Effects Of Various Neurotransmitters Research Articles

TMIC-18. ROLE OF NEUROTRANSMITTERS IN GLIOBLASTOMA PATHOPHYSIOLOGY: EMERGING INSIGHTS

Abstract INTRODUCTION Glioblastoma (GBM) are the most common primary brain tumor in adults associated with a dismal patient outcome. While it is well-known that glutamatergic neurons can form functional synapses with glioblastoma cells to enhance tumor growth, lesser is known about the effects of activity of other neuronal types on glioblastoma biology, especially among different glioblastoma molecular subtypes. Here, we examined the effects of various neurotransmitters on the growth of glioblastoma cells characterized as classical, proneural and mesenchymal subtypes. METHODS Patient-derived glioblastoma cell lines were exposed to varying concentrations of different neurotransmitters and assessed for cell viability using CCK-8 assay. Transcriptomic data from TCGA (The Cancer Genome Atlas) database was analyzed for correlation of expression of neurotransmitter receptors (NTRs) with patient survival. Using IVY-GAP database, we compared the expression of NTRs at leading-edge versus tumor core of tumors to assess their possible involvement in cell migration and microenvironmental interactions. RESULTS Consistent with previous findings, we observed an increase in cell viability in all GBM cell lines after being incubated with L-glutamate. The classical subtype has a stronger growth response to L-glutamate compared to the other two subtypes. TCGA data revealed the expression of GRIK4 (glutamate ionotropic receptor kainate type subunit 4) as highest in the classical subtype as well as inversely correlated with worse patient survival in this GBM subtype, as opposed to proneural or mesenchymal patient groups. CCK8 assay also suggested that acetylcholine and dopamine increase glioblastoma cell growth. A subset of cholinergic and glutamatergic receptors (CHRM1, GRM2) was found upregulated in infiltrating/leading-edge regions of glioblastoma tumors compared to the tumor core, suggesting possible involvement in glioblastoma-neuron interactions. CONCLUSION Our findings suggest that GBM subtypes may differentially leverage neuro-modulatory mechanisms to support their growth. Future studies will investigate the differential neuronal responses in GBM subtypes using pharmacological/genetic approaches.

SOMATOMEDIN C (IGF-1) IN BRAIN TRAUMA: POTENTIAL EFFECT ON NEUROPROTECTION

In recent years, through experimental studies, the effects of various neurotransmitters, as well as proteins, enzymes, and hormones involved in the inflammatory response during and after traumatic brain injury, have been investigated in depth, finding a substance called insulin-like growth factor type I (IGF-1), this protein, has shown to be important in processes of neuroprotection, synaptogenesis, myelination, and prevention of apoptosis, among others. This article aims to clarify the role of Somatomedin C or type I insulin-like factor and its potential neuromodulatory function after head trauma. Factors such as age, sex, physical activity, diet, and the influence of other hormones have been related to the brain's levels and functioning of somatomedin C. IGF-1 receptors are found in higher concentration in some specific regions of the nervous system where neuronal tissue is more susceptible and have binding proteins that regulate the degradation of this substance, which in inflammatory conditions such as brain trauma has been shown to promote angiogenesis and attenuate the production of proinflammatory cytokines.

Neurotransmitters induce larval settlement and juvenile growth of the sea cucumber, Holothuria scabra

The sea cucumber, Holothuria scabra, is a high-value economic animal in Thailand for local consumption and exportation. One major drawback in aquaculture of this species is that their larvae have low settlement and survival rates during the early developmental period. In the present study, we investigated the effects of various neurotransmitters, including GABA, dopamine (DA), L-DOPA, and monosodium glutamate (MSG) on larval settlement in both laboratory and practical models. In laboratory models, treatments of doliolaria with GABA or MSG, at a dose of 10−1 mM for 72 h could induce larval settlement at about 90% and 93%, respectively, compared with the control group (about 20%) (P < 0.05), while treatments with DA or L-DOPA at a dose of 10−2 mM for 12 h, were capable of inducing 100% settlement, compared with the control group (P < 0.05). In practical models, at day 37 after treatment, GABA or MSG significantly induced larvae to settle and survive at approximately 6% and 4%, respectively, while L-DOPA induced at about 3%, compared with the control group (about 0.2%) (P < 0.05). At day 37, all neurotransmitters-treated groups exhibited faster growth rates, while at 51 days, the growth rates of groups treated with DA, L-DOPA and MSG were faster, than the control group. GABA- and DA-treated groups also attained juvenile features earlier than MSG and L-DOPA-treated groups, and control groups. Taken together, this study shows significant effects of neurotransmitters on inducing settlement, increased metamorphosis and survival rates of the larvae of this sea cucumber, which could potentially be applied to enhance the production of this sea cucumber species.

Neuronal activity controls the development of interneurons in the somatosensory cortex.

Neuronal activity in cortical areas regulates neurodevelopment by interacting with defined genetic programs to shape the mature central nervous system. Electrical activity is conveyed to sensory cortical areas via intracortical and thalamocortical neurons, and includes oscillatory patterns that have been measured across cortical regions. In this work, we review the most recent findings about how electrical activity shapes the developmental assembly of functional circuitry in the somatosensory cortex, with an emphasis on interneuron maturation and integration. We include studies on the effect of various neurotransmitters and on the influence of thalamocortical afferent activity on circuit development. We additionally reviewed studies describing network activity patterns. We conducted an extensive literature search using both the PubMed and Google Scholar search engines. The following keywords were used in various iterations: "interneuron", "somatosensory", "development", "activity", "network patterns", "thalamocortical", "NMDA receptor", "plasticity". We additionally selected papers known to us from past reading, and those recommended to us by reviewers and members of our lab. We reviewed a total of 132 articles that focused on the role of activity in interneuronal migration, maturation, and circuit development, as well as the source of electrical inputs and patterns of cortical activity in the somatosensory cortex. 79 of these papers included in this timely review were written between 2007 and 2016. Neuronal activity shapes the developmental assembly of functional circuitry in the somatosensory cortical interneurons. This activity impacts nearly every aspect of development and acquisition of mature neuronal characteristics, and may contribute to changing phenotypes, altered transmitter expression, and plasticity in the adult. Progressively changing oscillatory network patterns contribute to this activity in the early postnatal period, although a direct requirement for specific patterns and origins of activity remains to be demonstrated.

463. Leucine-enkephalin metabolism in various patient populations. Drug effects

Endogenous peptides with opioid-like activity and some of their metabolites modulate the central effects of various neurotransmitters. This has raised the possibility that alterations in leucine-enkephalin (LEU) metabolism, resulting in significant changes in its bioavailability, may influence the course of some conditions characterized by abnormal synaptic transmission. We have tested this hypothesis by determining kinetic parameters, as well as by identifying the products, from the in vitro plasma LEU degradation by samples obtained from various patient populations. The effect of various psychotropic drugs upon this reaction was also studied. Subjects included male chronic schizophrenics (n = 15), chronic users of various drugs of addiction, including (n = 9) or excluding (n = 8) alcohol, chronic alcoholics (n = 12) and female migraineurs (n = 10) during or outside of an acute migraine episode; for comparison we used a group of sex-matched (20 males and 10 females), age-comparable, drug-free, healthy volunteers. LEU was rapidly and completely metabolized in each and every one of the samples studied. Neither gender (64 males and 20 females sample tested individually), age (males and females range of 23 to 70 and 25 to 65 years, respectively), nor subjects medical condition appeared to make a significant difference in either the t12 of LEU elimination, the Iv of this reaction (x ± SD, median, minimum and maximum of 12.0 min ± 0.9, 12.0 min and 10.6 to 13.7 min, and 1.2 pg/min ± 0.3, 1.1 pg/min, and 0.6 to 2.0 pg/min, respectively), or in the Km and Vmax values for aminopeptidase LEU degradation (x ± SD; 0.81 mM ± 0.01 and 14.30 umol/L/min ± 1.17, respectively). LEU degradation was strongly inhibited by aminopeptidase inhibitors, by some selected neuroleptics and specific serotonin reuptake inhibitors, and to a lesser extent by various L-tyrosine-containing LEU fragments. The kinetics of this reaction was not significantly affected by either thiorphan, N-carboxyphenylmethyl leucine or any other of a number of monoamine neurotransmitters, substances of abuse, nonsteroidal antiinflammatory agents, triptan-type antimigraine agents and miscellaneous compounds tested. The possible relevance of these results in explaining some of the differences in the pharmacological profile of the drugs studied will be discussed.

Factors regulating amylase secretion from chicken pancreatic acini in vitro

In mammals, cholecystokinin regulates pancreatic exocrine secretion under physiological conditions. We have shown, however, that cholecystokinin at physiological concentrations does not induce pancreatic amylase secretion in birds. Therefore, we investigated the effects of various neurotransmitters and gut hormones on the pancreatic amylase secretory response in isolated chicken pancreatic acini. Acetylcholine (half-maximal stimulation at 800 nM) and vasoactive intestinal polypeptide (half-maximal stimulation at 40 pM) produced a concentration-dependent increase in amylase secretion at physiological concentrations. The combination of acetylcholine and vasoactive intestinal polypeptide produced an additive response in amylase secretion. Sodium nitroprusside, a spontaneous nitric oxide releaser, and bombesin, induced amylase secretion at concentrations greater than 10 nM and 100 nM, respectively. Gastrin and secretin increased amylase secretion at pharmacological concentrations (10 to 100 nM). Our findings suggest that neural regulation is important for pancreatic enzyme secretion in birds and the contribution of gut hormones seems to be physiologically unimportant.

Modulation of neuropeptide effects by achatin-I, an Achatina endogenous tetrapeptide

Achatin-I (Gly-D-Phe-L-Ala-L-Asp), an endogenous tetrapeptide in the ganglia of Achatina fulica Férussac, at 3 × 10 −6 M suppressed both the inward current (I in) of an Achatina giant neurone, PON (periodically oscillating neurone), caused by locally ejected oxytocin, and the outward current (I out) of v-RCDN (ventral-right cerebral distinct neurone) induced by APGW-amide. Dose (pressure duration)-response studies with oxytocin and APGW-amide showed that their ED 50 values were not affected by achatin-I, whereas the E max values were suppressed. The v-RCDN I out caused by FMRF-amide was enhanced by achatin-I, but the same current induced by [Ser 2] Mytilus inhibitory peptide ([Ser 2]MIP) was not affected. Achatin-I suppressed the I out of TAN (tonically autoactive neurone) caused by acetylcholine, but did not affect the I in of v-RCDN elicited by acetylcholine. The I out caused by γ-aminobutyric acid, threo-β-hydroxy-L-glutamic acid and dopamine was not affected by achatin-I. It is considered that achatin-I acts as a neuromodulator and has both suppressing and enhancing actions on the effects of various neurotransmitters, including peptides, in Achatina giant neurones.

Effect of various neurotransmitters and electrical field stimulation on smooth muscle preparations from the esophagus of horses.

The effects of various neurotransmitters and electrical field stimulation on muscle strips from the distal equine esophagus were studied. Acetylcholine (ACH) caused concentration dependent (1.1-55 x 10(-6) mol/l) contractions of the longitudinal and circular muscle strips from the distal esophagus as well as from the lower esophageal sphincter (LES). Atropine (10(-5) mol/l) blocked these contractions. Noradrenaline (NA) induced concentration related (1.1-55 x 10(-6) mol/l) contractions of the muscle strips from the LES. This excitatory effect of noradrenaline was antagonized by the alpha 1-receptor antagonist prazosin. Tetrodotoxin (5 x 10(-6) mol/l) did not affect the contractile response of the muscle strips to noradrenaline (55 x 10(-6) mol/l). Noradrenaline (1.1-55 x 10(-6) mol/l) had no excitatory effect on the circular and the longitudinal muscle strips from the esophagus. Furthermore, noradrenaline induced a concentration dependent (1.1-55 x 10(-6) mol/l) relaxation of the longitudinal muscle strips from the esophagus. The relaxing effect of NA was antagonized by the beta-receptor antagonist propranolol (10(-5) mol/l). Histamine (10(-7)-10(-6) mol/l) elicited a contraction in 4 out of 18 muscle preparations from the LES. The histamine induced contractions were partly antagonized by the H1-receptor antagonist clemastine (10(-4) mol/l) and fully abolished by the H2-receptor antagonist clemastine (10(-4) mol/l). Electrical field stimulation (EFS, 5 Hz, 2 ms; 500 mA; 10 Hz, 2 ms; 500 mA) produced tetrodotoxin sensitive contractions in all three types of muscle strips. Atropine (10(-5) mol/l) fully suppressed these contractions in most preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of various neurotransmitters and neuropeptides on the release of corticotropin-releasing hormone from the rat cortex in vitro.

Corticotropin-releasing hormone (CRH), in addition to its neuroendocrine role, may act as a central neurotransmitter. Cerebral cortical CRH may have an important role in behavioral and neurodegenerative disorders. To gain an understanding of factors that may influence cortical CRH, we investigated the effect of several neurotransmitters and neuropeptides on the release of immunoreactive CRH (iCRH) from various cerebral cortical regions [frontal (FC), parietal (PC), temporal (TC), and occipital (OC)] in vitro. The hypothalamic release of iCRH was also evaluated under the same experimental conditions. Basal release of iCRH was approximately 2-fold, and KCl-stimulated iCRH release was approximately 4-fold higher in the hypothalamus than in any of the cortical regions. Cortical iCRH release was stimulated by 10 nM somatostatin (SRIF) in PC and 1 nM neuropeptide Y (NPY) in TC. Cortical iCRH release was inhibited by 1 and 10 nM acetylcholine (ACh), 0.1 microM glutamate, and 10 nM NPY. These effects were confined to the FC and/or PC. Hypothalamic iCRH release was stimulated by 1 and 10 nM ACh, 10 microM GABA, and 1 and 10 nM serotonin but was inhibited by 10 nM SRIF and 1 microM GABA. Growth hormone-releasing hormone did not affect cortical or hypothalamic iCRH release. These results demonstrate that CRH release from the cerebral cortex and the hypothalamus are under different regulatory mechanism(s). Furthermore, they indicate that the release of CRH in various cortical regions may be regulated differentially by the same neurotransmitter.

Activation of Muscarinic and Serotonergic Receptors Results in Phosphoinositide Hydrolysis but Not in Mobilization of Calcium in Sympathetic Neurons

The effects of various neurotransmitters on phosphoinositide hydrolysis, mobilization of Ca2+ and release of [3H]-norepinephrine ([3H]-NE) were studied in cultures of sympathetic neurons of chick embryos. [3H]-inositol-1,4,5-triphosphate ([3H]-IP3) was increased in sympathetic neurons by acetylcholine (ACh), muscarine and serotonin (5-HT). Dopamine and norepinephrine did not stimulate phosphoinositide hydrolysis. Intracellular concentration of free Ca2+ ([Ca2+]i) was measured in Indo-1-loaded sympathetic neurons at rest and after addition of test agents. Measurements were made in the cell body and growth cone regions since Ca2+ mobilization is known to be different in different regions of the sympathetic neurons. ACh (nicotinic component was blocked by hexamethonium) and 5-HT failed to increase the [Ca2+]i, in the cell body as well as in the growth cone. The spontaneous release of [3H]-NE was not affected by ACh and 5-HT. Caffeine increased the [Ca2+]i only in the cell body but not in the growth cone and had no effect on the release of [3H]-NE. These results suggest that an IP3-insensitive but caffeine-sensitive pool of Ca2+ is present only in the somatic region of sympathetic neurons and is not coupled to the transmitter release.

The effect of various neurotransmitters and some of their agonists and antagonists on the crayfish abdominal positioning system

1. Crayfish abdominal nerve cords were perfused with selected transmitters or their agonists or antagonists. Motor activity underlying abdominal positioning behavior was monitored. 2. All the neurotransmitters except glycine had a measurable effect on this system. 3. Acetylcholine and its agonists were slightly stimulatory. Both muscarinic and nicotinic receptors were indicated. 4. GABA was weakly inhibitory. Picrotoxin was strongly stimulatory, perhaps as a result of its known ability to block GABA and inhibitory acetylcholine receptors. 5. Histamine was strongly inhibitory. Both H1 and H2 receptors were indicated. 6. Glutamate was found to be slightly inhibitory while its agonist, NMDA, showed no effect. 7. Finally, L-Dopa was stimulatory, but only at a high concentration.

Regulation of cyclic AMP levels in mammalian retina: Effects of depolarizing agents and transmitters

Cellular depolarization in brain results in a modulation of cAMP levels by releasing neurotransmitters having receptors linked via GTP-binding proteins to adenylate cyclase. In order to determine the transmitters regulating cAMP during cellular depolarization in mammalian retina, the modulation of cAMP by depolarizing media was investigated. Cyclic AMP levels in light adapted retinas increased following exposure to depolarizing media, but levels in dark adapted retinas remained unaltered. The depolarization-induced modulation of cAMP levels persisted in dystrophic retinas, suggesting that the response occurred in the inner retina. In microdissected discrete retinal layers from rabbit, levels of cAMP were increased following perfusion with depolarizing medium in the outer plexiform and inner nuclear layers, consistent with the observation seen with mouse retinas. To begin to identify transmitters released by cellular depolarization, a variety of transmitters and/or antagonists were included in the incubation medium. Haloperidol reduced the depolarization induced increase in cAMP levels by 25% in normal mouse retinas, and 75% in dystrophic retinas. Dopamine elevated cAMP levels in normal and dystrophic mouse retinas, and when combined with depolarizing medium, additive increases were observed. The effects of various neurotransmitters on retinal cAMP levels in the absence of any phosphodiesterase inhibitors were assessed, and both dopamine and norepinephrine were found to increase cAMP levels in normal and dystrophic retinas. Phentolamine antagonized the increase elicited by norepinephrine. When dopamine and norepinephrine were combined non-additive increases were observed. Serotonin, GABA, acetylcholine, histamine and adenosine had little or no significant effect on the retinal levels of cAMP in either normal or dystrophic mouse retinas.These results indicate that depolarizing media increase cAMP levels partially by releasing dopamine. The processes regulating cAMP levels in retina are both different and similar to those in brain.

Hemicholinium-3 selectively alters the rhythmically bursting activity of septo-hippocampal neurons in the rat

The medial septal area contains neurons which project to the hippocampal formation. A sizeable proportion of these septo-hippocampal neurons (SHNs) are cholinergic. About 40% of them also display a characteristic discharge pattern in rhythmic bursts. We hypothesized that SHNs with a rhythmically bursting activity (RBA) are the cholinergic ones. To test this hypothesis we studied the effects of acetylcholine synthesis blockade by hemicholinium-3 (HC-3) on the properties of the SHNs. HC-3 (16, 32 or 64 μg total dose) or saline were injected in the lateral ventricles of adult male Sprague-Dawley rats anesthetized with urethane. Extracellular recordings from SHNs in the medial septal area were obtained within hours after HC-3 injections ( n = 24 animals). SHNs were identified by their antidromic response following electrical stimulation of the fimbria-fornix. The pharmacological properties of SHNs were studied in some animals using microiontophoretic applications from multibarreled electrodes filled with various neurotransmitters. The hippocampal rhythmic slow activity (RSA or theta) was abolished even after the lowest dose of HC-3 tested (16 μg). No significant change in SHNs conduction velocity or spontaneous activity was observed at any dose of HC-3. The percentage of SHNs with RBA was unchanged. In contrast the mean frequency of the RBA was decreased by HC-3 in a dose-dependent fashion. The mean frequency was lowest within the first 3 h after injection. Although the mean spontaneous activity was unchanged SHNs tended to have more spikes per burst. The effects of various neurotransmitters on SHNs were qualitatively unchanged after HC-3 injection. These results suggest that acetylcholine synthesis blockade by HC-3 leads not only to the disappearance of the hippocampal RSA in urethane-anesthetized animals, but also to a decrease in the frequency of the rhythmically bursting activity of the SHNs. Since the 4-Hz hippocampal theta is atropine-sensitive, the results provide indirect evidence that the SHNs with rhythmically bursting activity are the cholinergic SHNs.

Antidiuretic effects of dibutyryl-cyclic GMP by micro-injecting into the supraoptic and paraventricular nuclei in the rat hypothalamus

We have reported antidiuretic effects of various neurotransmitters, such as noradrenaline(NA) and acetylcholine(ACh), and cyclic AMP and dibutyryl-cyclic AMP(db-cAMP) on urine outflow by microinjecting into the vasopressinergic supraoptic(SON) and paraventricular(PVN) nuclei. In this study, the effects of cyclic GMP(cGMP) and dibutyryl-cyclic GMP(db-cGMP) were investigated. The microinjections of cGMP into PVN only and of db-cGMP into both nuclei elicited dose-dependent antidiuretic effects. The median effective doses(ED50) for db-cGMP injected into SON and PVN were approx. 150 and 200 nmol, respectively. The effect of db-cGMP in SON was more potent than that of cGMP and was approx. equal to that of db-cAMP, which was almost completely blocked by the pretreatment of atropine. The effect of db-cGMP in PVN was slightly more potent than that of cGMP and less potent than that of db-cAMP, which was almost perfectly blocked by both atropine and phenoxybenzamine. A repeated microinjection of db-cGMP into these nuclei reduced the effect markedly. These results suggest that cGMP may have a role as a second messenger in the release of ACh in both nuclei and in the release of NA in PVN.

Effects of neurotransmitters on calcium efflux from cultured glioma cells.

The effects of various neurotransmitters and cyclic nucleotides on 45Ca2+ efflux in cultured human glioma cells were investigated. Glutamate and glycine, but not GABA, stimulated 45Ca2+ release from the cells. Stimulation of beta-adrenergic receptors but not alpha-adrenergic receptors also increased 45Ca2+ efflux. Cholinergic receptor stimulation by carbachol had the same effect. The stimulatory effect of carbachol was abolished in the presence of either atropine or hexamethonium. C-AMP and c-GMP increased the 45Ca2+ efflux, suggesting that these agents are involved in the transmitter-stimulated release of 45Ca2+ from the cell. Kinetic analysis of the efflux revealed four calcium compartments. The carbachol-stimulated efflux represented a net release of calcium and could be ascribed to the slowest compartment. The physiological role of the transmitter-stimulated calcium release is discussed in terms of calcium-regulated stimulus-response coupling in glial-neural interaction during excitation.

Technique for applying neurotropic substances onto single units in awake animals

Methods are shown for the stereotaxic placement of twin cannulae, one for recording single unit activity and the other for microinjecting test substances directly on the recording site. The device is inexpensive, occupies a small space on the calvarium, and remains operational in the same animal for several months. This technique is being used to study the effects of various neurotransmitters and neuromodulators on the activity of single units in the hypothalamus of unanesthetized rabbits.

In vitro regulation of ACTH release from neurointermediate lobe of rat hypophysis. II. Effect of neurotransmitters.

The effect of various neurotransmitters on adrenocorticitropic hormone (ACTH) release from superfused neurointermediate lobes of rat hypophysis (NIL) was investigated. Acetylcholine, serotonin, and histamine were shown to have no significant effect on the spontaneous release of ACTH. In contrast, dopamine (DA) and noradrenaline (NA) stimulated NIL ACTH release in a dose-dependent manner. The stimulating effect of DA was mimicked by apomorphine and inhibited by haloperidol, whereas that of NA was abolished by phentolamine. In a comparative study, none of these neurotransmitters is shown to have any significant stimulating effect on ACTH release from superfused anterior lobes. It is concluded that the ACTH release from NIL might be controlled, at least in part, by catecholaminergic innervation.

Transmitter mediated arginine vasopressin release from superfused hypothalamus and pituitary gland.

The study was designed to investigate the effect of various neurotransmitters on the hypothalamus and pituitary gland to determine the sites of their action. Superfused isolated rat hypothalami and pituitary glands demonstrated basal secretion of arginine vasopressin (AVP) and repeated response to stimulation thus showing the viability of the preparation. Acetylcholine and histamine stimulated the release of AVP at the hypothalamic and pituitary levels; dopamine and norepinephrine released AVP in a dose related manner only from the hypothalamus; angiotensin II released AVP in the same fashion only from the pituitary gland. AVP secretion stimulated by dopamine and norepinephrine may represent synaptic inputs which are localized at the hypothalamus and must be distinguished from the site of action at the pituitary gland of angiotensin II.