Effects of long-chain fatty alcohol on peripheral nerve conduction and bladder function in diabetic rats

Diabetic cystopathy as manifested by an enlarged bladder is mainly caused by peripheral neuropathy. Long-chain fatty alcohol, which has been isolated from the Far-Eastern traditional medicinal plant, Hygrophilia erecta, Hochr., has been found to possess some neurotrophic activities on the central neuron. Cyclohexenonic long-chain fatty alcohol (FA) used in this study were synthesized in order to improve the efficiency of the molecules. The effects of this compound on peripheral nerves, however, have not yet been studied. To get more information, we evaluated the effects of this compound on peripheral nerves in streptozotocin-induced diabetic rats in terms of nerve conduction velocity and bladder function. Three experiments were performed 8 weeks after the administration of streptozotocin to 8-week-old rats: (i) motor sciatic nerve conduction (MNCV), (ii) monitoring micturition behavior in the metabolic cage, and (iii) cystometrogram under urethane anesthesia (CMG). Half of the diabetic rats were treated with FA (8 mg/kg/day, i.p.). The difference in MNCV between control rats (49.0 +/- 2.2 m/s) and untreated diabetic rats (42.4 +/- 0.5 m/s) after 8 weeks reached significance (p = 0.0183). FA-administrated diabetic rats showed an improved MNCV (45.8 +/- 1.2 m/s). We also identified a significant improvement of bladder function in these animals. The diabetic rats had a much higher maximal micturition volume per 24 hours (4.9 +/- 0.4 ml) than control animals (1.5 +/- 0.1 ml). However, the diabetic rats treated with FA had a maximal micturition volume of only 3.7 +/- 0.3 ml. Likewise, the diabetic rats had a CMG bladder capacity of 0.90 +/- 0.14 ml while the diabetic rats treated with FA had a capacity of 0.54 +/- 0.07 ml. These results indicate that cyclohexenonic long-chain fatty alcohol has a beneficial effect on peripheral neuropathy and cystopathy in streptozotocin-induced diabetic rats.     

Nutrient control of brain neurotransmitter synthesis and function

Dietary fluctuations in nutrient availability are factors in the regulation of brain function. Until recently the prevailing view was that brain biochemistry and function were influenced by diet only when biochemical and clinical evidence of nutrient deficiency was present. It is now clear, however, that the brain is sensitive and responsive to diet composition. Preliminary data show that variation in vitamin and mineral nutrient intakes over ranges that are considered to maintain normal nutritional status may impact on brain biochemistry, owing to their many coenzyme roles. Furthermore, the synthesis of at least five brain neurotransmitters, namely serotonin, the catecholamines, acetylcholine, histamine, and glycine responds to dietary fluctuations in availability of their nutrient precursors, tryptophan, tyrosine, choline, histidine, and threonine, respectively. Not only are these biochemical events altered by normal variations in diet composition, but considerable evidence now exists to show that the brain uses this information to regulate many functions. Future studies can be expected to continue to elucidate the links between diet, brain neurotransmission, and brain function, and to exploit the application of these links in understanding the function of the brain under normal and disease conditions.     

Influence of potassium chloride on alcohol absorption

Simultaneous intragastric administration of large doses of KCl (430 mg/kg and 860 mg/kg) with ethanol (4 g/kg) significantly reduces blood alcohol levels and diminishes manifestations of alcohol intoxication in rats. It was shown with parenteral administration of alcohol that the effect is not related to an acceleration of alcohol metabolism. Analysis of alcohol concentrations of gastric and intestinal content as well as $\text{in situ}$ studies with animals whose stomachs were ligated at the pylorus revealed that KCl interferes with the absorption of alcohol through inhibition of gastric absorption and gastric emptying. The finding that equimolal concentrations of NaCl were unable to duplicate the described effects characterizes them as specific actions of the potassium ion.     

Minireview. Evidence that dopamine is a neurotransmitter in peripheral tissues

In the CNS, dopamine (DA) is a recognized neurotransmitter as well as a precursor for norepinephrine (NE) and epinephrine (EPI). In contrast to the CNS, DA has been assumed to be only a precursor in peripheral tissues. There is now, however, considerable evidence to support the hypothesis that it may function as a neurotransmitter and/or cotransmitter in peripheral tissues in addition to being a precursor. In this minireview we summarize evidence supporting the view that DA plays a role of its own in peripheral neurotransmission.     

Effects of drugs on brain neurotransmitter and pituitary-testicular function in male rats.

The effects of different drugs influencing brain neurotransmitter contents have been tested on the pituitary-testicular function in male rats. L-dopa (200 mg/kg body weight, i.p.) increased the dopamine and noradrenaline contents of the hypothalamus, amygdala, striatum and mesencephalon, but it was ineffective as regards the 5-hydroxytryptamine contents of the same brain areas, and increased the plasma testosterone level. alpha-Methyl-p-tyrosine (250 mg/kg b.w., i.p.) decreased the dopamine and noradrenaline contents of these brain areas, but it was ineffective to 5-hydroxytryptamine, and decreased the plasma testosterone level. Diethyldithiocarbamate (400 mg/kg b.w., i.p. twice a day) increased the dopamine levels in the hypothalamus, amygdala, striatum and mesencephalon, decreased the noradrenaline contents in the same brain regions but had no effect on the 5-hydroxytryptamine contents of these brain areas or on the testosterone level in the peripheral blood. p-Chlorophenylalanine (300 mg/kg b.w., i.p.) decreased the 5-hydroxytryptamine contents of the different brain areas, while it had no effect on the dopamine and noradrenaline levels or on the plasma testosterone level. 5-Hydroxytryptophan (200 mg/kg b.w., i.p.) increased the 5-hydroxytryptamine contents of all brain areas studied, but was without effect on the dopamine and noradrenaline contents or the plasma testosterone level. The data suggest that both dopamine and noradrenaline may be involved in the regulation of the pituitary-testicular function, and the ratio of the two transmitters might be more important that their actual levels in definite brain areas.     

Sphingolipid/cholesterol regulation of neurotransmitter receptor conformation and function

Like all other monomeric or multimeric transmembrane proteins, receptors for neurotransmitters are surrounded by a shell of lipids which form an interfacial boundary between the protein and the bulk membrane. Among these lipids, cholesterol and sphingolipids have attracted much attention because of their well-known propensity to segregate into ordered platform domains commonly referred to as lipid rafts. In this review we present a critical analysis of the molecular mechanisms involved in the interaction of cholesterol/sphingolipids with neurotransmitter receptors, in particular acetylcholine and serotonin receptors, chosen as representative members of ligand-gated ion channels and G protein-coupled receptors. Cholesterol and sphingolipids interact with these receptors through typical binding sites located in both the transmembrane helices and the extracellular loops. By altering the conformation of the receptors (“chaperone-like” effect), these lipids can regulate neurotransmitter binding, signal transducing functions, and, in the case of multimeric receptors, subunit assembly and subsequent receptor trafficking to the cell surface. Several sphingolipids (especially gangliosides) also exhibit low/moderate affinity for neurotransmitters. We suggest that such lipids could facilitate (i) the attachment of neurotransmitters to the post-synaptic membrane and in some cases (ii) their subsequent delivery to specific protein receptors. Overall, various experimental approaches provide converging evidence that the biological functions of neurotransmitters and their receptors are highly dependent upon sphingolipids and cholesterol, which are active partners of synaptic transmission. Several decades of research have been necessary to untangle the skein of a complex network of molecular interactions between neurotransmitters, their receptors, cholesterol and sphingolipids. This sophisticated crosstalk between all four distinctive partners may allow a fine biochemical tuning of synaptic transmission.     

中药天年饮对衰老大鼠脑单胺类神经递质含量的影响

目的：观察中药天年饮（Tiannianyin,TNY-traditional chinese medicine）对D-半乳糖衰老大鼠脑单胺类神经递质去甲肾上腺素（NE）、多巴胺（DA）、5-羟色胺（5-HT）含量的影响。方法：选用成年雄性SD大鼠40只．随机分为4组．每组均为10只：正常组、衰老模型组、TNY用药组、阴性对照组。Ⅱ半乳糖连续腹腔注射制作亚急性衰老的大鼠模型．采用高效液相色谱-电化学法检测各组大鼠下丘脑、海马NE、DA、5-HT的含量。结果：D-半乳糖衰老大鼠下丘脑、海马NE、DA、5-HT的含量明显降低（与正常大鼠相比P〈0．01）：TNY可明显提高脑单胺类神经递质的含量（用药组与模型组相比P〈0．05）。结论：TNY可有效调整中枢神经递质的合成,具有良好延缓衰老的作用。     

Influence of leptin on neurotransmitter overflow from the rat brain in vitro.

The 16-kDa polypeptide hormone, leptin along with the neurotransmitters noradrenaline and serotonin (5-HT) have important physiological roles in the regulation of a number of neuroendocrine actions particularly feeding. Leptin receptor mRNA and immunoreactivity has been reported in various brain regions, while recent studies suggest that leptin is released from the human brain. This study investigated the interactions between leptinergic and neurotransmitter systems of the rat brain in vitro. Techniques were established to simultaneously monitor the release of endogenous noradrenaline and its metabolite 3,4 dihydroxyphenylglycol (DHPG), and 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) from the rat brain. The neuromodulatory action of leptin (0.2 and 3 nM) on the overflow of noradrenaline and DHPG from the medulla and hypothalamus was examined. The effect of leptin on 5-HT and 5-HIAA overflow from the hypothalamus was also investigated. Administration of 0.2 and 3 nM leptin significantly increased medullary noradrenaline overflow to 172% and 174% of basal levels, respectively. Leptin had no significant effect on hypothalamic noradrenaline overflow, while leptin perfusion induced a significant increase in 5-HIAA overflow from the hypothalamus. This study lends support to the notion of a complex interaction of the leptinergic and brain neurotransmitters involved in the control of feeding and energy metabolism.     

Influence of calcium ionophore A23187 on neurotransmitter release in rat brain synaptosomes

The effect of calcium ionophore A23187 on the release of nonmetabolizable glutamate analogues [3H]D-aspartate and the exocytosis registered by fluorescent dyes in synaptosomes was investigated. It was shown that A23187 is able to induce neurotransmitter release both in calcium-containing and calcium-free medium, the effect in the latter case being more pronounced. Calcium ionophore is able to induce exocytosis registered by acridine orange and FM 2-10. The influence of A23187 on the fluorescence of acridine orange was mainly calcium-independent, whereas the change in the fluorescence of FM 2-10 was calcium-dependent. It was suggested that the calcium-independent increase in acridine orange fluorescence is related to the dissipation of pH gradient in synaptic vesicles. Probably, the calcium-independent release of D-aspartate is also associated with the dissipation of pH gradient and subsequent leakage of neurotransmitters.     

Effects of dihydroergotoxine (hydergine) on peripheral blood alcohol levels

To examine the effects of dihydroergotoxine (DHET) on peripheral blood ethanol levels of adult female mice, ethanol (2 g/kg) was administered orally, either alone or in combination with DHET (2, 4, or 8 mg/kg). Blood was drawn after the first day of drug administration (acute study) and again after 21 days (chronic study). Two additional groups of mice received a single dose of ethanol (2 g/kg) and DHET (2 mg/kg) 15 minutes apart, one group receiving ethanol first, the other DHET as the first dose. Blood samples (100μ1) were collected from the tail vein at 5, 15, 30, 60, 120 and 180 minutes after treatment. Samples were analyzed by headspace gas chromatography. Results indicate that (a) combining ethanol with DHET significantly reduced blood ethanol levels compared to administration of ethanol alone, (b) chronic conditions produced higher blood ethanol levels, and (c) administration of ethanol 15 minutes before DHET produced a 27% lowering of peripheral blood alcohol levels compared to the reverse order of administration. These data suggest that DHET may be useful for alleviating some of the symptoms associated with alcohol intoxication.     

Regulation of ion channel/neurotransmitter receptor function by RNA editing

RNA editing by select adenosine deamination (A-to-I editing) alters functional determinants in certain ion channels and neurotransmitter receptors in vertebrates and invertebrates. In most cases, edited and unedited versions of a given receptor/channel co-exist to expand the functional space of the receptor population. Recent studies have characterized K(+) channels in squid that are edited at multiple positions, revealed a role for Q/R site editing in AMPA receptor assembly, and demonstrated a link between serotonin levels and the extent of editing of a mammalian serotonin receptor.     

Influence of hindlimb unloading on the modulation of neurotransmitter secretion through the autoreceptor system

In experiments on neuromuscular junctions of fast (m. extensor digitorum longus, EDL) and slow (m. soleus) muscles of rats under hindlimb unloading of varied duration, we compared the intensity of spontaneous quantal secretion of neurotransmitter in response to potassium depolarization and activation of presynaptic cholinoreceptors with a nonhydrolyzable acetylcholine analog. Secretion was assessed by the mean frequency of miniature endplate potentials. In the controls, carbachol raised this index by 363% in EDL and by 62% in soleus. Secretion in the fast muscle was also more sensitive to [K⁺]. Hindlimb unloading abolished the sensitivity to carbachol in EDL while in soleus it did not change. Preservation of the sensitivity of the fast muscle to potassium depolarization suggested that unloading reduced the number of functional presynaptic receptors.     

Effect of alcohol consumption on peripheral blood Alu methylation in Korean men

Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create a substantial public health problem worldwide. To date, no therapeutic can effectively solve these problems. They are complex diseases characterized by both genetic and environmental factors. DNA methylation can act as a downstream effector of environmental signals and account for multi-factorial nature of the disease. Global DNA methylation of peripheral blood cells has recently been proposed as a potential biomarker for disease risk. Alu elements host one-quarter of CpG dinucelotides in the genome to function as proxies for global DNA methylation. In this study, we evaluated the Alu methylation in the peripheral blood DNA of healthy volunteers and AUD patients using the pyrosequencing technology. The Alu methylation level is significantly higher in AUD compared to healthy controls (23.4?±?1.6 versus 22.1?±?1.0, t?=?7.83, p?<?0.0001). Moreover, significant correlation was found between Alu methylation and alcohol use disorders identification test score (r?=?0.250, p?<?0.0001), alcohol problem (r?=?0.294, p?<?0.0001), and life position (r?=?–0.205, p?=?0.0005). Overall, these novel findings indicate that alcohol-related increase in Alu methylation might play a complex role in the etiology and pathogenesis of AUD. Further studies are required to elucidate the mechanisms underlying this relationship.     

神经递质转运体的研究进展

近年来,一种位于突触前膜、囊泡膜及神经胶质细胞膜上的糖蛋白－神经递质转运体,逐渐成为神经科学界研究的热点。它们能高选择性地与突触间的递质相结合,将递质运回细胞内,从而终止递质在细胞间的传递,并进而参与突触间信息的调控。有关神经递质转运体的研究国内尚未见报道。本文仅就近年来国外有关方面的研究概况,从分子结构、分型、研究方法、分布、功能、调节因素、基因调控、以及研究焦点和尚待解决的问题等诸方面做一综述     

Influence of circadian disruption on neurotransmitter levels,physiological indexes,and behaviour in rats

Brain monoamines – such as noradrenaline (NA), dopamine (DA) and serotonin (5-HT) – regulate several important physiological functions, including the circadian rhythm. The purpose of this study was to examine changes in NA, DA and 5-HT levels in various brain regions and their effect on core body temperature (T_c), heart rate (HR) and locomotor activity (Act) in rats following exposure to an artificial light/dark (LD) cycle. For this, male Wistar rats were housed at an ambient temperature (T_a) of 23?°C and 50% relative humidity with free access to food and water. Rats were exposed to either natural (12?h:12?h) or artificial (6?h:6?h) LD cycles for 1 month, after which each brain region was immediately extracted and homogenized to quantify the amounts of NA, DA and 5-HT by high-performance liquid chromatography. Behavioural changes were also monitored by the ambulatory activity test (AAT). Notably, we found that artificial LD cycles disrupted the physiological circadian rhythms of T_c, HR and Act. Although the 5-HT levels of rats with a disrupted circadian rhythm decreased in cell bodies (dorsal and median raphe nuclei) and projection areas (frontal cortex, caudate putamen, preoptic area and suprachiasmatic nucleus) relative to the control group, NA levels increased both in the cell body (locus coeruleus) and projection area (paraventricular hypothalamus). No significant changes were found with respect to DA. Moreover, circadian rhythm-disrupted rats also showed anxious behaviours in AAT. Collectively, the results of this study suggest that the serotonergic and noradrenergic systems, but not the dopaminergic system, are affected by artificial LD cycles in brain regions that control several neural and physiological functions, including the regulation of physiological circadian rhythms, stress responses and behaviour.