[Effects of Histamine and Related Compounds on the Central Nervous System].

There has been little information about the role of histamine on the central nervous system (CNS), different from dopamine and serotonin. In the present study, therefore, the effects of histamine and related compounds on the CNS were studied using rats. Intracerebroventricular (i.c.v.) injection of histamine and 2-methylhistamine ameliorated memory deficit after long interrution of learning in active avoidance response. First generation H1-antagonists inhibited active avoidance response, whereas newly develpoed H1-antagonists showed little effect. α-Fluoromethylhistidine, an histidine decarboxylase inhibitor, also inhibited active avoidance response. In radial maze performance, almost the same findings were obtained. I.c.v. injection of histamine and H1-agonists inhibited amygdaloid kindled seizures. First generation H1-antagonists attenuated histamine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and intraperitoneal injections of H3-antagonist, thioperamide, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of thioperamide was inhibited by an H3-agonists and H1-antagonists. Similar to nitrazepam, diphenhydramine and chlorpheniramine caused a shortening of sleep latency. On the other hand, no significant effects were observed with second generation H1-antagonists. These findings suggest that histamine plays an important role in learning and memory via H1-receptors, an inhibition of amygdaloid kindled seizures induced by histamine occurred through not only H1-receptors but also H3-receptors, and that classic H1-antagonists can be useful as a effective hypnotic for difficulty in falling asleep.

Apomorphine-induced turning behavior in 6-hydroxydopamine lesioned rats is increased by histidine and decreased by histidine decarboxylase, histamine H1 and H2 receptor antagonists, and an H3 receptor agonist.

The role of histamine and its receptors in basal ganglia neurocircuitry was assessed in apomorphine-induced turning behavior. Rats with unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta and medial forebrain bundle were administered histaminergic agents, and apomorphine-induced turning behavior was tested on Days 7 and 14 post-lesion. Compared with saline-treated rats, histidine (500 mg/kg, i.p.), a precursor of histamine, increased turning behavior (p<0.05), while alpha-fluoromethylhistidine (alpha-FMH, 25 microg, i.c.v.), an irreversible inhibitor of histidine decarboxylase, decreased turning behavior (p<0.05) but only on Day 14 post-lesion. Both the histamine H(1) receptor antagonist pyrilamine (10 and 50 microg, i.c.v.) and the H(2) receptor antagonist cimetidine (10 and 50 microg, i.c.v.) significantly decreased turning behavior on Days 7 and 14 post-lesion. The histamine H(3) receptor agonist immepip (10 microg, i.c.v.) decreased turning behavior (p<0.05) on Day 14 post-lesion. The present findings indicate the complex interactions of histamine on basal ganglia function.

Lesion of the tuberomammillary nucleus E2-region attenuates postictal seizure protection in rats.

Postictal seizure protection (PSP) is an endogenous anticonvulsant phenomenon that follows an epileptic seizure and inhibits the induction of further seizures. The tuberomammillary nucleus (TM), located in the posterior hypothalamus, consists of five subregions and is the sole source of histaminergic neurons in the brain. To determine whether the TM is involved in PSP in rats, we tested the effects of bilateral electrolytic lesions of the TM E2-region on seizures induced by intermittent maximal electroshock (MES). The TM E2-region lesions significantly attenuated PSP during the intermittent MES procedure. Furthermore, intracerebroventricular injection of alpha-fluoromethylhistidine (100 microg), a selective and irreversible histidine decarboxylase inhibitor, mimicked the attenuation of PSP induced by the lesion of TM E2-region. In addition, neurochemical experiments revealed that the TM E2-region lesions markedly decreased basal histamine levels in the cortex, hippocampus, brainstem and hypothalamus, but had no significant effect on basal glutamate and GABA levels. Moreover, intermittent MES induced a persistent decrease of brain histamine levels in both sham-operated and lesioned rats. These results indicate that through its intrinsic histaminergic system, the TM may exert powerful inhibitory function during the intermittent MES procedure and actively participate in the mechanisms of PSP.

Safety and efficacy of Sofenz ceruminolytic solution.

We conducted an open-label study of 109 untreated patients who had excessive or impacted cerumen. Our goal was to evaluate the safety and efficacy of Sofenz Cerumenolytic Solution, a methyltrypsin-containing earwax removal solution. Each patient's external auditory canal was filled with Sofenz for 15 minutes. The primary measure of efficacy--visibility of the tympanic membrane--was assessed after the solution had been drained from the canal and again after the canal had been irrigated with lukewarm water. If the tympanic membrane was not completely visible following either application, the procedure was repeated. A safety examination was conducted 1 to 3 days after treatment. Secondary outcomes measures included relief of otologic symptoms (e.g., hearing loss, tinnitus, etc.) and patients'overall satisfaction with treatment. Immediately after treatment, we found that the external auditory canal was completely visible in 81 patients (74.3%) after 1 application of Sofenz and subsequent irrigation, and in 98 patients (89.9%) after 2 applications of each. At the safety follow-up visit, we determined that the number of otologic symptoms had declined by 93.2%. A self-reported assessment completed by each patient following the procedure revealed a high degree of satisfaction with treatment. A total of 58 adverse events were reported, but only 16 were directly related to treatment, and all were transient and either mild or moderate. We conclude that 1 or 2 applications of Sofenz followed by irrigation with lukewarm water is a safe, well-tolerated, and effective treatment for excessive or impacted cerumen in the external auditory canal.

Effects of carnosine on amygdaloid-kindled seizures in Sprague-Dawley rats.

The effects of carnosine (beta-alanyl-L-histidine) on amygdaloid-kindled seizures were investigated in rats. I.p. injection of carnosine (500, 1000, 1500 mg/kg, i.p.) significantly decreased seizure stage, afterdischarge duration and generalized seizure duration, and significantly prolonged generalized seizure latency of amygdaloid-kindled seizures, in a dose-dependent, and time-related manner. The protective effect of carnosine (1500 mg/kg) was completely antagonized by histamine H1-antagonists pyrilamine (2, 5 mg/kg, i.p.) and diphenhydramine (5, 10 mg/kg, i.p.), but not by histamine H2-antagonist zolantidine even at a high dose of 10 mg/kg. Carnosine (1500 mg/kg, i.p.) caused a significant increase of carnosine and histidine levels in the hypothalamus, thalamus, hippocampus, amygdala and cortex, as well as histamine levels in the hippocampus and amygdala. I.c.v. injection of alpha-fluoromethylhistidine (50 microg, i.c.v.), a selective and irreversible histidine decarboxylase inhibitor, only partially reversed the inhibition of amygdaloid-kindled seizures induced by carnosine. In addition, carnosine significantly decreased glutamate contents in the amygdala and hippocampus. These results indicate that carnosine could protect against amygdaloid-kindled seizures in rats, and its action may be due to the activation of histamine postsynaptic H1-receptors via two different mechanisms, one being carnosine's direct action, and the other being indirectly mediated by histaminergic pathway. The study suggests that carnosine may be an endogenous anticonvulsant factor in the brain and could be used as a new antiepileptic drug in the future.

Submucosal microinfusion of endothelin and adrenaline mobilizes ECL-cell histamine in rat stomach, and causes mucosal damage: a microdialysis study.

Rat stomach ECL cells release histamine in response to gastrin. Submucosal microinfusion of endothelin or adrenaline, known to cause vasoconstriction and gastric lesions, mobilized striking amounts of histamine. While the histamine response to gastrin is sustainable for hours, that to endothelin and adrenaline was characteristically short-lasting (1-2 h). The aims of this study were to identify the cellular source of histamine mobilized by endothelin and adrenaline, and examine the differences between the histamine-mobilizing effects of gastrin, and of endothelin and adrenaline. Endothelin, adrenaline or gastrin were administered by submucosal microinfusion. Gastric histamine mobilization was monitored by microdialysis. Local pretreatment with the H1-receptor antagonist mepyramine and the H2-receptor antagonist ranitidine did not prevent endothelin- or adrenaline-induced mucosal damage. Submucosal microinfusion of histamine did not cause damage. Acid blockade by ranitidine or omeprazole prevented the damage, suggesting that acid back diffusion contributes. Gastrin raised histidine decarboxylase (HDC) activity close to the probe, without affecting the histamine concentration. Endothelin and adrenaline lowered histamine by 50-70%, without activating HDC. Histamine mobilization declined upon repeated administration. Endothelin reduced the number of histamine-immunoreactive ECL cells locally, and reduced the number of secretory vesicles. Thus, unlike gastrin, endothelin (and adrenaline) is capable of exhausting ECL-cell histamine. Microinfusion of alpha-fluoromethylhistidine (known to deplete ECL cells but not mast cells of histamine) reduced the histamine-mobilizing effect of endothelin by 80%, while 1-week pretreatment with omeprazole enhanced it, supporting the involvement of ECL cells. Somatostatin or the prostanoid misoprostol inhibited gastrin-, but not endothelin-stimulated histamine release, suggesting that endothelin and gastrin mobilize histamine via different mechanisms. While gastrin effectively mobilized histamine from ECL cells in primary culture, endothelin had no effect, and adrenaline, a modest effect. Hence, the striking effects of endothelin and adrenaline on ECL cells in situ are probably indirect, possibly a consequence of ischemia.

Immunoelectron-microscopic demonstration of histamine depletion in the gastric enterochromaffin-like cells of rats treated with alpha-fluoromethylhistidine.

We conducted an immunoelectron-microscopic study for histamine (HA) in the enterochromaffin-like (ECL) cells of normal rats and rats given alpha-fluoromethylhistidine (alpha-FMH, 3 mg/kg per hour) via osmotic minipumps over a period of 24 h. The indirect immunoperoxidase procedure utilized a mouse monoclonal antibody (mAb), AHA-2, which is produced against glutaraldehyde-conjugated HA. alpha-FMH is a potent and irreversible inhibitor of the HA-forming enzyme histidine decarboxylase and is known to reduce tissue HA concentrations in several tissues. The present study clearly demonstrated that HA immunoreactivity, which was found to a high degree in the cores of the granules and secretory vesicles and in the cytoplasm of ECL cells of control rats, was completely abolished from the corresponding compartments in the cells of alpha-FMH-treated rats. Furthermore, treatment with alpha-FMH drastically lowered the number of secretory vesicles and was associated with larger cores in the granules of the ECL cells. These results seem to support the idea of a HA-pathway mechanism, emphasizing that the granules in normal ECL cells take up HA from the cytosol during its transport from the Golgi zone to the more peripheral portion of the cell and condense it in their cores, thus forming mature secretory vesicles. However, the present study showed that not only the secretory vesicles but also almost all the granules seen in ECL cells were already loaded with HA in their cores, suggesting that the newborn granules very rapidly take up HA from the cytosol. Also suggested was the fact that HA depletion impairs the maturation of the granules into secretory vesicles.

Effects of intracerebroventricular injection of alpha-fluoromethylhistidine on radial maze performance in rats.

The effects of alpha-fluoromethylhistidine (alpha-FMH) on spatial cognition were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (ICV) injection of alpha-FMH resulted in spatial memory deficits characterized by an increase in the number of total errors (TE) and a decrease in the number of initial correct responses (ICR). There was a strong correlation between increases in the number of TE and decreases in histamine contents of the cortex and hippocampus regions of the brain, which are known to participate in learning and memory. On the other hand, both histamine (50-100 ng, ICV) and thioperamide (10 microg, ICV) significantly ameliorated the memory deficit induced by alpha-FMH. However, metoprine showed no significant effect on the alpha-FMH-induced memory deficit. Pyrilamine and R-(alpha)-methylhistamine enhanced the memory deficit induced by alpha-FMH, at doses that had no appreciable effect when administered alone. In contrast, no significant influence on alpha-FMH-induced memory deficit was observed with zolantidine.

Evidence of a key-role for histamine from mast cells in the analgesic effect of clomipramine in rats.

OBJECTIVE AND DESIGN: We investigated the role of neuronal and mast cell histamine in the analgesic effect of clomipramine. SUBJECTS: Male Sprague-Dawley rats (4-6 weeks old) were used (n = 228). TREATMENT: Clomipramine (10, 20 or 40 mg/kg i.p.) was injected in rats pretreated with [a] saline i.cv. or i.p., [b] alpha-fluoromethylhistidine (alpha-FMH, 200 microg i.cv.), [c] compound 48/80 (C48/80, 1 mg/kg i.p.). Other rats were pretreated with clomipramine, before C48/80. METHODS: Antinociceptive responses were determined before and 30, 60, 90, 120 min after drug injection by tail-flick (TFT) and hot-plate (HPT) tests. Results for each treatment group are given as mean %MPE +/- SEM (Student's t-test, ANOVA). RESULTS: Clomipramine produced no significant changes in TFT and HPT in saline- or alpha-FMH-pretreated rats. Following C48/80, clomipramine (10 and 20 mg/kg) produced a dose-related significant increase in latencies, between 30 and 120 min: 28.5 +/- 5.7 vs 8 +/- 1.6 (p < 0.05), 56 +/- 5 vs 9.2 +/- 1.9 (p < 0.01) in TFT; 31 +/- 4.3 vs 12 +/- 2.5 (p < 0.05), 46.2 +/- 6 vs 11.5 +/- 1.9 (p < 0.01) in HPT. Clomipramine (40 mg/kg, after C48/80) produced marked and persistent increase in latencies 83.2 +/- 4.2 vs 10.5 +/- 3 (p < 0.01) in TFT and 91.2 +/- 4.6 vs 10.5 +/- 3 (p < 0.01) in HPT, followed by symptoms of toxicity and death of some animals. In rats pretreated with clomipramine, C48/80 was unable to show antinociceptive effects on TFT and HPT. CONCLUSIONS: Results suggest that the antinociceptive effect of clomipramine may depend on mast cell histamine levels.

Depletion of enterochromaffin-like cell histamine increases histidine decarboxylase and chromogranin A mRNA levels in rat stomach by a gastrin-independent mechanism.

BACKGROUND: Gastrin activates histidine decarboxylase (HDC) and increases HDC and chromogranin A (CGA) mRNA levels in histamine-producing enterochromaffin-like (ECL) cells in the rat stomach. We have studied how histamine depletion by subcutaneous infusion of the HDC inhibitor alpha-fluoromethyl-histidine (alpha-FMH) affects how ECL cells respond to hypergastrinemia in terms of HDC and CGA mRNA levels. METHODS: In one experiment rats received alpha-FMH for 24 h. In another experiment rats received alpha-FMH, omeprazole (perorally), or a combination of the two drugs for 10 days. In a third experiment antrectomized rats were treated with alpha-FMH for 48 h. The circulating gastrin level, oxyntic mucosal histamine concentration, HDC activity, and HDC and CGA mRNA levels were determined. RESULTS: alpha-FMH for 24 h increased the HDC and CGA mRNA levels without increasing the serum gastrin concentration. alpha-FMH for 10 days increased the serum gastrin concentration twofold. alpha-FMH + omeprazole resulted in the same serum gastrin concentration as after omeprazole alone (eightfold increase). HDC mRNA levels were higher after alpha-FMH + omeprazole than after omeprazole alone. alpha-FMH alone induced an HDC mRNA level that was similar in magnitude to that observed after omeprazole, although the serum gastrin concentration after alpha-FMH was much lower. In antrectomized rats alpha-FMH increased the HDC and CGA mRNA levels without increasing the serum gastrin concentration. CONCLUSION: ECL-cell histamine depletion will increase mRNA levels for HDC and CGA by a gastrin-independent mechanism, possibly involving abolished histamine autofeedback inhibition.

Quantitative urinary excretion of unmetabolised N tau-[Me-14C] methylhistidine by the common ringtail possum (Pseudocheirus peregrinus) marsupialia.

Six common ringtail possums (Pseudocheirus peregrinus) were intravenously injected with a standard dose of radioactive 3-Methylhistidine (N tau-[Me-14C]MeH). The dose was rapidly and quantitatively excreted by the possums. More than 90% of radioactivity was recovered within 3 days. Thin layer chromatography and mass spectroscopy showed that 97% of recovered radioactivity was associated with unmetabolised N tau-[Me-14C]MeH. These data satisfy two key requirements for the validity of urinary 3-Methylhistidine (N tau-3MeH) excretion as an index of muscle protein catabolism, in P. peregrinus.

Disposition of histamine, its metabolites, and pros-methylimidazoleacetic acid in brain regions of rats chronically infused with alpha-fluoromethylhistidine.

In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), forming tele-methylhistamine (t-MH), then tele-methylimidazoleacetic acid (t-MIAA). We previously showed that imidazoleacetic acid (IAA), a GABA agonist, and histamine's metabolite in the periphery, is present in brain where its concentration increased after inhibition of HMT. Also, when [3H]histamine was given intracerebro-ventricularly to rats, a portion was converted to IAA, a process increased by inhibition of HMT. These results indicated that brain has the capacity to oxidize histamine but did not show whether this pathway is operative under physiological conditions. To address this question, rats were infused for > 4 weeks with alpha-fluoromethylhistidine (alpha-FMHis), an irreversible inhibitor of histamine's synthetic enzyme, L-histidine decarboxylase. Compared with controls (untreated and saline-treated rats), brain levels of histamine, t-MH, and t-MIAA in all regions were markedly reduced in treated rats. As a percentage of controls, depletion of t-MIAA > t-MH > histamine in all regions, and regional depletions of histamine co-responded to its turnover rates in regions of rat brain. In contrast, levels of IAA were unchanged as were levels of pros-methylimidazoleacetic acid, an isomer of t-MIAA unrelated to histamine metabolism. Results suggest that in brains of rats, unlike in the periphery, most IAA may not normally derive from histamine. Because histamine in brain can be converted to IAA under certain conditions, direct oxidation of histamine may be a conditional phenomenon. Our results also support the existence of a very slow turnover pool of brain histamine and use of chronic alpha-FMHis infusion as a model to probe the histaminergic system in brain.

Long-term depletion of brain histamine induced by alpha-fluoromethylhistidine increases feeding-associated locomotor activity in mice with a modulation of brain amino acid levels.

We examined the long-term effects of administration of (S)-alpha-fluoromethylhistidine (FMH), a specific inhibitor of histidine decarboxylase, on the spontaneous locomotor activity, food intake and brain contents of histamine, catecholamines, serotonin and amino acids of ICR mice. The distance of ambulation and number of rearings significantly increased from 8 to 15 h (20.00-03.00 h) after treatment with FMH (100 mg/kg, i.p.) and the 24-h food intake also increased significantly. On FMH treatment, the locomotor activity in movements of 3-15 cm/0.5 s was greater than that of control mice, whereas the number of slight movements (0-1 cm/0.5 s) decreased, suggesting that once a mouse treated with FMH is in motion, it moves a longer distance than a control mouse. We sacrificed mice 12 or 24 h after FMH treatment to measure the brain contents of histamine, monoamines and amino acids. Decrease of the brain histamine content to 35% of the control level was observed until 24 h after FMH treatment, but no significant changes in the brain catecholamine and serotonin contents were detected. However, the brain GABA content of ICR mice decreased to 85% of control 12 h after FMH treatment. Moreover, decrease of the brain GABA content after FMH treatment was greater in mast cell-deficient W/Wv mice, being 70 and 62% of the control level 12 and 24 h after treatment, respectively. The present experiments support the idea that the locomotor activity is affected by the central histaminergic system, directly and/or indirectly.

Histaminergic components in carbachol-induced pituitary-adrenocortical activity.

The involvement of central histaminergic mechanisms in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by carbachol, a muscarinic cholinergic agonist, was investigated in conscious rats. The HPA activity was assessed indirectly, through corticosterone secretion. Carbachol given intracerebroventricularly elicited a dose-related increase in serum corticosterone levels. The corticosterone response to carbachol was totally abolished by systemic pretreatment 2h earlier with alpha-fluoro-methylhistidine (alpha-FMH), a specific inhibitor of brain histamine synthesis, which also significantly decreased histamine level in hypothalamus. Mepyramine, a histamine H1-receptor antagonist, moderately diminished the carbachol-induced corticosterone response and abolished the rise in hypothalamic histamine levels. Ranitidine a H2-receptor antagonist, considerably diminished the corticosterone response to carbachol but did not change the elevated hypothalamic histamine levels. Also atropine, a cholinergic antagonist, abolished the corticosterone response to carbachol, but did not significantly affect the carbachol-induced increase in hypothalamic histamine concentration. Ranitidine and atropine can directly block homologous hypothalamic receptors involved in CRF secretion. Partial inhibition of the carbachol-induced corticosterone secretion by mepyramine may be connected with prevention of the carbachol-induced increase in hypothalamic histamine content. These results suggest that hypothalamic histamine and histamine receptors are involved in the HPA stimulation by the muscarinic agonist carbachol.

Hypothalamo-preoptic histaminergic projections in sleep-wake control in the cat.

Cats were chronically implanted with electrodes for polygraphic recordings and cannulae for intracerebral microinjections in order to study the functional role of histaminergic innervation of the preoptic-anterior hypothalamus in sleep-wake control. alpha-Fluoromethylhistidine (alpha FMH, 50 micrograms in 1 microliter), a specific inhibitor of the histamine-synthesizing enzyme, when injected bilaterally into the preoptic area, where numerous histaminergic fibres and terminal-like structures are present, caused a significant increase in deep slow wave sleep (S2) and paradoxical sleep (PS) and a decrease in wakefulness. In contrast, microinjections of histamine (5 or 30 micrograms in 1 microliter) in the same area dose-relatedly increased wakefulness and decreased both slow wave sleep and paradoxical sleep. The effects of histamine were reduced by pretreatment with mepyramine (1 mg/kg i.p.), a well known histamine H1 receptor antagonist, and were mimicked by a local injection of impromidine (1 microgram in 1 microliter), a potent histamine H2 receptor agonist. Microinjections of mepyramine alone (120 micrograms in 1 microliter) caused an increase in slow wave sleep. These results suggest that preoptic histaminergic innervation is involved in sleep-wake control and that the action might be mediated via both H1 and H2 receptors.

Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats.

To clarify involvement of hypothalamic neuronal histamine in feeding circadian rhythm, we analyzed rat behavioral patterns using chemical probes which affect endogenous histaminergic activity. Sustained infusion of alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine-synthesizing enzyme, into the rat third cerebral ventricle disrupted light-dark cycles of feeding, drinking, and ambulatory behavior. Food and water intake and ambulatory activity during the 12-h light period increased, and those during the 12-h dark period decreased after the infusion. The ratio of the light period to the 24-h total period (L/T ratio) increased in all behavioral parameters. Assessed by 3-h cumulative analysis, amplitudes of circadian rhythmicity decreased in all behavioral parameters, whereas only the acrophase of ambulatory activity shifted forward after FMH infusion. Chlorpheniramine, an H1-antagonist, selectively increased food intake during the light and decreased it during the dark period. Consequently, the antagonist increased the L/T ratio in food intake, but did not affect the ratio in water intake or ambulatory activity. Famotidine, an H2-antagonist, did not affect the ratio in any parameter. Thioperamide, an antagonist of auto-inhibitory effects on histamine synthesis and release at presynaptic H3-receptor sites, decreased food intake during the dark, but did not affect the L/T ratio in any parameter. These findings indicate that neuronal histamine may regulate feeding circadian rhythm through the hypothalamic histamine H1-receptor in rats.

Measurement of 3-methylhistidine production in lambs by using compartmental-kinetic analysis.

The kinetics of 3-methylhistidine (3MH) metabolism in four crossbred lambs were studied. Each lamb was injected with an intravenous dose of 3-[2H3]methylhistidine (d3-3MH) and the stable isotope disappearance in plasma and appearance in both urine and muscle were measured. Immediately after the administration of tracer there was a phase of rapid disappearance of tracer from the plasma, which was followed by a more gradual decrease in d3-3MH from the plasma during the last 4 d of the experiment. A minimum of three exponentials was required to describe the plasma decay curve adequately. The kinetic model of 3MH in the whole animal was constructed by using the SAAM/CONSAM computer modelling program. Two different configurations of a three-compartment model are described: (1) a simple three-pool model, in which plasma kinetics were entered into pool 1 out of which they had one undefinable exit; (2) a plasma-urinary three-pool model with two exits, in which the urinary kinetics were entered as an exit out of pool 1 and required a second exit out of pool 3 to produce an adequate fit. In addition, muscle kinetics from biopsies of the longissimus dorsi were entered into either pool 2 or 3 using the plasma-urinary model. Steady-state mass and transport rate values were obtained for each model construct described, and a de novo production rate corresponding to a fractional breakdown rate of myofibrillar protein of approximately 5%/d was also calculated. The model predicted that only 15% of 3MH was excreted in urine as free 3MH, which is consistent with current knowledge of 3MH excretion in sheep. The simple three-pool plasma kinetic model, therefore, could be used to estimate, by a relatively simple injection-sampling technique, the extent of muscle protein turnover in lambs.

Influence of histamine depletion on learning and memory recollection in rats.

To clarify the role of endogenous histamine in learning and memory, the effect of alpha-fluoromethylhistidine on active avoidance response in rats was studied. alpha-Fluoromethylhistidine (20-100 mg/kg or 10-50 micrograms) significantly (P < 0.05 or P < 0.01) prolonged the response latency in active avoidance response when administered by either intraperitoneal or intracerebroventricular injection. These effects were dose-related and long lasting. A prolongation of the response latency induced by an intraperitoneal injection of alpha-fluoromethylhistidine (100 mg/kg) was antagonized by intracerebroventricular injection of histamine (10 and 20 ng) in a dose-dependent manner. In addition, the acquisition of this response was retarded by a consecutive intracerebroventricular injection of alpha-fluoromethylhistidine (50 micrograms), whereas histamine (100 ng) facilitated the response acquisition when administered by the same route. Both intraperitoneal (100 mg/kg) and intracerebroventricular injection of alpha-fluoromethylhistidine (50 micrograms) significantly (P < 0.05 or P < 0.01) decreased the brain histamine content, especially in the hippocampus and hypothalamus. When alpha-fluoromethylhistidine (50 micrograms) was injected intracerebroventricularly, there is a high correlation between a prolongation of the response latency and a decrease in histamine content of these brain areas. Based on these findings, it was concluded that an intimate relation may exist between a prolongation of response latency in the active avoidance response and a decrease in the brain histamine content; endogenous histamine may play an important role in learning and memory recollection in rats.

Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of alpha-fluoromethylhistidine and metoprine.

The purpose of this study was to investigate the possible role of the central histaminergic neuron system in electrically-induced seizure in mice. For this purpose, we examined the effects of intraperitoneal (i.p.) injections of histaminergic agents, such as L-histidine, metoprine, and alpha-fluoromethylhistidine (FMH), on electrically-induced seizure. L-Histidine decreased the duration of clonic convulsion in electrically-induced seizure, but not affected that of tonic convulsion. This effect of L-histidine was antagonized by pretreatment with FMH, indicating that it was due to histamine formed by decarboxylation of L-histidine in the central nervous system. The anticonvulsive effect of L-histidine was also reduced by the H1-antagonist pyrilamine, but not by the H2-antagonist zolantidine, indicating that the effect on electrically-induced seizure is mediated through central H1-receptors. Metoprine, which increased the histamine levels in the cerebral cortex, diencephalon and midbrain of mice, decreased the duration of clonic convulsions dose-dependently. Conversely, FMH, which decreased the brain histamine levels, increased the duration of clonic convulsions. Good inverse correlations were found between the duration of clonic convulsions and brain histamine levels, especially in the diencephalon: the histamine levels were inversely proportional to the duration of clonic convulsions. No correlation was found between the duration of tonic convulsions and brain histamine levels. These results suggest that the histaminergic neuron system is important in inhibition of the duration of clonic convulsion on electrically induced seizure in mice.

alpha-Fluoromethylhistidine but not diphenhydramine prevents motion-induced emesis in the cat.

PURPOSE: This study seeks to evaluate the comparative role of alpha-fluoromethylhistidine and diphenhydramine in the prevention of motion sickness. METHOD: The role of histaminergic mechanisms in motion sickness were evaluated in a feline model. Twenty-six female cats were studied. A variety of doses of fluoromethylhistidine and diphenhydramine were administered before motion testing. RESULTS: Fluoromethylhistidine was effective in preventing motion sickness. The efficacy was dose dependent. In contrast, diphenhydramine failed to prevent motion sickness in any of the tested doses. CONCLUSIONS: The failure of diphenhydramine to prevent motion sickness was unexpected. This may reflect the route of administration or the animal model studied. Depletion of histamine with fluoromethylhistidine prevented motion sickness in cats. Our results suggest that this drug may provide a very long duration of protection in cats.