Disposition of Histamine, Its Metabolites, and pros-Methylimidazoleacetic Acid in Brain Regions of Rats Chronically Infused with α-Fluoromethylhistidine

Abstract: 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 intracerebroventricularly 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 α-fluoromethylhistidine (α-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 corresponded 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 α-FMHis infusion as a model to probe the histaminergic system in brain.     

Inhibitors of Histamine Methylation in Brain Promote Formation of Imidazoleacetic Acid, Which Interacts with GABA Receptors

Abstract: In brain, the precursor of imidazoleacetic acid (IAA), a GABA_A agonist but a GABA_C antagonist, is not known. In the periphery, IAA derives from oxidation of histamine. But in brain, histamine is thought to be metabolized solely by histamine methyltransferase (HMT), forming tele -methylhistamine (t-MH) and tele -methylimidazoleacetic acid (t-MIAA). We showed that [³H]histamine (intracerebroventricularly) could be converted to IAA in brains of rats, a process increased by inhibition of HMT. This demonstrated that brain can oxidize histamine and suggested that endogenous histamine might also be oxidized if HMT activity were reduced. We examined, in rat cerebral cortex, effects of the following HMT inhibitors (mg/kg i.p.): metoprine (10), tacrine (10), velnacrine (10, 30), and physostigmine (1, 2). Tacrine was a potent inhibitor ( K _i∼ 22 n M ). To measure histamine in tissue that contained HMT inhibitors, we developed a gas chromatography-mass spectrometry method. After 2 h, all drugs reduced endogenous levels of t-MH and t-MIAA and increased levels of histamine and IAA. Our results show that inhibition of HMT promotes oxidation of histamine in brain, probably by shunting histamine to an alternative metabolic pathway. Formation of IAA provides a novel interaction between histaminergic and GABAergic systems in brain. Accumulation of IAA should be considered when inhibitors of HMT are used to probe brain histamine function.     

Regional distribution of the histamine metabolite, tele-methylimidazoleacetic acid, in rat brain: effects of pargyline and probenecid

Abstract: tele -Methylimidazoleacetic acid (t-MIAA), a major brain histamine metabolite, was measured in nine rat brain regions by a gas chromatography-mass spectrometric method that also measures the precursor amine, tele -methylhistamine (t-MH). The t-MIAA concentration of cerebellum, medulla-pons, midbrain, caudate nucleus, hypothalamus, frontal cortex, hippocampus, and thalamus varied 15-fold, hypothalamus showing the highest level (2.21 nmol/g) and cerebellum the lowest (0.15 nmol/ g). The concentrations of t-MIAA and t-MH were significantly correlated in all regions except midbrain, which had relatively more t-MIAA. Probenecid did not alter whole-brain t-MIAA levels. Treatment with pargyline, an inhibitor of monoamine oxidase, lowered the t-MIAA levels in all regions.     

Histamine Metabolites in Cerebrospinal Fluid of the Rhesus Monkey (Macaca mulatto): Cisternal-Lumbar Concentration Gradients

Similar to metabolites of other aminergic transmitters, histamine metabolites of brain, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), could have a concentration gradient between rostral and caudal sites of CSF. To test this hypothesis, cisternal and lumbar CSF samples were collected in pairs from eight monkeys (Macaca mulatta), and levels of t-MH and t-MIAA were measured by gas chromatography-mass spectrometry. pros-Methylimidazoleacetic acid (p-MIAA), an endogenous isomer of t-MIAA that is not a histamine metabolite, was also measured. Cisternal levels (in picomoles per milliliter, mean +/- SEM) of t-MH (9.9 +/- 1.4) and t-MIAA (40.8 +/- 7.6), but not of p-MIAA (9.7 +/- 1.2), exceeded those in lumbar CSF (t-MH, 1.8 +/- 0.3; t-MIAA, 6.8 +/- 0.9; p-MIAA, 8.6 +/- 0.6) in every monkey. The magnitudes of the mean cisternal-lumbar concentration gradients for t-MH (6.6 +/- 1.1) and t-MIAA (6.5 +/- 1.3) were indistinguishable. These gradients exceed those of metabolites of most other transmitters. There was no gradient for the levels of p-MIAA. The cisternal, but not lumbar, levels of t-MH and t-MIAA were correlated. There was no significant difference between the means of the metabolite concentration ratios (t-MIAA/t-MH) in cisternal (4.0 +/- 0.4) and lumbar (4.4 +/- 0.9) CSF. The steepness of these gradients suggests that levels of t-MH and t-MIAA in lumbar CSF might be useful probes of histaminergic metabolism in brain.     

pros-Methylimidazoleacetic Acid in Rat Brain: Its Regional Distribution and Relationship to Metabolic Pathways of Histamine

pros-Methylimidazoleacetic acid (p-MIAA; 1-methylimidazole-5-acetic acid), an isomer of the histamine metabolite, tele-methylimidazoleacetic acid (t-MIAA), is present in brain and CSF. Its relationship to histamine synthesis and catabolism was assessed in brains of rats. p-MIAA distribution in brain regions was heterogeneous although the concentrations in regions with the highest (hypothalamus) and the lowest (medulla-pons) levels differed less than four-fold. There was no significant correlation between the regional distributions of p-MIAA with those of histamine or its metabolites. pros-Methylhistidine (1 g/kg, i.p.) produced a 20-fold increase in mean levels of p-MIAA and up to a 50-fold increase in levels of pros-methylhistamine (p-MH), a putative intermediate; levels of histamine and its metabolites were unaltered. L-Histidine (1 g/kg, i.p.) or alpha-fluoromethylhistidine (100 mg/kg, i.p.), the irreversible inhibitor of histamine synthesis, did not alter the levels of p-MIAA in brain. Like the levels of t-MIAA, the levels of p-MIAA were unaltered after probenecid administration. Contrary to its effects in lowering t-MIAA levels, pargyline (75 mg/kg, i.p.) produced a slight rise in levels of p-MIAA in all regions. These findings suggest that, in brain, the metabolic pathways of histamine are independent of pathways that generate p-MIAA. Further, since brain is capable of p-MH formation, its use as an internal standard in analytical methods merits caution.     

Effects of the Histamine H3-Agonist (R)-α-Methylhistamine and the Antagonist Thioperamide on Histamine Metabolism in the Mouse and Rat Brain

To study the feedback control by histamine (HA) H3-receptors on the synthesis and release of HA at nerve endings in the brain, the effects of a potent and selective H3-agonist, (R)-alpha-methylhistamine, and an H3-antagonist, thioperamide, on the pargyline-induced accumulation of tele-methylhistamine (t-MH) in the brain of mice and rats were examined in vivo. (R)-alpha-Methylhistamine dihydrochloride (6.3 mg free base/kg, i.p.) and thioperamide (2 mg/kg, i.p.), respectively, significantly decreased and increased the steady-state t-MH level in the mouse brain, whereas these compounds produced no significant changes in the HA level. When administered to mice immediately after pargyline (65 mg/kg, i.p.), (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) inhibited the pargyline-induced increase in the t-MH level almost completely during the first 2 h after treatment. Thioperamide (2 mg/kg, i.p.) enhanced the pargyline-induced t-MH accumulation by approximately 70% 1 and 2 h after treatment. Lower doses of (R)-alpha-methylhistamine (1.3 mg/kg) and thioperamide (1 mg/kg) induced significant changes in the pargyline-induced t-MH accumulation in the mouse brain. In the rat, (R)-alpha-methylhistamine (3.2 mg/kg, i.p.) and thioperamide (2 mg/kg, i.p.) also affected the pargyline-induced t-MH accumulation in eight brain regions and the effects were especially marked in the cerebral cortex and amygdala. These results indicate that these compounds have potent effects on HA turnover in vivo in the brain.     

Changes in Histamine Metabolism in the Mouse Hypothalamus Induced by Acute Administration of Ethanol

The effect of acute ethanol administration on histamine (HA) dynamics was examined in the mouse hypothalamus. The steady-state level of HA did not change after intraperitoneal administration of ethanol (0.5-5 g/kg), whereas the level of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, increased when 3 and 5 g/kg of ethanol was given. Pargyline hydrochloride (80 mg/kg, i.p.) increased the level of t-MH by 72.2% 90 min after the treatment. Ethanol at any dose given did not significantly affect the t-MH level in the pargyline-pretreated mice. Decrease in the t-MH level induced by metoprine (10 mg/kg, i.p.), an inhibitor of HA-N-methyltransferase, was suppressed by ethanol (5 g/kg), thereby suggesting inhibition of the elimination of brain t-MH. Ethanol (5 g/kg) significantly delayed the depletion of HA induced by (S)-alpha-fluoromethylhistidine (50 mg/kg, i.v.), a specific inhibitor of histidine decarboxylase. Therefore, a large dose of ethanol apparently decreases HA turnover in the mouse hypothalamus.     

Imidazoleacetic Acid, a γ-Aminobutyric Acid Receptor Agonist, Can Be Formed in Rat Brain by Oxidation of Histamine

Abstract: It is generally accepted that in mammalian brain histamine is metabolized solely by histamine methyltransferase (HMT), to form tele -methylhistamine, then oxidized to tele -methylimidazoleacetic acid. However, histamine's oxidative metabolite in the periphery, imidazoleacetic acid (IAA), is also present in brain and CSF, and its levels in brain increase after inhibition of HMT. To reinvestigate if brain has the capacity to oxidize histamine and form IAA, conscious rats were injected with [³H]histamine (10 ng), either into the lateral ventricles or cisterna magna, and decapitated 30 min later. In brains of saline-treated rats, most radioactivity recovered was due to tele -methylhistamine and tele -methylimidazoleacetic acid. However, significant amounts of tritiated IAA and its metabolites, IAA-ribotide and IAA-riboside, were consistently recovered. In rats pretreated with metoprine, an inhibitor of HMT, labeled IAA and its metabolites usually comprised the majority of histamine's tritiated metabolites. [³H]Histamine given intracisternally produced only trace amounts of oxidative metabolites. Formation of IAA, a potent GABA-A agonist with numerous neurochemical and behavioral effects, from minute quantities of histamine in brain indicates a need for reevaluation of histamine's metabolic pathway or pathways in brain and suggests a novel mechanism for interactions between histamine and the GABAergic system.     

Brain Histaminergic System in Mast Cell-Deficient (Ws/Ws) Rats: Histamine Content, Histidine Decarboxylase Activity, and Effects of (S)α-Fluoromethylhistidine

Abstract: The mast cell-deficient [ Ws/Ws ( W hite spotting in the skin)] rat was investigated with regard to the origin of histamine in the brain. No mast cells were detected in the pia mater and the perivascular region of the thalamus of Ws/Ws rats by Alcian Blue staining. The histamine contents and histidine decarboxylase (HDC) activities of various brain regions of Ws/Ws rats were similar to those of +/+ rats except the histamine contents of the cerebral cortex and cerebellum. As the cerebral cortex and cerebellum have meninges that are difficult to remove completely, the histamine contents of these two regions may be different between Ws/Ws and +/+ rats. We assume that the histamine content of whole brain with meninges in Ws/Ws rats is <60% of that in +/+ rats. So we conclude that approximately half of the histamine content of rat brain is derived from mast cells. Next, the effects of ( S )α-fluoromethylhistidine (FMH), a specific inhibitor of HDC, on the histamine contents and HDC activities of various regions of the brain were examined in Ws/Ws rats. In the whole brain of Ws/Ws rats, 51 and 37% of the histamine content of the control group remained 2 and 6 h, respectively, after FMH administration (100 mg/kg of body weight). Therefore, we suggest that there might be other histamine pools including histaminergic neurons in rat brain.     

Feeding-Related Circadian Variation in tele-Methylhistamine Levels of Mouse and Rat Brains

Circadian changes in the brain histamine (HA) and tele-methylhistamine (t-MH) levels were studied in mice and rats after adaptation to an alternating 12-h light/dark cycle (lights on at 0600). Although there was no significant circadian fluctuation of the brain HA levels, the levels of t-MH, a major metabolite of brain HA, showed a marked circadian variation. In mice, the t-MH levels were about 80 ng/g from 1200 to 1800 but about two times higher values were obtained from 2400 to 0600 of the next morning. In rats, the t-MH levels ranged from 24 to 28 ng/g at 0600 and 1200, slightly increased at 1800, and reached at 2400 a peak twice as high as the levels seen during the light period. The t-MH levels again rapidly decreased during the subsequent 3 h. In mice fasted from 1200, the t-MH levels did not increase during the period of darkness. When mice were fed at 1200 after a 24-h fast, a significant increase in the t-MH levels was observed at 1800. There was no significant circadian variation of the HA and t-MH levels in the plasma of mice and rats. These results suggest that circadian variation in brain t-MH levels is related to feeding and possible subsequent changes in elimination of t-MH from the brain and/or turnover of HA in the brain. This phenomenon should be given due attention when HA dynamics in the brain are being assessed.     

Glucoprivic regulation of estrous cycles in the rat

Previous research has shown that glucoprivation induced by chronic 2-deoxy-D-glucose (2DG) treatment extends estrous cycle length and disrupts reproductive behaviors in female hamsters, similar to food deprivation. Such treatment also suppresses food intake, which is reversed in male rats by reducing brain histamine levels prior to 2DG treatment. We, therefore, determined if 2DG extends estrous cycles in the female rat and if this is due to elevated brain histamine levels. We measured estrous cycle length during 2DG-induced glucoprivation, in the presence and absence of alpha-fluoromethylhistidine (FMH), a treatment that reduces brain histamine levels. Adult female rats were treated for 72 h with either saline (n = 8), 2DG (200 mg/kg S.C. every 6 h; n = 9), or FMH (100 mg/kg i.p. daily) + 2DG (200 mg/kg; n = 7). An additional group was treated with FMH (100 mg/kg i.p.; n = 5) alone. To determine if 2DG extends estrous cycles due to glucoprivation or to decreased caloric intake, a group of rats (n = 7) received a reduced diet equal to the mean daily food intake of rats receiving 2DG alone. 2DG induced more long estrous cycles compared to rats receiving saline, FMH + 2DG, or FMH alone. In rats treated with FMH + 2DG, the percentage of 4-5-day cycles was similar to that of saline-treated rats, and a high percentage of 4-5-day cycles was also observed in rats receiving a reduced diet. These data suggest that 2DG does not suppress estrous cycles through a decrease in total calorie intake, but rather by inducing glucoprivation. In addition, during 2DG-induced glucoprivation, elevated brain histamine levels contribute to the mechanism that suppresses reproductive function.     

Regulation of Histamine Turnover via Muscarinic and Nicotinic Receptors in the Brain

To clarify the regulation of central histaminergic (HAergic) activity by cholinergic receptors, the effects of drugs that stimulate the cholinergic system on brain histamine (HA) turnover were examined, in vivo, in mice and rats. The HA turnover was estimated from the accumulation of tele-methylhistamine (t-MH) during the 90-min period after administration of pargyline (65 mg/kg, i.p.). In the whole brain of mice, oxotremorine, at doses higher than 0.05 mg/kg, s.c., significantly inhibited the HA turnover, this effect being completely antagonized by atropine but not by methylatropine. A large dose of nicotine (10 mg/kg, s.c.) also significantly inhibited the HA turnover. This inhibitory effect was antagonized by mecamylamine but not by atropine or hexamethonium. A cholinesterase inhibitor, physostigmine, at doses higher than 0.1 mg/kg, s.c., significantly inhibited the HA turnover. This effect was antagonized by atropine but not at all by mecamylamine. None of these cholinergic antagonists used affected the steady-state t-MH level or HA turnover by themselves. In the rat brain, physostigmine (0.1 and 0.3 mg/kg, s.c.) also decreased the HA turnover. This inhibitory effect of physostigmine was especially marked in the striatum and cerebral cortex where muscarinic receptors are present in high density. Oxotremorine (0.2 mg/kg, s.c.) and nicotine (1 mg/kg, s.c.) also decreased the HA turnover in the rat brain. However, these effects showed no marked regional differences. These results suggest that the stimulation of central muscarinic receptors potently inhibits the HAergic activity in the brain and that strong stimulation of central nicotinic receptors can also induce a similar effect.     

Inhibition of Histamine Synthesis in Brain by α-Fluoromethylhistidine, a New Irreversible Inhibitor: In Vitro and In Vivo Studies

a-Fluoromethylhistidine (α-FMH), a new potent inhibitor of histidine decarboxylase (HD), has been used for in vitro and in vivo studies of brain HD. Following a preincubation with (+)-α-FMH, brain HD activity was inhibited in a time-dependent and concentration-dependent manner. The enzyme activity was not restored by overnight dialysis against standard buffer. The (–) antimer of α-FMH was ineffective. When injected intraperitoneally in a single dose of 20 mg/kg, (±)-α-FMH induced a complete loss in HD activity in cerebral cortex and hypothalamus as well as in peripheral tissues, such as stomach. At a dosage of 100 mg/kg (±)-α-FMH did not alter histamine-N-methyltransferase, DOPA decarboxylase, and glutamate decarboxylase activities. The maximal decrease of HD activity occurred after 2 h in both cerebral cortex and hypothalamus, but the time course of the recovery of enzyme activity was slower in the cerebral cortex. The enzyme activity reached control value within 3 days in hypothalamus and was not fully restored after 4 days in cerebral cortex. Contrasting with the diminished HD activity, a substantial concentration of histamine remained present in five regions of mouse brain. Thus, α-FMH is a highly specific irreversible inhibitor of brain HD activity and its efficacy makes it useful to study the physiological role of brain histamine.     

The Effects of Caffeine on <Emphasis Type="SmallCaps">l</Emphasis>-Arginine Metabolism in the Brain of Rats

In our study, the short-term effects of caffeine on L- arginine metabolism in the brains of rats were investigated. Caffeine was given orally at two different doses: 30 mg/kg and 100 mg/kg (a high non-toxic dose). Brain tissue arginase activity in rats from the caffeine-treated groups decreased significantly compared with the control group. Malondialdehyde (MDA) levels in the brain tissue and serum of animals in the caffeine groups also decreased significantly. Brain tissue and serum nitric oxide (NO) levels increased significantly after caffeine administration. Tumor necrosis factor-α (TNF-α) levels were also investigated in rat serum, but there was no statistically significant difference between the TNF-α levels of the caffeine-treated rats groups and the control rats. Our study indicates that brain arginase activity decreases after caffeine administration at doses of 30 mg/kg and 100 mg/kg. As a result, we can say that arginine induces production of NO in the organism.     

Morphine-Induced Changes in Histamine Dynamics in Mouse Brain

The effect of the acute morphine treatment on histamine (HA) pools in the brain and the spinal cord was examined in mice. Morphine (1-50 mg/kg, s.c.) administered alone caused no significant change in the steady-state levels of HA and its major metabolite, tele-methylhistamine (t-MH), in the brain. However, depending on the doses tested, morphine significantly enhanced the pargyline (65 mg/kg, i.p.)-induced accumulation of t-MH and this effect was antagonized by naloxone. A specific inhibitor of histidine decarboxylase, alpha-fluoromethylhistidine (alpha-FMH) (50 mg/kg, i.p.), decreased the brain HA level in consequence of the almost complete depletion of the HA pool with a rapid turnover. Morphine further decreased the brain HA level in alpha-FMH-pretreated mice. Morphine administered alone significantly reduced the HA level in the spinal cord, an area where the turnover of HA is very slow. These results suggest that the acute morphine treatment increases the turnover of neuronal HA via opioid receptors, and this opiate also releases HA from a slowly turning over pool(s).     

Loss of Protein Kinase C-αβ in Brain of Heroin Addicts and Morphine-Dependent Rats

Abstract: The biochemical status of human brain protein kinase C (PKC)-αβ during opiate dependence was studied by means of immunoblotting techniques in postmortem brain of heroin addicts who had died by opiate overdose. In the frontal cortex, a marked decrease (53%, p < 0.05) in the immunoreactivity of PKC-αβ was found in heroin addicts compared with matched controls. The loss of PKC-αβ in the brain of human addicts paralleled that observed in the frontal cortex of rats after chronic treatment with morphine (10–100 mg/kg i.p. for 5 days) (PKC-αβ decreased by 34%, p < 0.05). Chronic treatment with naloxone (1 mg/kg i.p. every 12 h for 5 days) did not alter PKC-αβ immunoreactivity in the rat brain. However, in morphine-dependent rats, naloxone-precipitated withdrawal induced a rapid and strong behavioral reaction with a concomitant up-regulation of PKC-αβ immunoreactivity to control values. These results indicated that the decrease of brain PKC-αβ induced by heroin/morphine is a μ-opioid receptor-mediated effect. The chronic administration of opiates has been associated with a marked sensitization of the adenylyl cyclase/cyclic AMP system, although this phenomenon is not exclusive of the opioid system but the general cellular adaptation to chronic inhibition of adenylyl cyclase. In this context, chronic treatment of rats with other inhibitory agonists (e.g., clonidine, 1 mg/kg i.p. every 12 h for 14 days) acting through receptors (e.g., α₂-adrenoceptors) also coupled to adenylyl cyclase did not alter brain PKC-αβ immunoreactivity. Together these findings suggest that the brain PKC system might play a major role in opiate addiction.     

Histamine Turnover in the Brain of Different Mammalian Species: Implications for Neuronal Histamine Half-Life

The turnover of neuronal histamine (HA) in nine brain regions and the spinal cord of the guinea pig and the mouse was estimated and the values obtained were compared with data previously obtained in rats. The size of the neuronal HA pool was determined from the decrease in HA content, as induced by (S)-alpha-fluoro-methylhistidine (alpha-FMH), a suicide inhibitor of histidine decarboxylase. The ratios of neuronal HA to the total differed with the brain region. Pargyline hydrochloride increased the tele-methylhistamine (t-MH) levels linearly up to 2 h after administration in both the guinea pig and the mouse whole brain. Regional differences in the turnover rate of neuronal HA, calculated from the pargyline-induced accumulation of t-MH, as well as in the size of the neuronal HA pool, were more marked in the mouse than in the guinea pig brain. The hypothalamus showed the highest rate in both species. There was a good correlation between the steady-state t-MH levels and the turnover rate in different brain regions. Neither the elevation of the t-MH levels by pargyline nor the reduction of HA by alpha-FMH was observed in the spinal cord, thereby suggesting that the HA present in this region is of mast cell origin. The half-life of neuronal HA in different brain regions was in the range of 13-38 min for the mouse and 24-37 min for the guinea pig, except for HA from the guinea pig hypothalamus, which had an extraordinarily long value of 87 min. These results suggest that there are species differences in the function of the brain histaminergic system.     

Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain

Leptin regulates feeding behavior and energy metabolism by affecting hypothalamic neuromodulators. The present study was designed to examine hypothalamic neuronal histamine, a recently identified mediator of leptin signaling in the brain, in genetic obese animals. Concentrations of hypothalamic histamine and tele-methylhistamine (t-MH), a major histamine metabolite, were significantly lower in obese (ob/ob) and diabetic (db/db) mice, and Zucker fatty (fa/fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates (P < 0.05 for each). A bolus infusion of leptin (1.0 microg) into the lateral ventricle (ilvt) significantly elevated the turnover rate of hypothalamic neuronal histamine, as assessed by pargyline-induced accumulation of t-MH, in ob/ob mice compared with phosphate-buffered saline (PBS) infusions (P < 0.05). However, this same treatment did not affect hypothalamic histamine turnover in db/db mice. In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed. These amine levels in A(y)/a mice showed no change until 16 weeks of age, although the mice were remarkably obese by this time. Infusions of corticotropin releasing hormone (CRH), one of neuropeptide related to leptin signaling, into the third ventricle (i3vt) increased histamine turnover in the hypothalamus of Wistar King A rats (P < 0.05 versus PBS infusion). Infusion of neuropeptide Y (NPY) or alpha-melanocyte stimulating hormone (MSH), a POMC-derived peptide failed to increase histamine turnover. These results indicate that lowered activity of hypothalamic neuronal histamine in ob/ob and db/db mice, and fa/fa rats may be due to insufficiency of leptin action in the brains of these animals. These results also suggest that disruption of POMC signaling in A(y)/a mice may not impact on neuronal histamine. Moreover, CRH but neither POMC-derived peptide nor NPY may act as a signal to neuronal histamine downstream of the leptin signaling pathway.     

ELEVATION IN RAT BRAIN HISTAMINE CONTENT AFTER FOCUSED MICROWAVE IRRADIATION1

Abstract— —Microwave irradiation focused on the head of small rodents is now widely used as a means of more accurately measuring acetylcholine, choline, cyclic AMP, and several other important brain constituents. Because of its probable neurotransmitter role and rapid turnover, a similar approach was taken to study brain histamine. Histamine was measured by a modified radio-enzymatic method and was found to be nearly tripled in brains from microwave treated rats, compared to decapitation controls (124 vs 42 ng/g). Possible explanations include a microwave-induced inactivation of histamine breakdown, a microwave-induced redistribution of previously unmeasured histamine, and microwave-induced histidine decarboxylation. Brain histamine remained unchanged up to 30 min after decapitation and microwave heated brains from decapitated rats also had elevated histamine levels, indicating that brain histamine levels in decapitated rats do not represent the remainder of a rapidly depleting pool. No evidence for previously unmeasured histamine was found. Furthermore, microwave irradiation did not enhance the formation of [³H]histamine after intraventricular [³H]histidine administration, indicating a lack of microwave-induced histidine decarboxylation. It is concluded that the elevation in rat brain histamine after focused microwave irradiation is probably not artifactual, although the mechanism responsible for this phenomenon remains obscure.     

Effects of histamine and cimetidine on the levels of serotonin and 5-hydroxyindoleacetic acid in various parts of the digestive tract and in the blood and brain of rats

In the investigations on male Wistar rats it was demonstrated that histamine (0.05 and 0.5 mg/kg) decreased the serotonin level, without affecting the level of 5-HIAA in the stomach and duodenum. Contrary to this, cimetidine (15, 75 and 150 mg/kg) raised slightly the level of serotonin and decreased the 5-HIAA level in the stomach and duodenum. In the jejunum histamine in the lower dose raised the levels of serotonin and 5-HIAA, and in the higher dose it decreased only the concentration of serotonin. Cimetidine, on the other hand, only in the highest dose increased the serotonin level and decreased significantly the level of 5-HIAA. In the brain a rise of the serotonin level was observed only after histamine. No effects were observed of histamine and cimetidine on the blood serotonin level. Histamine reduced the number of enterochromaffinocytes in the duodenum. These results point to an evident interaction between the histaminergic and the serotoninergic structures in the digestive tract of rats.