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PubMed1998

Levels of monoamine and amino acid neurotransmitters in the developing male mouse hypothalamus and in histotypic hypothalamic cultures.

The variation in the levels of the monoamine and amino acid neurotransmitters was studied during the period of neurogenesis in male mouse hypothalamus, from embryonic day 15 until the age of young adult. The results shown in this study demonstrate that the monoamines appear early in the fetal brain and that the maximum expression of the catecholaminergic system, particularly that of dopamine, occurs during the late neonatal period or mouse infancy, when the role played by the catecholamines on the maturation of the neurosecretory systems is more significant. In relation to the amino acid neurotransmitters, glutamate and taurine seem to be the principal transmitters of the hypothalamus since their concentrations were about five-tenfold higher than the levels of glycine and GABA. Both amino acids had the same pattern of variation during development, showing elevated values during the prenatal, late neonatal and early pubertal period. Increased concentrations of the inhibitory neurotransmitter GABA were observed on the day before birth, at the end of the neonatal period and throughout the prepubertal period, suggesting that the influence of GABA on hypothalamic neurogenesis increases by the time when the hypothalamic nuclei have reached maturity and the local circuits have been established. To determine the intrinsic neurotransmitter production, primary hypothalamic histotypic cultures prepared from mice at postnatal days 8-10 were analyzed for their content of neurotransmitters. The in vitro analysis revealed that the hypothalamic neurons intrinsically produce dopamine, glutamate, taurine and glycine in homologable amounts with those of young adult animals. The comparative analysis also showed that about 50% of the GABA content and less than 5% of the hypothalamic epinephrine level are locally produced, while serotonin comes mainly from extrinsically located neurons.

Animals↗
PubMed2003

A novel method for noninvasive detection of neuromodulatory changes in specific neurotransmitter systems.

Over the last decade, it has become possible to study theories of cognition using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These methods yield statistical parametric maps of changes in cerebral blood flow (CBF) elicited by cognitive tasks. A limitation of these studies is that they provide no information about the underlying neurochemistry. However, it is possible to extend the concept of activation studies to include measurements targeting neurotransmitters and specific receptor populations. Cognitive activation increases neuronal firing rate, increasing the endogenous neurotransmitter level. The increased neurotransmitter level can be used to alter the kinetics of specifically bound radioligands. We describe a new approach to the design and analysis of neuromodulation experiments. This approach uses PET, a single-scan session design, and a linear extension of the simplified reference region model (LSSRM) that accounts for changes in ligand binding induced by cognitive tasks or drug challenge. In the LSSRM, an "activation" parameter is included that represents the presence or absence of change in apparent dissociation rate. Activation of the neurotransmitter is detected statistically when the activation parameter is shown to violate the null hypothesis. Simulation was used to explore the properties of the LSSRM with regard to model identifiability, effect of statistical noise, and confounding effects of CBF-related changes. Simulation predicted that it is possible to detect and map neuromodulatory changes in single-subject designs. A human study was conducted to confirm the predictions of simulation using (11)C-raclopride and a motor planning task. Parametric images of transport, binding potential, areas of significant dopamine release, and statistical parameters were computed. Examination of the kinetics of activation demonstrated that maximum dopamine release occurred immediately following task initiation and then decreased with a half-time of about 3 min. This method can be extended to explore neurotransmitter involvement in other behavioral and cognitive domains.

Adult↗
PubMed2001

Superfusion of synaptosomes to study presynaptic mechanisms involved in neurotransmitter release from rat brain.

Neurotransmitter release, as the primary way for neuron signaling, represents the target of a staggering number of studies in order to understand complex neural functions. The corpus striatum is a brain area especially rich in neurotransmitters where cholinergic neurons are supposed to play an associative role between different neuronal types, and therefore their activity is modulated by multiple neurotransmitter systems [Trends Neurosci. 17 (1994) 228; Trends Neurosci. 18 (1995) 527] [13,25]. In this regard, superfusion of synaptosomes is a useful in vitro approach to study the neurotransmitter release allowing an unequivocal interpretation of results obtained under accurately specified experimental conditions. Synaptosomes are sealed presynaptic nerve terminals obtained after homogenating brain tissue in iso-osmotic conditions [J. Physiol. 142 (1958) 187] [22]. Synaptosomes have been extensively used to study the mechanism of neurotransmitter release in vitro because they preserve the biochemical, morphological and electrophysiological properties of the synapse [J. Neurocytol. 22 (1993) 735] [42]. The superfusion, strictly a perfusion, allows both the continuous removal of the compounds present in the biophase of the presynaptic proteins and the easy exchange of the medium. We herein describe the method of superfusion of rat striatal synaptosomes to study the [(3)H]ACh release under basal and stimulated conditions. To depolarize the synaptosomal preparation three different strategies were employed: high extracellular concentration of K(+) (15 mM), a K(+) channel-blocker (4-aminopyridine, 1-30 microM), or veratridine (10 microM) which blocks the inactivation of voltage-dependent Na(+) channels.

4-Aminopyridine↗
PubMed2006

Neurotransmitter transporters and their impact on the development of psychopharmacology.

The synaptic actions of most neurotransmitters are inactivated by reuptake into the nerve terminals from which they are released, or by uptake into adjacent cells. A family of more than 20 transporter proteins is involved. In addition to the plasma membrane transporters, vesicular transporters in the membranes of neurotransmitter storage vesicles are responsible for maintaining vesicle stores and facilitating exocytotic neurotransmitter release. The cell membrane monoamine transporters are important targets for CNS drugs. The transporters for noradrenaline and serotonin are key targets for antidepressant drugs. Both noradrenaline-selective and serotonin-selective reuptake inhibitors are effective against major depression and a range of other psychiatric illnesses. As the newer drugs are safer in overdose than the first-generation tricyclic antidepressants, their use has greatly expanded. The dopamine transporter (DAT) is a key target for amphetamine and methylphenidate, used in the treatment of attention deficit hyperactivity disorder. Psychostimulant drugs of abuse (amphetamines and cocaine) also target DAT. The amino-acid neurotransmitters are inactivated by other families of neurotransmitter transporters, mainly located on astrocytes and other non-neural cells. Although there are many different transporters involved (four for GABA; two for glycine/D-serine; five for L-glutamate), pharmacology is less well developed in this area. So far, only one new amino-acid transporter-related drug has become available: the GABA uptake inhibitor tiagabine as a novel antiepileptic agent.

Amino Acid Transport Systems↗
PubMed2002

Glial uptake of neurotransmitter glutamate from the extracellular fluid studied in vivo by microdialysis and (13)C NMR.

Glial uptake of neurotransmitter glutamate (GLU) from the extracellular fluid was studied in vivo in rat brain by (13)C NMR and microdialysis combined with gas-chromatography/mass-spectrometry. Brain GLU C5 was (13)C enriched by intravenous [2,5-(13)C]glucose infusion, followed by [(12)C]glucose infusion to chase (13)C from the small glial GLU pool. This leaves [5-(13)C]GLU mainly in the large neuronal metabolic pool and the vesicular neurotransmitter pool. During the chase, the (13)C enrichment of whole-brain GLU C5 was significantly lower than that of extracellular GLU (GLU(ECF)) derived from exocytosis of vesicular GLU. Glial uptake of neurotransmitter [5-(13)C]GLU(ECF) was monitored in vivo through the formation of [5-(13)C,(15)N]GLN during (15)NH(4)Ac infusion. From the rate of [5-(13)C,(15)N]GLN synthesis (1.7 +/- 0.03 micromol/g/h), the mean (13)C enrichment of extracellular GLU (0.304 +/- 0.011) and the (15)N enrichment of precursor NH(3) (0.87 +/- 0.014), the rate of synthesis of GLN (V'(GLN)), derived from neurotransmitter GLU(ECF), was determined to be 6.4 +/- 0.44 micromol/g/h. Comparison with V(GLN) measured previously by an independent method showed that the neurotransmitter provides 80-90% of the substrate GLU pool for GLN synthesis. Hence, under our experimental conditions, the rate of 6.4 +/- 0.44 micromol/g/h also represents a reasonable estimate for the rate of glial uptake of GLU(ECF), a process that is crucial for protecting the brain from GLU excitotoxicity.

Acetates↗
PubMed2002

Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin.

Clostridial neurotoxins potently and specifically inhibit neurotransmitter release in defined cell types. Here we report that a catalytically active derivative (termed LH(N)/A) of the type A neurotoxin from Clostridium botulinum has been coupled to a lectin obtained from Erythrina cristagalli to form a novel conjugate. This conjugate exhibits an in vitro selectivity for nociceptive afferents compared with the anatomically adjacent spinal neurons, as assessed using in vitro primary neuronal culture systems to measure inhibition of release of neurotransmitters. Chemical conjugates prepared between E. cristagalli lectin and either natively sourced LH(N)/A or recombinant LH(N)/A purified from Escherichia coli are assessed, and equivalence of the recombinant material are demonstrated. Furthermore, the dependence of inhibition of neurotransmitter release on the cleavage of SNAP-25 is demonstrated through the use of an endopeptidase-deficient LH(N)/A conjugate variant. The duration of action of inhibition of neurotransmitter released by the conjugate in vitro is assessed and is comparable with that observed with Clostridium botulinum neurotoxin. Finally, in vivo electrophysiology shows that these in vitro actions have biological relevance in that sensory transmission from nociceptive afferents through the spinal cord is significantly attenuated. These data demonstrate that the potent endopeptidase activity of clostridial neurotoxins can be selectively retargeted to cells of interest and that inhibition of release of neurotransmitters from a neuronal population of therapeutic relevance to the treatment of pain can be achieved.

Animals↗
PubMedDate not supplied

Calcium channels involved in neurotransmitter release at adult, neonatal and P/Q-type deficient neuromuscular junctions (Review).

Different types of voltage-dependent calcium channels (VDCCs) have been recognized based on their molecular structure as well as their pharmacological and biophysical properties. One of these, the P/Q type, is the main channel involved in nerve evoked neurotransmitter release at neuromuscular junctions (NMJs) and many central nervous system synapses. However, under particular experimental or biological conditions, other channels can be involved. L-type VDCC presence at the NMJ has been demonstrated by the contribution to the perineural calcium currents (Ica) at adult mice Bapta-loaded NMJs. This is probably a result of a reduction in Ca(2+) inactivation. The L-type current was not coupled to neurotransmitter release, but became coupled, as demonstrated by the release of acetylcholine, after the inhibition of serine/threonine protein phosphatases with okadaic acid (OA). Thus, under these conditions, L-type channels were unmasked at Bapta- but not at Egta-loaded NMJs. This suggests that the speed, not the capacity, of the calcium chelator was decisive in preventing Ca(2+)-inactivation and facilitating the contribution to neurotransmitter release. At neonatal rat NMJs, N-type VDCCs were involved early during development whereas P/Q-type VDCCs play a main role at all stages of development. Furthermore, P/Q-type VDCCs were more efficiently coupled to neurotransmitter release than N-type VDCCs. This difference could be accounted for by a differential location of these channels at the release site. Neuromuscular transmission in P/Q-type calcium channel knock out ataxic mice jointly depends on both N-type and R-type channels and shows several altered properties including low quantal content. Thus, calcium channels may be recruited to mediate neurotransmitter release with a functional hierarchy where the P/Q channel seems to be the channel most suited to mediate exocytosis at NMJs.

Animals↗
PubMed1996

Immunohistochemical localization of neuropeptides and neurotransmitters in the nucleus solitarius.

The nucleus tractus solitarii (NTS), which receives visceral afferent information from the cardiovascular, respiratory, gastrointestinal and taste systems, contains multiple neurotransmitters and neuropeptides throughout its rostral to caudal extent. The neurotransmitters and neuropeptides immunoreactivity is located predominately in varicose fibers and small puncta throughout the neuropil. In addition, immunoreactive NTS neurons for a variety of neurotransmitters and neuropeptides are present in subnuclear regions. The neuroactive substances localized immunohistochemically in the NTS include acetylcholine, the neuropeptides, substance P, methionine- and leucine-enkephalin, beta-endorphin, cholecystokinin, neurotensin, galanin, calcitonin gene-related peptide, somatostatin, FMRMamide, neuropeptide Y, angiotensin II, vasoactive intestinal polypeptide, vasopressin, oxytocin, thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, atrial natriuretic peptide, the catecholamines, dopamine, norepinephrine, epinephrine, serotonin, histamine and the amino acids, GABA and glutamate. The pattern of innervation for each neurotransmitter and neuropeptide is not homogeneously distributed throughout the NTS. Each substance has a unique pattern within the NTS as each subnuclear region contains different immunohistochemical staining patterns and densities of fibers. At the ultrastructural level both neurotransmitters and neuropeptides are present in synaptic terminals that are in contact with different parts of the neuronal membranes. Typically, the labeled terminals contain both small, clear vesicles and large, dense core vesicles with the exception of synaptic terminals containing acetylcholine, GABA and glutamate which do not typically have the large, dense core vesicles. The most frequent post-synaptic target are dendrites and spinous processes. Less frequently, synaptic contacts are present on the cell soma.

Animals↗
PubMed2004

Altered expression of neurotransmitter-receptor subunit and uptake site mRNAs in hemimegalencephaly.

PURPOSE: Hemimegalencephaly (HMEG) is characterized by unilateral hemispheric enlargement and severe cytoarchitectural abnormalities that are highly associated with intractable epilepsy. No studies have defined alterations in neurotransmitter-receptor subunit gene expression in HMEG. We hypothesize that a differential expression of excitatory amino acid and gamma-aminobutyric acid (GABA)A-receptor subunit messenger RNAs (mRNAs) exists in HMEG. METHODS: The expression of mRNAs encoding 20 neurotransmitter-receptor subunits, synthetic enzymes, and uptake sites as well as select additional candidate genes was defined in HMEG samples (n=8) compared with homotopic control cortex specimens by using targeted complementary DNA (cDNA) arrays. Expression of GLT-1 (a glial glutamate transporter), EAAC-1 (neuronal glutamate transporter), and NMDA2B was corroborated by immunohistochemical, Western, and ligand-binding assays. RESULTS: Differential expression of 11 neurotransmitter-related mRNAs was demonstrated in HMEG compared with control cortex. For example, expression of GLT-1 and GluR6 mRNAs was enhanced, whereas diminished expression of the neuronal glutamate transporter EAAC-1, GABAAalpha2, GABAAgamma2, GABAAgamma3, NMDA2B, GluR1, GluR2, GluR4, and GluR5 subunits occurred. Reduced NMDA2B subunit mRNA expression in HMEG was confirmed by receptor ligand-binding assays by using the NMDA2B-receptor antagonist ifenprodil, which revealed barely detectable levels of NMDA2B binding compared with that in control cortex. CONCLUSIONS: Selective alterations occur in distinct neurotransmitter-receptor and -uptake sites in HMEG. Differential expression of neurotransmitter-receptor and -uptake sites in HMEG may contribute to epileptogenesis in HMEG.

Adolescent↗
PubMed2002

Perturbation of synaptic vesicle delivery during neurotransmitter release triggered independently of calcium influx.

Although much evidence suggests that calcium (Ca(2+)) usually triggers synaptic vesicle exocytosis and neurotransmitter release, the role of Ca(2+) in vesicle endocytosis and in the delivery of fusion-competent vesicles (i.e. mobilisation and/or priming) in nerve terminals remains unclear. To address this issue, we have studied synaptic vesicle dynamics in cultured rat neurones under conditions where neurotransmitter release is triggered independently of Ca(2+) using the secretagogue Ruthenium Red (RR). Using a prolonged stimulation protocol, we find that RR causes a rapid increase in neurotransmitter release followed by a gradually decrementing response. In contrast, when release is triggered by moderate membrane depolarisation caused by saline containing 18 mM K(+), release is sustained. These observations suggest that when release is triggered independently of a rise in Ca(2+), endocytosis or vesicle mobilisation/priming are perturbed. Using FM2-10, a fluorescent indicator of synaptic vesicle cycling, we find that neurotransmitter release triggered by RR is accompanied by both uptake and release of this dye, thereby suggesting that vesicle endocytosis is not blocked. To evaluate whether synaptic vesicle mobilisation/priming is perturbed in the absence of a rise in Ca(2+), we compared the kinetics of FM2-10 loss during prolonged stimulation. While 18 mM K(+) induced gradual and continuous dye loss, RR only induced substantial dye loss during the first minute of stimulation. In the presence of low concentrations of the Ca(2+) ionophore ionomycin, release caused by RR was prolonged. Taken together, these results provide evidence suggesting that, although a rise in intraterminal Ca(2+) is not required for endocytosis, it is essential for the continuous delivery of fusion-competent vesicles and to maintain neurotransmitter release during prolonged stimulation.

Animals↗
PubMed2003

Signaling pathways take aim at neurotransmitter transporters.

Neurotransmitter transporters are the target of various pharmacological agents used to treat psychological or cognitive conditions, such as depression and attention-deficit disorder. In addition, some of the effects of stimulant-type drugs of abuse result from inhibition of neurotransmitter transporters. Robinson describes the intersection between neurotransmitter transporters and signaling pathways. Neurotransmitter transporters can be regulated by altering the rate of internalization and insertion into the plasma membrane to control cell surface expression or by altering the activity of the transporters within the membrane. As the mechanisms governing regulation of these transporters become elucidated, new potential therapeutic targets may be revealed, given the many processes affected by the activity of neurotransmitter transporters.

Amino Acid Transport Systems↗
PubMed1997

A role for neurotransmitters in early follicular development: induction of functional follicle-stimulating hormone receptors in newly formed follicles of the rat ovary.

The initiation of follicular growth in the mammalian ovary is a gonadotropin-independent phenomenon. Although some of the intraovarian signaling molecules that control the later phases of this process have been recently identified, the factors involved in the acquisition of gonadotropin receptors by early growing follicles have not been fully defined. In the rat, development of the ovarian innervation precedes the onset of folliculogenesis and occurs before follicles acquire responsiveness to gonadotropins. Because vasoactive intestinal polypeptide (VIP) and norepinephrine (NE), two of the neurotransmitters contained in ovarian nerves, are present in the ovary before the gland becomes responsive to gonadotropins, we sought to determine if VIP and/or NE are able to act on early follicles to facilitate the process of molecular differentiation that leads to gonadotropin dependency. In vitro exposure of 2-day-old rat ovaries to isoproterenol (ISO), a beta-adrenoreceptor agonist, or VIP, a neurotransmitter contained in both sympathetic and sensory nerves, increased the steady state levels of the messenger RNAs encoding cytochrome P-450 aromatase (P-450arom) and FSH receptors (FSHR) within 8 h of treatment. A similar effect was observed following forskolin-induced activation of cAMP formation. In situ hybridization experiments revealed that both the P-450arom and FSHR hybridization signals were localized to follicles. The increase in FSHR messenger RNA was accompanied by formation of functional receptor molecules, as demonstrated by the ability of FSH to stimulate cAMP formation in ovaries preexposed to either ISO or VIP, but not in untreated ovaries. The stimulatory effect of ISO and VIP on the formation of FSHR coupled to the cAMP generating system was not reproduced by phenylephrine, an alpha-adrenergic agonist, or secretin, a member of the VIP family not recognized by ovarian VIP receptors. Treatment of VIP-primed ovaries with FSH resulted in follicular growth, demonstrating that exposure of the gland to the neurotransmitter led to the formation of a functional complement of FSH receptors. These results suggest that ovarian nerves, acting via neurotransmitters coupled to the cAMP generating system, contribute to the differentiation process by which newly formed primary follicles acquire FSH receptors and responsiveness to FSH. Follicles that begin to grow in more densely innervated ovarian regions, may have a selective advantage over those not exposed to neurotransmitter-activated, cAMP-dependent signals and, thus, may become more rapidly subjected to gonadotropin control.

Adrenergic beta-Agonists↗
PubMed2004

Phosphorylation by cAMP-dependent protein kinase is essential for synapsin-induced enhancement of neurotransmitter release in invertebrate neurons.

Synapsins are synaptic vesicle-associated phosphoproteins involved in the regulation of neurotransmitter release and synapse formation; they are substrates for multiple protein kinases that phosphorylate them on distinct sites. We have previously found that injection of synapsin into Helix snail neurons cultured under low-release conditions increases the efficiency of neurotransmitter release. In order to investigate the role of phosphorylation in this modulatory action of synapsins, we examined the substrate properties of the snail synapsin orthologue recently cloned in Aplysia (apSyn) for various protein kinases and compared the effects of the intracellular injection of wild-type apSyn with those of its phosphorylation site mutants. ApSyn was found to be an excellent in vitro substrate for cAMP-dependent protein kinase, which phosphorylated it at high stoichiometry on a single site (Ser-9) in the highly conserved domain A, unlike the other kinases reported to phosphorylate mammalian synapsins, which phosphorylated apSyn to a much lesser extent. The functional effect of apSyn phosphorylation by cAMP-dependent protein kinase on neurotransmitter release was studied by injecting wild-type or Ser-9 mutated apSyn into the soma of Helix serotonergic C1 neurons cultured under low-release conditions, i.e. in contact with the non-physiological target neuron C3. In this model of impaired neurotransmitter release, the injection of wild-type apSyn induced a significant enhancement of release. This enhancement was virtually absent after injection of the non-phosphorylatable mutant (Ser-9-->Ala), but it was maintained after injection of the pseudophosphorylated mutant (Ser-9-->Asp). These functional effects of apSyn injection were paralleled by marked ultrastructural changes in the C1 neuron, with the formation of extensive interdigitations of neurite-like processes containing an increased complement of C1 dense core vesicles at the sites of cell-to-cell contact. This structural rearrangement was virtually absent in mock-injected C1 neurons or after injection of the non-phosphorylatable apSyn mutant. These data indicate that phosphorylation of synapsin domain A is essential for the synapsin-induced enhancement of neurotransmitter release and suggest that endogenous kinases phosphorylating this domain play a central role in the regulation of the efficiency of the exocytotic machinery.

Animals↗
PubMed1978

Central neurotransmitter function and its behavioral correlates in man.

The past decade has witnessed a tremendous increase in knowledge towards understanding the function of various brain neurotransmitter substances in behavior. Experimental observations in animals, utilizing specific pharmacological agents, have enabled the development of certain hypotheses regarding neurochemical substrates of behavior. These have led to cautious applications of complementary studies in humans. As a result, several neurotransmitter-related hypotheses have been developed for the explanation of normal behaviour, as well as of various abnormal behavior states in psychiatry and neurology. These hypotheses are currently undergoing extensive investigation. Highlights of the above sequence of events are presented, in order to provide as general, yet extensive, an overview of the subject as possible. Examples are provided from both basic laboratory investigations and from clinical findings. Principles of brain neurotransmitter function and interactions are reviewed. Various neurotransmitter-related hypothese of psychiatric and neurologic interest are introduced. Finally, the role that toxicants may have on behavior via alteration of brain neurotransmitter function is discussed, using the lead intoxicated animals as an illustrative example.

Animals↗
PubMed2004

Neurotransmitter receptor analysis in transgenic mouse models.

One of the characteristic findings in human Huntington's disease (HD) is the alteration of neurotransmitter receptors. To a remarkable degree, transgenic HD mouse models recapitulate neurotransmitter receptor alterations. Neurotransmitter receptors can be assessed at the protein level by using receptor-binding autoradiography. One can also measure levels of receptor messenger RNA with in situ hybridization (ISH), employing either oligonucleotide or ribonucleotide probes. Both of these techniques-receptor-binding autoradiography and in situ hybridization-yield quantitative and regionally specific information regarding neurotransmitter receptors. We describe techniques for performing receptor-binding autoradiography and two types of in situ hybridization using oligonucleotide and ribonucleotide probes. With receptor binding and ISH, one can obtain quantitative region-specific assessments of neurotransmitter receptor alteration, a key pathologic event in HD pathogenesis.

Animals↗
PubMed1996

Clinical applications of neurotransmitter-receptor studies in geriatric neuropharmacology.

The use of ligand-binding methods to study neurotransmitter-receptor sites has made its impact on almost all aspects of biological pursuits including research on aging and neurodegenerative diseases. In the past, most of the research in biochemical gerontology has largely centered around changes in various neurotransmitters and enzymatic activities. The molecular basis of aging and neurodegeneration at the level of neurotransmitter-receptor interactions has been highly appreciated in the last two decades as a result of receptor binding studies. It is now possible to obtain information about the regional distribution of neurotransmitter receptors in the brain, the pharmacological and biochemical characteristics of these sites, and the functional interrelationships between different neuronal systems in normal and pathological conditions. The passage of time after maturity is accompanied by measurable physiologic decline in virtually all systems. It is the aim of this work to discuss the practical aspects of neurotransmitter and/or drug (ligand)-receptor binding studies, highlighting some examples of their applications to geriatric neuropharmacology research, with special consideration to learning impairment and memory loss in normal and in pathological aging processes.

Aged↗
PubMed1994

Adrenergic and nitrergic neurotransmitters are released by the autonomic system of the pig long posterior ciliary artery.

The role played by adrenergic, muscarinic and nitric oxide putative neurotransmitters released from autonomic nerve endings onto the pig proximal long posterior ciliary artery (LPCA) was determined. The proximal LPCA in the pig usually supplies both the uveal and retinal circulations. In this study, in vitro ring segments of the artery, passively stretched and with noradrenaline-induced tone, were neurogenically stimulated (NS) using electrical field stimulation with 5-sec trains of 0.2 msec pulses. NS produced a frequency dependent contraction in all vessels which was completely abolished by 10(-6) M tetrodotoxin. 40 Hz stimulation was used throughout the study as it produced a maximal NS contraction. 10(-5) M guanethidine abolished the NS-induced contraction and revealed a NS-induced relaxation, as did the alpha adrenergic blocker, phentolamine, in vessels passively stretched. The beta adrenergic blocker, propranolol, only slightly reduced the NS-induced constriction. In vessels pre-contracted with noradrenaline, NS produced a relaxation (D) which was proportional in magnitude to the tone (C) viz. D = (0.30 +/- 0.04).C + (0.24 +/- 0.06). The muscarinic blocker, atropine, had no effect on the NS-induced relaxation, implying that it is a non-adrenergic, non-cholinergic mediated system. Incubation with Nw-nitro-L-arginine methyl ester reduced the NS-induced relaxation to 48% of its control value, a reduction which was reversed in the presence of excess L-arginine. Damage to endothelial cell function did not reduce the NS-induced relaxation. It is concluded that the autonomic innervation of the proximal LPCA releases both contraction and relaxation neurotransmitters. Contraction is mediated by an alpha adrenergic neurotransmitter. At least two neurotransmitters mediate relaxation, one of which is probably nitric oxide. There is no functional evidence for the release of beta adrenergic neurotransmitter from the sympathetic system or acetylcholine from the parasympathetic system.

Acetylcholine↗
PubMed1998

Why do neurotransmitters act like growth factors?

It is now well established that neurotransmitters act as growth-regulatory signals for neuronal and non-neuronal cells of both primitive and higher organisms, where they control cell proliferation, motility, survival, growth, differentiation, and gene expression. Many of these actions are reminiscent of the actions of other growth-regulatory signals such as growth factors, neurotrophins, and proto-oncogenes. How, then, do neurotransmitters exert these effects? Although some information is available concerning second messengers activated by these neurotransmitters in developing cells, little is known about subsequent steps involving signal transduction cascades leading to their final outcomes. This review attempts to provide testable hypotheses regarding possible cellular and molecular mechanisms downstream of second messengers activated by neurotransmitters, based on recent insights into signal transduction cascades activated by classical growth-regulatory signals. In many cases, there are clear points of convergence between these pathways, raising the interesting possibility that neurotransmitters and other growth-regulatory signals may cooperate to regulate developmental functions of cells and tissues.

Animals↗