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We review here the current status of neuroimaging and neurochemical research on Rett syndrome (RTT), with reference to neurophysiological, neuropathological, and immuno-histochemical changes previously described. Abnormalities have been reported in the intermediates of the biogenic amine neurotransmitters/receptor systems, and of beta-phenylethylamine (PEA), an endogenous amine synthesized by the decarboxylation of phenylalanine in dopaminergic neurons of the nigrostratal system. We also discuss the roles of other neurotransmitters including beta-endrophin, substance P and neurotrophic factors including nerve growth factors. Recently, mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2), mapped to Xq28, have been identified in patients with RTT. Multiple abnormalities in various neurotransmitter/receptor systems may accounts for the pervasive defects in RTT.

Biogenic amines, including acetylcholine, act as neurotransmitters or neuromodulators in the brain of mammals. Accumulated evidences suggest the relevance of these amines to the regulatory system of sleep-wakefulness cycle. Recent development of an in vivo, microdialysis technique has revealed the existence of circadian variation in the release of these amines from various brain regions related to the regulation of sleep-wakefulness. This review focuses on the characteristics of the release of these amines determined by the microdialysis method in rats and cats during sleep-wakefulness cycle, and speculates their roles in the mechanism underlying the control of sleep and arousal state.

A marked increase in lethality in grouped mice (group toxicity) following the administration of methamphetamine, a central nervous stimulant, has been well known. Pharmacological effects, behavioral characteristics and toxicities of cocaine are fairly similar to those of methamphetamine. Thus, in this study, the possibility of producing group toxicity induced by cocaine and the participation of biogenic amines and neurotransmitters in the production of behavioral sensitization with cocaine was investigated in ddY male mice. 1) In acute experiment, LD50s of cocaine were not different significantly between control (5 mice) and grouped mice (20 mice), and following continuous administration of cocaine (40 and 50 mg/kg, once a day for 10 days) lethal cases were not observed in control, but mortality was calculated to about 20 and 60% in grouped mice, respectively. 2) The number of deaths was related to environmental condition that mice were restricted. And in the stronger restricted condition, the number of deaths increased. 3) The number of deaths was highly dependent on the environmental temperature and the doses. 4) The repeated administration of cocaine produced the behavioral sensitization in the non-restricted mice but not in the restricted mice. 5) The drugs that changed amines or neurotransmitters inhibited the effects of cocaine in the first administration, but following the repeated administration behavioral sensitization was produced gradually. It is concluded that group toxicity was induced by cocaine. It is also considered that the behavioral sensitization with cocaine was intricately related to many amines or transmitters.

This study was carried out to clarify the effects of methylmercury intoxication on the ethanol-induced sleeping time of mice. The mice were injected with methylmercury chloride (MMC) (10 mgMMC/kg body weight) subcutaneously for 1, 5 and 10 successive days (1, 5 and 10 inj.), and control mice received only saline. Twenty-four hours, after the last injection, these mice were treated with ethanol (4.5 mgEtOH/kg body weight) intraperitoneally and subsequent sleeping time was observed. After 24 hours, mice were sacrificed to measure the concentration of MMC in various brain regions and liver. A similar experiment with ethanol treatment was also performed to assay the biogenic monoamines in various brain regions and alcohol dehydrogenase (ADH) activity in liver. The results can be summarized as follows: 1) Ethanol-induced sleeping time was 170 min. in the 10 inj. and it was significantly longer than saline, 1 and 5 inj. However, other experimental groups showed no change when compared with saline. 2) Norepinephrine levels increased in white matter and pons + medulla after 1 inj. 3) Dopamine levels increased only in white matter of the 10 inj. when compared with saline. No changes were shown in the other groups. 4) Serotonin levels increased in all the regions after 1 inj. 5) ADH activity in liver did not show any alteration during the experimental period when compared with saline.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to elucidate the action of an H2 blocker (cimetidine) and gastric mucosal protection agents (sucralfate and sofalcone) on the relapse and recurrence of gastric ulcer, the effects of cimetidine, sucralfate and sofalcone on the contents of histamine and serotonin and histidine decarboxylase (HDC) activity in the gastric mucosa were examined in the ulcer region and the intact region at the 10th day after the operation to produce acetic acid-induced gastric ulcer in rats. The following results were obtained: 1) HDC activity in the gastric mucosa of rats treated with cimetidine (100 mg/kg twice daily) tended to increase in the intact region, and it was significantly increased in the ulcer region. 2) Increased HDC activity due to cimetidine treatment was observed at the 10th day after interruption of cimetidine administration. 3) The HDC activity in the gastric mucosa was not changed by the treatment with sucralfate (500 mg/kg/day) and sofalcone (200 mg/kg/day). The results suggest that the increased HDC activity in the gastric mucosa might participate in the relapse and recurrence of gastric ulcer after discontinuation of cimetidine administration.

beta Phenylethylamine (PEA) is an endogenous amine that resembles amphetamine in chemical structure and has been identified in human and other mammalian brains and in many peripheral tissues. Although PEA exists in much smaller amounts than monoamines, the mode of action of PEA as a neuromodulator is of special interest. In this paper the author reviews animal and clinical studies on PEA. The first section deals the methods for the determination of PEA in mammalian brains and human urine. PEA is reliably measured using spectrofluorometric, gas chromatographic-mass spectrometric methods. The second chapter reviews the changes in animal behavior elicited by PEA. The administration of PEA induces stereotypy and increased motor activity in animals. The third part reviews the effect of PEA on dopamine, noradrenaline, serotonin and tyramine metabolism in mammalian brains. The fourth chapter examines recent clinical evidence suggesting a role for PEA in schizophrenia and affective disorders.

Levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid were measured fluorometrically in the whole brain of rats killed either by decapitation or by 5kW microwave irradiation for 1.6 sec. which inactivates the relevant brain enzymes rapidly and irreversibly. There were statistically no differences in the levels of NE, DA, 5-HT and 5-HIAA between the two methods of sacrifice, while the level of DA increased slightly in irradiated brains. On the other hand, the level of DOPAC, an oxidative deaminated metabolite of DA, increased significantly and the level of HVA, a final metabolite of DA, reduced markedly in the irradiated brains compared to that in the decapitated brains, respectively. These findings suggest that the turnover rates for metabolism of DA at synaptic nerve terminals and synaptic clefts may be relatively rapid. Therefore, it may be concluded that rapid inactivation of the brain enzymes involved in metabolism of DA is necessary prior to analysis of DA and its metabolites and microwave irradiation is the most suitable method available at the present time.

The effects of intracerebral injection of methionine-enkephalin (met-enk) and leucine-enkephalin (leu-enk) on the behavioral patterns were examined by using multi-dimensional behavioral analyser (Animex II) in relation to the mouse brain monoamine metabolism. The multi-dimensional behavioral analyser which is able to record 9 different measures of behavior exhibited by mice has been used. The results have indicated that met-enk (100 micrograms) and leu-enk (200 micrograms) caused a remarkable but transient increase in the linear locomotion recorded on the counter 1/1. In the biochemical study, it has been found that met-enk (100 micrograms) significantly increases the content of homovanillic acid (HVA) in the striatum. Leu-enk (200 micrograms) has negligible effect on the contents of dopamine (DA), 3,3-hydroxyphenylacetic acid and HVA in the cerebral cortex or the striatum. Met-enk (100 micrograms) and leu-enk (200 micrograms) did not affect the alpha-methyl-p-tyrosine-induced decrease in the content of DA and norepinephrine. Following the injection of met-enk (100 micrograms) and leu-enk (200 micrograms) and leu-enk (200 micrograms) into the cerebral ventricle, the content of 5-hydroxytryptamine in the cerebral cortex was increased but that of 5-hydroxyindoleacetic acid was not. Neither met-enk nor leu-enk influenced the activity of monoamine oxidase in the brain. These data suggest that, while monoamines in the brain are involved in the behavioral effects of enkephalins, the precise sites and/or mechanisms of enkephalins may differ.

The effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), on the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the metabolites in the various brain regions of rats were determined by means of high performance liquid chromatography with electrochemical detection. DN-1417 (20 mg/kg, i.p.) produced marked decreases in the levels of NE, DA and 5-HT, especially in the nucleus accumbens, striatum and hypothalamus. The maximum effect was observed at 15 min after the administration. DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased significantly in the nucleus accumbens, striatum and hypothalamus, whereas 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid remained unchanged. 3-Methoxytyramine increased significantly in the nucleus accumbens and striatum. Two week chronic administration of DN-1417 (20 mg/kg, i.p.) increased the levels of DA and NE in the nucleus accumbens and DA in the striatum. These results suggest that DN-1417 stimulates the turnover of the cerebral monoamines, especially the release of DA from the nucleus accumbens and striatum in the mesolimbic and nigro-striatal DAergic systems.

Male rats weighing about 50 g were fed a normal-balanced diet for 100 days during which time i.p. injections of saline solution (2 ml/kg) or insulin (4 IU/kg) and/or nialamide (30 mg/kg) were given every two days. The animals were sacrificed 16 hr after the last injection and the brains and livers were extracted for the measurement of tyramine consumption and liver glycogen deposition. It was found that the decrease of glycogen deposition and tyramine consumption induced by nialamide was inhibited by a simultaneous administration of insulin.

Restricted daily feeding (RF), in which free access to food and water is restricted to a fixed time of the day, has been demonstrated to elevate the plasma corticosterone level in rats prior to meal (prefeeding corticosterone peak). But the central mechanism for the hormone peak is unknown. In this study, the metabolism of the hypothalamic biogenic amines was investigated to know whether or not it was associated with the prefeeding corticosterone peak under RF. Male rats were subjected to RF (meal time from 10:00 to 12:00 h) under the light-dark cycle (lights from 06:00 to 18:00 h). Norepinephrine metabolism was estimated from the rate of decrease in norepinephrine content after the administration of a synthesis blocker, alpha-methyl-p-tyrosine (alpha-MPT). Dopamine and serotonin metabolisms were estimated from the accumulation rate of precursor amine after the inhibition of aromatic L-amino acid decarboxylase by m hydroxybenzylhydrazine (NSD 1015). Rats were sacrificed by decapitation and four hypothalamic nuclei (SCN, PVN, VMH, LH) were punched out according to Palkovits method. Amine contents in each nucleus were measured by HPLC. Results obtained are as follows; 1) Catecholamine was significantly involved in the formation of prefeeding corticosterone peak under RF in rats. 2) Norepinephrine metabolism was different in each hypothalamic nucleus. Especially, that in PVN seems to be parallel with the plasma corticosterone level under RF. This result suggests that norepinephrine in PVN stimulates corticotropin releasing hormone (CRH). 3) Dopamine metabolism in the four hypothalamic nuclei showed similar changes; prefeeding rise (except for VMH), high activity during feeding, decrease after food deprivation, and persistence of high activity during fast. 4) Serotonin metabolism in the four hypothalamic nuclei showed similar changes; prefeeding rise (except for VMH), decrease during feeding, and persistence of high activity during fast.

The effects of S-Adenosyl-L-methionine (SAMe) on cerebral monoamine turnover at 60 min of reoxygenation after hypoxia (PaO2, 31-35 mmHg) for 15 min were studied in 44 rats anesthetized with nitrous oxide. The accumulations of monoamine metabolites: 3-methoxy 4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were determined after probenecid. The accumulations of noradrenaline (NA) and dopamine (DA) were also determined after pargyline. In the non-treated group, there was an impairment of degradation of NA to MHPG and of DA to DOPAC or HVA in the control group (no hypoxia). These changes were accompanied by higher levels of NA and DA in the cerebral cortex, hypothalamus and striatum than those of the control group. In the group treated with 100 mg/kg SAMe plus 38 mg/kg mannitol 3 min after the start of reoxygenation, there were no significant changes in these metabolites and amines. Mannitol alone did not cause significant changes. There were no changes in serotonin and 5-HIAA in any of the groups studied. The effects of SAMe were studied in an additional 16 awake rats. MHPG in all regions measured after probenecid in the rats treated with SAMe was higher than that without SAMe. It appears that SAMe ameliorates perturbation of cerebral catecholamine turnover produced by reoxygenation after hypoxia.

The present study was an attempt to determine whether the circadian rhythm as recorded by Animex and EEG can be used as an indicator of drug dependence in rats, and also to examine the correlation between drug dependence and changes in several monoamines. Repetitive injections of morphine (MP), methamphetamine (MAPT) and cocaine (CC) markedly increased motor activity for about 4 hours post-injection, depending on the number of injections and also remarkably increased the state of wakefulness (AW), but decreased the amount of both slow wave sleep (SWS) and fast wave sleep (FWS) in the EEG sleep-wakefulness cycles during the 7-hour observation period. The injection of MP induced the dissociation between EEG and behavior. SWS increased in phenobarbital (PNB)- and diazepam (DZP)-dependent rats. Abrupt withdrawal of MP resulted in a consistent decrease in motor activity, an increase in AW, and a decrease in SWS and FWS both during the day and at night. The withdrawal of PNB and DZP produced an increase in motor activity and AW, and a decrease in SWS both during the day and at night. The circadian rhythm seen during the course of repetitive injections of MAPT and CC disappeared immediately following the withdrawal. Normal rhythm was recovered with an increase in SWS at night. Repetitive administration and subsequent abrupt withdrawal of the drugs altered the contents and turnover rates of the three monoamines.

Elucidation of the alterations of intracerebral neurotransmitters in cerebrovascular dementia is of prime importance not only in revealing patho-physiological mechanism but also in developing the therapy for the disease. We measured monoamine metabolites and norepinephrine (NE) in cerebrospinal fluid of patients with cerebrovascular dementia, to study the effects of administration of 6-(10-hydroxydecyl)-2, 3-dimethoxy-5-metyl-1,4-benzoquinone (idebenone, CV-2619). Six patients with cerebral infarction and 1 with cerebral hemorrhage, at the mean age of 65.4 years, were enrolled as subjects. All patients had mental and intelligent impairment, and the Hasegawa's Dementia Rating (DR) Scale was performed. The patients were medicated with 90 mg daily dose of CV-2619 for 1 to 2 months, and homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylethylenglycol (MHPG), NE in cerebrospinal fluid were determined by high-performance liquid chromatography before and also after the medication. Before the medication, HVA was 21.7 +/- 1.4 ng/ml (mean +/- SE), which was significantly low (p less than 0.01), compared with controls at a similar age: 5-HIAA was 18.5 +/- 2.7 ng/ml, and MHPG, 9.5 +/- 0.7 ng/ml, both of which were not significantly low, but tended to be low, compared with the controls. NE was similar to the control value. With the administration of CV-2619, HVA measured 27.1 +/- 3.2 ng/ml, showing a tendency to increase; 5-HIAA was 26.7 +/- 2.3 ng/ml, and MHPG, 10.7 +/- 0.6 ng/ml, both of which increased significantly (p less than 0.05), compared with the respective premedication values.(ABSTRACT TRUNCATED AT 250 WORDS)

A preliminary work with in vivo voltammetry (IVV) in the ischemic brain had been performed by the authors in rats after cardiac arrest, which showed that the IVV system is useful to investigate ischemic brain. In the present report, IVV was applied to ischemic brain by 4-vessel occlusion in rat and changes in dopamine and serotonin metabolism were investigated by measuring peak 2 (3,4-dihydroxyphenylacetic acid, DOPAC) and peak 3 (5-hydroxyindoleacetic acid, 5-HIAA) in the striatum. The change of cerebral blood flow (CBF) were also assessed by a temperature-controlled thermoelectrical method in the striatum of the same model. The heights of peaks 2 and 3 were significantly increased to 600-900% and 200-300% respectively in the striatum during 30 minutes of 4-vessel occlusion. The increase of each peak was maximum at 10 minutes after occlusion. These changes may reflect that release of monoamine neurotransmitters is increased by the ischemia and outward transport of their metabolites are disturbed. On the other hand, after reperfusion by release of carotid occlusion, the heights of peaks 2 and 3 rapidly decreased below the control values, thereafter, peaks 2 and 3 gradually increased to over control values at 180-210 minutes after reperfusion. rCBF in the striatum decreased to almost 0 ml/100 g/min during 4-vessel occlusion ischemia and increased to over control values transiently for 30 minutes after reperfusion, followed by gradual decrease for about 240 minutes. Since monoamine neurotransmitters are known to have various effects on cerebral metabolism and CBF, their disorders may contribute to the change of CBF and the development of postischemic brain damage.(ABSTRACT TRUNCATED AT 250 WORDS)

In recent years, considerable interest has been directed towards the role of neurotransmitters in various types of brain dysfunctions. There are increasing experimental and clinical evidences that disturbances in the metabolism of central monoamine play an important role in the pathogenesis of brain diseases. Brain tumors are thought to affect and change the neurotransmitter function of the surrounding cerebral tissues. In this study, we tried to analyze and accumulate data about tissue concentrations of biogenic amines in brain tumors and their distribution. Samples from thirty-four intracranial tumors removed at operations were studied. The concentrations in tumor tissues were measured by high performance liquid chromatography systems which were equipped with electrochemical detection (LCEC) and were particularly well suited for the separation and the measurement of the concentration of norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), and their metabolites; homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methyoxy-4-hydroxyphenylethyleneglycol (MHPG) in brain tissues. NE levels were under 3ng/g in twenty-five of thirty cases. DA levels were not detected in more than half of the cases. 5-HT levels varied from 0 ng/g to 166.4 ng/g. HVA levels were detected in one glioblastoma, one metastatic tumor, one meningioma and one hemangioblastoma. 5HIAA levels were not detected in most cases except for two meningiomas and one malignant lymphoma. Distribution of tissue concentrations of biogenic amines and their metabolites in four demarcated brain tumors was studied. Samples for determination of tissue concentrations were taken from tumor tissue at central, middle, and peripheral or adjacent portion from the edge of tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of Y-8894 (+/-) 2-[[o-(2-thenyl)phenoxy]methyl] morpholine maleate, which has been shown to improve experimentally induced learning and memory deficits, on cerebral monoamine uptake and turnover was studied in the mouse. The following results were obtained: 1) It inhibited in vitro norepinephrine (NE) uptake to the mouse cerebral synaptosomal fractions about 800 and 1250 times more potently than it did those of dopamine (DA) and serotonin (5-HT), respectively. 2) It dose-dependently inhibited in vivo NE uptake, but not DA or 5-HT uptake. 3) It reduced the accumulation of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), increased that of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and had no effect on that of the DA metabolite, homovanillic acid (HVA). These effects were compared with those of imipramine, calcium hopantenate (Ca-hopantenate) and dihydroergotoxine. Y-8894 appeared to act by stimulating the noradrenergic receptor, and it acts to a lesser extent by blocking the serotonergic receptor in the brain.

The distribution of nerve fibers in the cerebral blood vessels was studied by a catecholamine histofluorescence method, acetylcholinesterase (AChE) staining and immunohistochemistry. The ultrastructure of the terminal boutons in the vessel wall was also studied. In the adventitia of the cerebral artery, green fluorescence aminergic fibers and brownish AChE-positive (probably cholinergic) fibers were observed. In contrast, the cerebral venous system showed no AChE-positive fibers. The highest density of aminergic fibers were found in the dural sinus and the second highest in the internal cerebral vein. Serotonin immunoreactive nerve fibers were found along small intraparenchymal blood vessels such as perforating arteries in the brain stem, and arterioles and venules in the cerebral cortex. Under ultrastructural observation, a serotonin immunoreactive terminal was demonstrated in conjunction with the basement membrane of the capillary.

Interactions between buprenorphine, narcotic analgesic, and centrally acting drugs were studied in prolongation of halothane-induced sleeping and analgesia using the D'Amour-Smith method in mice, and the effect of buprenorphine on monoamine metabolism was studied in rat brain. Diazepam and chlorpromazine prolonged the halothane-induced sleeping time dose-dependently. Buprenorphine (0.01, 0.1, and 1 mg/kg s.c.) inhibited the effect of diazepam, but not that of chlorpromazine. Pentazocine and naloxone also inhibited the effect of diazepam, but morphine did not. It is suggested that the inhibitory effect of buprenorphine on prolongation of halothane-induced sleeping time by diazepam is due to its opiate antagonistic property. Since narcotic antagonists inhibited the effect of diazepam, the endogenous opiate system seems to be involved in this effect. Diazepam or droperidol had no effect on the analgesia of buprenorphine, morphine, and pentazocine. Buprenorphine analgesia was inhibited by reserpine and p-chlorophenylalanine, potentiated by 5-hydroxytryptophan, and not affected by alpha-methyl-p-tyrosine or 3,4-dihydroxyphenylalanine. These results suggest that the serotonergic system plays a modulating role in buprenorphine analgesia. Imipramine and nialamide inhibited buprenorphine analgesia in the test at low stimulus intensity, but potentiated at high stimulus intensity. Buprenorphine (0.1, 1 and 10 mg/kg s.c.) increased the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in various brain areas and the serotonin metabolite, 5-hydroxyindoleacetic acid, in midbrain.

The pharmacological properties of MO-8282 (1,2,3,4-tetrahydro-2-methyl-9H-dibenzo [3,4: 6,7]cyclohepta [1,2-c]pyridine maleate) as an antidepressant were investigated. At doses 10 times less than those of amitriptyline, MO-8282 showed similar potencies in reducing the duration of immobility during forced swimming in rats and in potentiating stereotype induced by L-DOPA. Intermediate doses of MO-8282 reduced the duration of immobility during forced swimming, in mice as well, suppressed muricide behavior of olfactory-bulbectomized rats and antagonized clonidine-induced suppression of exploratory activity in mice. MO-8282 moderately antagonized the ptosis but not the hypothermia induced by reserpine in mice. MO-8282 exhibited weak antagonism against the tremor, lacrimation and diarrhea induced by tremorine, but its activity was milder than that of amitriptyline. The uptake of noradrenaline into rat hypothalamic synaptosomes was inhibited by MO-8282 at concentrations 20 times less than equally effective doses of amitriptyline, but the uptake of dopamine or serotonin was unaffected by MO-8282. A single oral administration of MO-8282 at a dose of 30 mg/kg accelerated noradrenaline turnover, but did not affect dopamine and serotonin turnover in the rat brain. MO-8282 strongly inhibited noradrenaline-, histamine- or adenosine-sensitive adenylate cyclase activity of guinea pig brain. Its mode of action differed from that of imipramine, rather resembling that of mianserin. MO-8282 did not affect monoamine oxidase activity of rat liver. These results suggest that the pharmacological characteristics of MO-8282 are different from those of tricyclic antidepressants and rather similar to those of mianserin, but more potent. The results, therefore, indicate that MO-8282 is possibly a novel antidepressant.