). However, both mean body weight and mean body weight gain were not significantly changed as were true for hematological and clinical chemistry profiles, except for serum Na(+) concentration (male) and serum K(+) concentration in male and female mice (high dose levels). Hepatocellular necrosis occurred in male and female mice (in a dose-dependent fashion). Renal cortical vacuoles and myocardial necrosis with low numbers of lymphocytic infiltrations were present in female mice (middle and high doses). Lesions in the liver, kidney and heart were mild with (very small) changes in serum biochemical values. These data suggest that BRB-I-28 has limited toxic potential, and coupled with low proarrhythmic and other desirable cardiovascular effects, makes BRB-I-28 worthy of further development.

Activity of buparvaquone against Theileria cervi in white-tailed deer.

Buparvaquone, a naphthoquinone with known efficacy against Theileria parva parva in cattle, was tested for activity against Theileria cervi piroplasms in both an in vitro culture system and in vivo in experimentally infected white-tailed deer. The in vitro data showed a significant decrease in the incorporation of 3H-hypoxanthine by infected red blood cells treated with buparvaquone when compared to that seen with imidocarb and chloroquine treatment. In both intact and splenectomized deer treated with buparvaquone (2.5 mg kg-1) a gradual decrease in piroplasm parasitaemia was observed following treatment. However, in the splenectomized deer, parasitaemia levels returned to near pretreatment values after approximately 2 weeks.

Effects of naloxone on ad libitum intake and plasma insulin, glucose, and free fatty acids in maintenance-fed sheep.

The dose-dependent effects of naloxone on feed intake, and plasma chemicals (insulin, glucose, FFA) purportedly involved in feed intake regulation, were determined in 16-hr fasted sheep that were lean and chronically fed maintenance. Dorset ewes (n = 5) were treated with 0 (saline), 0.3, 1 or 3 mg/kg of naloxone in a generalized randomized block experiment with at least 7 d between successive doses. Feed intakes and plasma insulin, glucose and FFA were determined frequently during 24 hr of ad libitum intake after each naloxone treatment. The 0.3, 1 and 3 mg/kg doses of naloxone reduced (P less than 0.01) the 4-hr feed intake by 30, 40, and 60% respectively, whereas the initial feed intake (10 min) was decreased (P less than 0.05) 45% only by 3 mg/kg naloxone. However, total 24-hr intakes were similar across all doses because intakes between 4 and 24 hr of feeding in sheep treated with 0.3 (839 g), 1.0 (802 g) and 3.0 (1330 g) mg/kg naloxone exceeded (P less than 0.01) that in saline-treated sheep (391 g). Feeding-induced changes in plasma insulin, glucose and FFA concentrations were independent of naloxone treatment, suggesting that endorphinergic control of feed intake may not involve coincidental changes in plasma insulin, glucose and FFA levels which are thought to play a role in systemic regulation of appetite in animals. The endorphinergic regulation of appetite in sheep may involve the central nervous system, rather than peripheral opiate mechanisms that utilize blood-borne signals. Further, the ability of naloxone to suppress appetite in sheep appears inversely related to the duration of fasting or severity of negative energy balance.

Influence of naloxone and yohimbine administration on pulsatile LH secretion in luteal phase beef cows.

This study examined the effects of two specific neurotransmitter receptor antagonists, naloxone (NAL; mu-opioid) and yohimbine (YOH; alpha(2)-adrenergic), on pulsatile luteinizing hormone (LH) release during the luteal phase (Day 10; Day 0 = estrus) of beef cows. Treatments were saline i.m. (C; n = 4); 1mg/kg NAL i.m. followed 3 h later by two 0.5 mg/kg injections spaced 2.5 h apart (N; n = 4); 0.2 mg/kg YOH i.v. (Y; n = 3); or combined N and Y regimens, with Y preceding N by 30 min (NY; n = 4). Blood samples were collected for 8 h before (Period I) and after (Period II) initiation of treatment. Respiration rates of Y cows were similar to C cows during Period II. However, respiration rates of N and NY animals increased 70% within 30 min of the first NAL injection. Acute LH release was not observed in response to either NAL or YOH. Pulsatile LH secretion was unchanged in N, Y and NY cows during Period II when compared with Period I. In contrast, basal and pulsatile LH secretion was inhibited in C cows during Period II. The inhibition of LH secretion in C animals following NAL indicate that the cows were under stress during Period II. Thus, these data suggest that the inhibition of LH release in stressed animals can be overcome by pharmacologic attenuation of inhibitory (N) or accentuation of stimulatory (Y) signals to LHRH-containing neurons.

Hypotension produced by rapid intravenous administration of chloramphenicol in anaesthetised dogs.

Rapid intravenous administration (60 mg s-1) of chloramphenicol (50 mg kg-1) in a 40 per cent w/v polyethylene glycol (400 to 600), 30 per cent ethyl alcohol, 2 per cent benzyl alcohol and 28 per cent distilled water vehicle produced a transient but significant decrease in systemic arterial blood pressure and heart rate with no effect on central venous pressure in sodium pentobarbital anaesthetised dogs. The vehicle alone had no significant effect on any of the parameters studied. Various approaches including the use of anticholinergic, antihistaminergic, antiadrenergic and ganglion blocking drugs failed to attenuate chloramphenicol induced hypotension and bradycardia. However, the hypertensive response to bilateral carotid arterial occlusion was significantly attenuated by rapid intravenous administration of chloramphenicol. The results clearly indicate that chloramphenicol itself, but not its vehicle, is responsible for the severe hypotension and bradycardia. These results also suggest that chloramphenicol-induced hypotension and bradycardia might be mediated peripherally via vasodilation due to its direct effect on vascular smooth muscle and centrally via interruption of the baroreceptor reflex pathway.

Effects of cimetidine and ranitidine on basal gastric pH, free and total acid contents in horses.

The basal gastric pH, free and total acid contents from five adult horses were determined at two-hour intervals for six- to eight-hour periods. The basal gastric pH, free and total acid contents varied from 2.14 +/- 0.08 to 2.41 +/- 0.14, 28.63 +/- 8.27 to 17.89 +/- 2.86 mmol litre-1 and 41.38 +/- 9.72 to 37.38 +/- 3.70 mmol litre-1, respectively. Cimetidine (8.8 mg kg-1 orally) and ranitidine (2.2 mg kg-1 orally) increased the basal gastric pH to above 3.6 (P less than 0.05) with a concomitant reduction of 75 per cent and 75 to 100 per cent in the basal gastric free acid content, respectively, for an eight-hour period. Cimetidine (4.4 mg kg-1, intramuscularly) and ranitidine (1.4 mg kg-1, intramuscularly) increased the basal gastric pH to above 3.6 with a concomitant reduction of 54 to 93 per cent and 69 to 100 per cent in the basal gastric free acid content, respectively, for an eight-hour period. This study shows that the horse is a basal acid secretor, and that cimetidine and ranitidine, two widely used histaminergic-H2 type antagonists in human clinical practice are effective in horses with ranitidine being approximately four times more potent than cimetidine.

Effects of misoprostol and omeprazole on basal gastric pH and free acid content in horses.

The basal gastric pH and free acid contents from five young adult healthy horses were determined at one hour intervals for eight hours. The basal gastric pH and free acid contents varied from 1.63 +/- 0.06 to 1.97 +/- 0.11 and 26.42 +/- 4.14 to 17.92 +/- 5.28 mmol litre-1, respectively. Misoprostol, a methylester analogue of prostaglandin (5 micrograms kg-1, orally) produced a time-dependent increase in the basal gastric pH to above 3.5 (P less than 0.05) at three, four and five hours after administration with a concomitant reduction of 80 to 90 per cent in the basal gastric free acid contents throughout the eight hour period monitored. Omeprazole, a benzimidazole derivative (0.5 mg kg-1, intravenously) increased the basal gastric pH to above 3.5 at two and three hours after administration with a concomitant reduction of 65 to 90 per cent in the basal gastric free acid contents for seven of the eight hour periods monitored. These results confirm that the horse is a basal acid secretor, and both misoprostol and omeprazole are effective inhibitors of the basal gastric acid secretion, thus establishing that both prostaglandins and H+/K+-ATPase play an important role in controlling parietal cell function of the equine gastric mucosa.

Effects of allopurinol on endotoxin-induced increase in serum xanthine oxidase in the horse.

Using a modified bovine milk enzyme kinetic assay, xanthine oxidase activity of serum collected from 34 adult, healthy horses of both sexes was determined. Enzyme activity varied from 0 to 126 mU litre-1 with a mean of 44.95 +/- 21.05 mU litre-1. The optimal pH and temperature for maximal activity were 7.8 and 28 degrees C, respectively. Freezing the serum for four days at -70 degrees C did not destroy the enzyme activity. Various doses (25, 50 and 75 micrograms kg-1, intraperitoneally) of endotoxin (lipopolysaccharide D1 Escherichia coli O26:B6) previously known to have caused moderate to severe systemic clinical signs of endotoxaemia in horses produced a significant dose related increase in serum xanthine oxidase activity. Pretreatment (12 hours) with allopurinol (5 and 50 mg kg-1, intravenously [corrected]) significantly reduced the rise in xanthine oxidase activity in endotoxin (50 micrograms kg-1, intraperitoneally) treated horses. The results of this study suggest that xanthine oxidase catalysed production of superoxide radicals may play a role in the pathogenesis of endotoxaemia and that allopurinol, an alternate substrate, should be further evaluated for its therapeutic potential in endotoxin related systemic diseases in horses.

Experimental chloramphenicol intoxication in neonatal calves: intravenous administration.

Chloramphenicol was administered intravenously for eight to 17 days to five newborn calves at a daily dosage of 100 mg kg-1. Haemodynamic, haematological, blood chemistry, serum enzyme, urinalysis and clinical responses were evaluated. High levels of serum chloramphenicol were observed throughout the study although a marked increase in elimination rate was seen with increasing age. The most severe adverse effects were severe hypotension following rapid intravenous administration and severe gastrointestinal dysfunction with diarrhoea accompanying prolonged high dosage. There appeared to have been a haematological effect in one calf, but it was of minor significance compared with the other effects.

Effects of cimetidine and ranitidine on basal gastric pH, free and total acid content in pigs.

The effects of intramuscular administration of multiple doses of cimetidine and ranitidine on basal gastric pH, free and total acid content from young adult pigs were studied. Cimetidine (4.5 mg kg-1, four times a day, intramuscularly, for three days) significantly (P less than 0.05) raised the basal gastric pH above 3.5 with a simultaneous reduction in free acid content at two, three and 26 hours after the administration of the eighth dose. Ranitidine (0.75 mg kg-1, four times a day, intramuscularly, for three days) significantly (P less than 0.05) raised the basal gastric pH above 3.5 with a concomitant reduction in free acid content at three and 38 hours after the administration of the eight dose. Neither cimetidine nor ranitidine had any significant effects on total acid content. These results confirm that the pig is a basal acid secretor and that the pharmacodynamics and pharmacokinetics of cimetidine and ranitidine in pigs might be different from those in humans.

Effects of allopurinol in experimental endotoxin shock in horses.

The effect of allopurinol pretreatment 12 hours before an intraperitoneal challenge with a sublethal dose of Escherichia coli endotoxin (50 micrograms kg-1) was evaluated in 18 horses. The horses were divided among three equal groups: 1-endotoxin alone; 2-5 mg allopurinol kg-1 bodyweight plus endotoxin; and 3-50 mg allopurinol kg-1 bodyweight plus endotoxin. A variety of evaluation parameters were used. No differences among the groups were noted in rectal temperature, heart rate, respiration rate, haematological values, blood PaO2, blood PaCO2, blood pH or blood bicarbonate. Significant (P less than 0.05) differences between the groups were noted as regards the changes in capillary refill time, base excess, blood glucose, blood lactate, blood beta-glucuronidase and recumbency time. The protection afforded by 5 mg allopurinol kg-1 appeared to be superior to that with 50 mg allopurinol kg-1.