Neurotransmission

This study investigated event-related potential (ERP) indices of information processing in sufferers of posttraumatic stress disorder (PTSD ). ERPs were obtained from 18 PTSD patients and 20 controls while they performed a target discrimination task requiring the detection of infrequent target tones from a background sequence of frequent and infrequent distractor tones. A delayed N2 and an attenuated P3 that failed to differentiate target from distractor tones indicated that patients had abnormal difficulty distinguishing task stimuli of differing relevance. It is proposed that this difficulty is reflected behaviorally in the slowed reaction time by patients to target stimuli and may underlie the disturbed concentration and memory impairments found in PTSD. It may also be related to dysfunction in central noradrenaline function, which has been shown to be both crucial in selective attention and abnormal in PTSD.

Recent advances in the study of alcoholism have thrown
light on the involvement of various neurotransmitters in the
phenomenon of alcohol addiction. Various neurotransmitters
have been implicated in alcohol addiction due to their
imbalance in the brain, which could be either due to their
excess activity or inhibition. This review paper aims to
consolidate and to summarize some of the recent papers
which have been published in this regard. The review
paper will give an overview of the neurobiology of alcohol
addiction, followed by detailed reviews of some of the recent
papers published in the context of the genetics of alcohol
addiction. Furthermore, the author hopes that the present
text will be found useful to novices and experts alike in the
field of neurotransmitters in alcoholism.

Neurochemistry and drug addiction. Neurocognitive approach. Cognitive Neuroscience. Research for the Postgraduate Program in Cognitive Sciences of the University of Costa Rica. This research establishes a theoretical basis for the biochemical and neurophysiological bases of behavior and mental phenomena, as well as analyzing the neuropathologies derived from the consumption of toxic substances. Plausible explanations are given for the relationships between toxic and addictive and addictive behaviors, and their neurophysiological and genetic bases. // Neuroquímica y toxicodependencia. Enfoque de neurocognoscitivo.  Neurociencias Cognoscitivas. Investigación para el Programa de Postgrado en Ciencias Cognoscitivas de la Universidad de Costa Rica.  Esta investigación, establece una fundamenta teórica de las bases bioquímicas y neurofisiológicas de la conducta y de los fenómenos mentales, así como analiza las neuropatologías derivadas del consumo de tóxicos. Se plantean explicaciones plausibles de las relaciones entre tóxicos y conductas dependientes y adictivas, y sus bases neurofisiológicas y genéticas. // Rodolfo J. Rodríguez-Rodríguez. E-Mail: [email protected]

Decades of research on schizophrenia have not produced major breakthroughs, but gradual progress has been made in identifying risk factors and clarifying the nature of the etiologic process. This article provides an overview of trends in research findings as well as current assumptions about the interplay between environmental and genetic factors in the etiology of schizophrenia. Based on the cumulative findings, it appears that both genetic and prenatal factors can give rise to constitutional vulnerability. Subsequent neuromaturational processes, especially those that occur during adolescence, and exposure to stressful events can trigger the behavioral expression of this vulnerability.

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine.

Although the second-generation or atypical antipsychotic drugs have been breakthrough medicines for the treatment of schizophrenia and other psychotic conditions, cognitive dysfunction and to some extent negative symptoms of the disease continue to be the main cause of poor vocational status of the patients. Thus, the majority of investigational drug development efforts today target these unmet medical needs. This review postulates that the field of schizophrenia research has advanced sufficiently to develop biochemical hypotheses of the etiopathology of the disease and target the same for revolutionary disease modifying therapy. This postulate is based on recent studies that have begun to provide a testable etiopathology model that integrates interactions between genetic vulnerability factors, neurodevelopmental anomalies, and neurotransmitter systems. This review begins with a brief overview of the nosology and etiopathology of schizophrenia and related psychotic disorders to esta...

Sensitive skin is a condition of subjective cutaneous hyper-reactivity to environmental factors. Subjects experiencing this condition report exaggerated reactions when their skin is in contact with cosmetics, soaps and sun screens, and they often report worsening after exposure to dry and cold climate. Although no sign of irritation is commonly detected, itching, burning, stinging and a tight sensation are constantly present. Generally substances that are not commonly considered irritants are involved in this abnormal response.Sensitive skin and subjective irritation are widespread but still far from being completely defined and understood. A correlation between sensitive skin and constitutional anomalies and/or other triggering factors such as occupational skin diseases or chronic exposure to irritants has been hypothesized. Recent findings suggest that higher sensitivity can be due to different mechanisms. Hyper-reactors may have a thinner stratum corneum with a reduced corneocyte area causing a higher transcutaneous penetration of water-soluble chemicals. Alterations in vanilloid receptors and changes in neuronal transmission have been described. Monitoring skin parameters such as barrier function, proclivity to irritation, corneocyte size and sensorial transmission can also be useful to identify regional differences in skin sensitivity.

Child abuse is associated with markedly elevated rates of major depression and other psychiatric disorders in adulthood. This article reviews preclinical studies examining the effects of early stress, factors that modify the impact of these experiences, and neurobiological changes associated with major depression. Preclinical studies demonstrate that early stress can alter the development of the hypothalamic-pituitary-adrenal axis, hypothalamic and extrahypothalamic corticotropin releasing hormone, monoaminergic, and ␥-aminobutyric acid/benzodiazepine systems. Stress has also been shown to promote structural and functional alterations in brain regions similar to those seen in adults with depression. Emerging data suggest, however, that the long-term effects of early stress can be moderated by genetic factors and the quality of the subsequent caregiving environment. These effects also can be prevented or reversed with various pharmacologic interventions. Preclinical studies of early stress can provide valuable insights in understanding the pathophysiology and treatment of major depression. They also can provide an important tool to use to investigate interactions between genes and environments in determining an individual's sensitivity to stress. More research is needed to understand how inherent factors interact with experiences of abuse and other psychosocial factors to confer vulnerability to develop depression. Biol Psychiatry 2000;48: 778 -790

To understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and song production. In this review, we bring together the two fields of investigations of dopamine action on voice control in humans and songbirds, who share similar behavioral and neural mechanisms for speech and song production. While human studies investigating the role of dopamine in speech control are limited to reports in neurological patients, research on dopaminergic modulation of bird song control has recently expanded our views on how this system might be organized. We discuss the parallels between bird song and human speech from the perspective of dopaminergic control as well as outline important differences between these species. and bats has provided some insights into the similarities and differences of their vocal motor pathways, which may lay a foundation for the understanding of the specialized control of their learned voice production.

This paper introduces a new model of artificial cognitive architecture for intelligent systems, the Neuromodulating Cognitive Architecture (NEUCOGAR). It is biomimetically inspired and adapts the neuromodulators role of human brains into computational environments. This way we aim at achieving more efficient Artificial Intelligence solutions based on the biological inspiration of the deep functioning of human brain, which is highly emotional. The analysis of new data obtained from neurology, psychology and even philosophical or anthropological contributions of the study of the emotion role into cognitive processes allow us to generate a mapping of monoamine neuromodulators and to apply it to computational system parameters. Thus we can make artificial cognitive systems that better perform more complex tasks (regarding information selection and discrimination, attention, innovation, creativity,) as well as able to show affordable emotional relationships with human users.

The existence of neurotransmitter receptor heteromers is becoming broadly accepted and their functional significance is being revealed. Heteromerization of neurotransmitter receptors produces functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Neurotransmitter receptor heteromers can function as processors of computations that modulate cell signaling. Thus, the quantitative or qualitative aspects of the signaling generated by stimulation of any of the individual receptor units in the heteromer are different from those obtained during coactivation. Furthermore, recent studies demonstrate that some neurotransmitter receptor heteromers can exert an effect as processors of computations that directly modulate both pre-and postsynaptic neurotransmission. This is illustrated by the analysis of striatal receptor heteromers that control striatal glutamatergic neurotransmission.

Positron emission tomography (PET) and single photon emission tomography (SPECT) are the most sensitive techniques to study, in vivo, neurotransmitter systems in normal human brain and in diseases. These methods have been applied over the last years to explore the integrity of cholinergic, serotonergic, GABAergic, and dopaminergic systems in Alzheimer's disease (AD) and in other dementias. The results of these investigations have provided new insights into the neurotransmission involvement in these disorders. Moreover, these methods provide objective quantitative markers for monitoring the progression of disease and the effects of therapies. The pathophysiological and clinical relevance of results from these studies are reviewed and the potential role in early and differential diagnosis discussed. New emerging radiotracers/methods for future investigations of neurochemical processes are delineated.

The 110-year-old metabolic hypothesis of Roy and Sherrington cannot fully explain the increases of cerebral blood flow (CBF) during increased functional activity of the central neurons. CBF may increase (a) much faster than the accumulation of the metabolic end products, (b) out of proportion to metabolic demands, (c) without significant change in local metabolism. The tight coupling of neuronal activity and blood flow in the brain is demonstrated by a large amount of data. Perivascular nerve endings were identified in the outer smooth muscle layer of the pial and intraparenchymal vessels. Their axon terminals contain a large variety of neurotransmitters, often co-localized in synaptic vesicles. Stimulation of the nerves results in a release of transmitters into the 80 -100-nm neuromuscular synaptic clefts, and their specific receptors were identified in the vessel wall. There is ample evidence to suggest that neurogenic stimuli via perivascular nerve endings may act as rapid initiators, inducing a moment-to-moment dynamic adjustment of CBF to the metabolic demands, and further maintenance of these adjusted parameters is ensured by the metabolic and chemical factors. The significance of the perivascular nerves in the regulation of the cerebral blood flow, however, is either underestimated or completely neglected in the majority of textbooks for both medical students and clinicians. Since the regulatory role of the nervous system in the cerebrovascular bed has been fully appreciated among investigators in the last decades, revision of this antiquated view of the common medical knowledge is urgent. D

Recent evidences suggest that glutamatergic dysregulation implicated in neural plasticity and cellular resilience may contribute to the pathophysiology of Major Depressive Disorder (MDD). Riluzole, which exerts its effect by targeting glutamate neurotransmission, has shown antidepressant effect in recent preclinical, observational and open label studies. This study aimed to assess the efficacy and tolerability of riluzole in patients with MDD. Sixty-four inpatients with diagnosis of moderate to severe major depressive disorder participated in a parallel, randomized, controlled trial, and sixty patients underwent 6 weeks treatment with either riluzole (50 mg/bid) plus citalopram (40 mg/day) or placebo plus citalopram (40 mg/day). All participants were inpatients for the whole duration of the study. Patients were assessed using Hamilton depression rating scale (HDRS) at baseline and weeks 2, 4 and 6. The primary outcome measure was to assess the efficacy of riluzole compared to placebo in improving the depressive symptoms. General linear model repeated measures demonstrated significant effect for time _ treatment interaction on HDRS [F (1.86, 107.82) ¼ 8.63, p < 0.001]. Significantly greater improvement was observed in HDRS scores in the riluzole group compared to the placebo group from baseline HDRS score at weeks 2, 4 and 6 (p < 0.001, p ¼ 0.001, p ¼ 0.002, respectively). Significantly greater response with greater speed to treatment was observed in the riluzole group than the placebo group. No serious adverse event occurred. This study showed a favorable safety and efficacy profile in patients with major depressive disorder. Larger controlled studies with longer treatment periods are needed to investigate long term safety, efficacy and optimal dosing.

Ascorbic acid is highly concentrated in the brain, being considered as a neuromodulator. This study investigated the effect of ascorbic acid in the tail suspension test (TST) and in the forced swimming test (FST) in mice and the contribution of the monoaminergic system to its antidepressant-like effect. Moreover, the effects of fluoxetine, imipramine and bupropion in combination with ascorbic acid in the TST were investigated. Ascorbic acid (0.1-10 mg/kg, i.p., 1-10 mg/kg p.o. or 0.1 nmol/mice i.c.v.) produced an antidepressant-like effect in the TST, but not in the FST, without altering the locomotor activity. The effect of ascorbic acid (0.1 mg/kg, i.p.) in the TST was prevented by i.p. pre-treatment with NAN-190 (0.5 mg/kg), ketanserin (5 mg/kg), MDL72222 (0.1 mg/kg), prazosin (62.5 µg/kg), yohimbine (1 mg/kg), propranolol (2 mg/kg), haloperidol (0.2 mg/kg), sulpiride (50 mg/kg), but not with SCH23390 (0.05 mg/kg, s.c.). Additionally, ascorbic acid (1 mg/kg, p.o.) potentiated the effect of subeffective doses (p.o. route) of fluoxetine (1 mg/kg), imipramine (0.1 mg/kg), or bupropion (1 mg/kg) in the TST. The combined treatment of ascorbic acid with antidepressants produced no alteration in the locomotion in the open-field test. In conclusion, our results show that administration of ascorbic acid produces an antidepressant-like effect in TST, which is dependent on its interaction with the monoaminergic system. Moreover, ascorbic acid caused a synergistic antidepressant-like effect with conventional antidepressants. Therefore, the present findings warrant further studies to evaluate the therapeutical relevance of ascorbic acid for the treatment of depression and as a co-adjuvant treatment with antidepressants.

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment 1,2 . A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology 3-7 . Facilitation of spinal c-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA A receptors should be able to compensate for this loss . With the use of GABA Areceptor point-mutated knock-in mice in which specific GABA A receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands 10-12 , we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA A receptors containing the a2 and/or a3 subunits. We show that their selective activation by the non-sedative ('a1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.

In Greek, the word “nature” derives from the verb phyō, to come forth, to grow, to become. It is life independent of thought, and non-constructed. Aristotle calls physis “the coming-to-be what it is” (1960: 193a). Nature as physis contains both the movement of emergence and the specific growth, becoming and being, productivity and product. Growth in this context implies that withering and demise belong to it; genesis is always phthora, decay is integral to the act of coming-to-light. In pre-Socratic thought, the human being is seen as part of physis, which contains the human as a whole and in his/her individuality. The focus of the Roman words nasci and natura is, however, on being conceived and being born. Natura now means “native” and “inherent,” but is also defined in terms of the right of disposal, which influenced the formation of the modern term of object (cf. Picht 1998: 90). Nature as the quintessence of objects is nature as the sum of everything that is at our disposal in thought and action.

Plus de 50 ans après la découverte des effets cliniques de la chlorpromazine et du lithium, les mécanismes moléculaires par lesquels les médicaments psychotropes exercent leurs actions thérapeutiques dans des pathologies comme la dépression, la schizophrénie ou encore les troubles bipolaires, restent mal compris. La découverte des récepteurs et des transporteurs des neurotransmetteurs de la famille des monoamines (dopamine, sérotonine et noradrénaline) a permis d'identifier les cibles pharmacologiques primaires de plusieurs de ces drogues, ce qui a favorisé la mise au point de nouveaux composés. Les monoamines activent principalement des récepteurs à sept domaines transmembranaires couplés à des protéines G (RCPG). Des études récentes ont révélé que ces récepteurs régulent des mécanismes cellulaires d'une grande complexité où interviennent non seulement les protéines G mais aussi des protéines de signalisation comme les bêta-arrestines (Arr) qui peuvent agir indépendamment . De plus, certains récepteurs régulent des cibles communes, ouvrant ainsi la porte à des mécanismes d'intégration des voies de signalisation subcellulaires . Il apparaît donc important d'examiner le rôle de ces différents mécanismes de signalisation sur les effets comportementaux que produisent des médicaments psychotropes, de manière à augmenter leur efficacité thérapeutique tout en réduisant leurs effets secondaires. Parmi les molécules de signalisation affectées par les médicaments psychotropes, la voie constituée par les protéine kinases Akt et glycogen synthase kinase 3 (GSK3) semble jouer un rôle important dans la régulation du comportement par la dopamine et la sérotonine . Akt, aussi appelée protéine kinase B (PKB), est une sérine/thréonine kinase activée en réponse à la stimulation de la voie des phosphatidylinositol phosphates. À la suite de son activation , Akt va phosphoryler les deux isoformes, alpha et bêta, de GSK3 dans leur domaine aminoterminal, menant ainsi à leur inactivation . Dans cette courte synthèse, nous ferons un survol des mécanismes par lesquels la dopamine et la sérotonine régulent la voie Akt/GSK3, nous considérerons également la contribution de la voie Akt/GSK3 dans l'action qu'exercent plusieurs catégories de médicaments employés en psychiatrie.

Interstitial cells of Cajal (ICC) are proposed to play a role in stretch activation of nerves and are under intense investigation for potential roles in enteric innervation. Most data to support such roles comes from in vitro studies with muscle strips while data at the whole organ level are scarce. To obtain insight into the role of ICC in distention-induced motor patterns developing at the organ level, we studied distension-induced adaptive relaxation in the isolated whole stomach of wild-type and W/W v mice. A method was developed to assess gastric adaptive relaxation that gave quantitative information on rates of pressure development and maximal adaptive relaxation. Pressure development was monitored throughout infusion of 1 ml solution over a 10 min period. The final intraluminal pressure was sensitive to blockade of nitric oxide synthase, in wildtype and W/W v mice to a similar extent, indicating NO mediated relaxation in W/W v mice. Adaptive relaxation occurred between 0.2 and 0.5 ml solution infusion; this reflex was abolished by TTX, was not sensitive to blockade of nitric oxide synthase but was abolished by apamin, suggesting that ATP and not nitric oxide is the neurotransmitter responsible for this intrinsic reflex. Despite the absence of intramuscular ICC (ICC-IM), normal gastric adaptive relaxation occurred in the W/W v stomach. Since pressure development was significantly lower in W/W v mice compared to wild-type in all the conditions studied, including in the presence of TTX, ICC-IM may play a role in development of myogenic tone. In conclusion, a mouse model was developed to assess the intrinsic component of gastric accommodation. This showed that ICC-IM are not essential for activation of intrinsic sensory nerves nor ATP driven adaptive relaxation nor NO mediated relaxation in the present model. ICC-IM may be involved in regulation of myogenic tone.

The 65 kDa human isoform of glutamate decarboxylase, GAD65, plays a central role in neurotransmission in higher vertebrates and is a typical autoantigen in several human autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM), Stiff-man syndrome and autoimmune polyendocrine syndrome type I. In autoimmune diabetes, an attack of inflammatory cells to endocrine pancreatic ␤-cells leads to their complete destruction, eventually resulting in the inability to produce sufficient insulin for the body's requirements. Even though the etiology of ␤-cell destruction is still a matter of debate, the role and antigenic potency of GAD65 are widely recognized. Herein a model of GAD65 is presented, which is based on the recently solved crystal structures of mammalian DOPA decarboxylase and of bacterial glutamate decarboxylase. The model provides for the first time a detailed and accurate structure of the GAD65 subunit (all three domains) and of its dimeric quaternary assembly. It reveals the structural basis for specific antibody recognition to GAD65 as opposed to GAD67, the other human isoform, which shares 81% sequence similarity with GAD65 and is much less antigenic. Literature data on monoclonal antibody binding are perfectly consistent with the detailed features of the model, which allows explanation of several findings on GAD65 immunogenicity. Importantly, by analyzing the active site, we identified the residues most likely involved in catalysis and substrate recognition, paving the way for rational mutagenesis studies of the GAD65 reaction mechanism, specificity and inhibition. Proteins 2005;59:7-14.

Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

The role of adenosine A 3 receptors in synaptic transmission under severe (7 min) and shorter (2-5 min) ischemic conditions, obtained by oxygen and glucose deprivation (OGD), was investigated in rat hippocampal slices. The effects of selective A 3 agonists or antagonists were examined on field excitatory postsynaptic potentials (fEPSPs) extracellularly recorded at the dendritic level of the CA1 pyramidal region. The novel, selective A 3 antagonist LJ1251 ((2R,3R,4S)-2-(2-chloro-6-(3iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol, 0.1-10 nM) protected hippocampal slices from irreversible fEPSP depression induced by severe OGD and prevented or delayed the appearance of anoxic depolarization. Similar results were obtained when severe OGD was carried out with a long, receptor-desensitizing exposure to various selective A 3 agonists: 5′-Nmethylcarboxamidoadenosine derivatives Cl-IB-MECA (N 6-(3-iodobenzyl)-2-chloro), VT72 (N 6methoxy-2-phenylethynyl), VT158 (N 6-methoxy-2-phenylethynyl), VT160 (N 6-methoxy-2-(2pyridinyl)-ethynyl), and VT163 (N 6-methoxy-2-p-acetylphenylethynyl) and AR132 (N 6-methyl-2phenylethynyladenosine). The selective A 3 antagonist MRS1523 (3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4propyl-3-pyridine carboxylate, 100 nM) reduced fEPSP depression evoked by 2-min OGD and induced a faster recovery of fEPSP amplitude after 5-min OGD. Similar results were obtained for 2or 5-min OGD applied in the presence of each of the A 3 agonists tested. Shorter exposure to A 3 agonists significantly delayed the recovery of fEPSP amplitude after 5-min OGD. This indicates that A 3 receptors, stimulated by selective A 3 agonists, undergo desensitization during OGD. It is inferred that CA1 hippocampal A 3 receptors stimulated by adenosine released during brief ischemia (2 and 5 min) might exert A 1-like protective effects on neurotransmission. Severe ischemia would transform the A 3 receptor-mediated effects from protective to injurious.

La Société de Biologie aété le théâtre de nombreuses polémiques au sujet du mode d'action du curare pendant plus de trente années. Après une période de mise au point technique des protocoles d'empoisonnement sur divers animaux,à laquelle contribuent Claude Bernard, Vulpian et leurs collègues, succède une autre, où l'électrophysiologie allemande entre en scène, se combine avec les nouvelles données histologiques sur les plaques motrices, pour soutenir les vues de physiologistes plus jeunes qui s'affrontentà Claude Bernard et finissent par le convaincre. Selon eux, Vulpian en premier lieu, le curare abolit la transmission entre la plaque motrice et le muscle. Cette premièreébauche d'une théorie de la neurotransmission nous aidè a comprendre comment une nouvelle physiologie se met en place dans le sillage de l'école bernardienne par une meilleure intégration des disciplines, une foi plus grande accordée au réductionnisme et au matérialisme.

Stereotaxic injections of pertussis toxin (3-4 micrograms) over the right hippocampus resulted in blockade of long-term potentiation (LTP) induction in the ipsilateral stratum radiatum-CA1 and stratum oriens-CA1 synaptic systems. LTP of intracellularly recorded excitatory postsynaptic potentials was prevented in slices obtained from the hippocampus at 3 and 4 but not 6 days post-toxin injection. Slices taken from the left (contralateral) hippocampus on the same days as above exhibited LTP which was similar to that obtained in control slices from uninjected rats. The post- but not presynaptic actions of adenosine were antagonized at 3, 4 and 6 days post-toxin injection. The observations suggest that the guanosine triphosphate binding proteins involved in LTP induction (GLTP) and those coupled to the postsynaptic adenosine receptors exhibit different turnover times.

Los fenómenos que implican cambios inesperados del reforzamiento comparten la característica principal de presentar una discrepancia entre la recompensa que los animales esperan y la que efectivamente reciben. En consecuencia, el comportamiento se modifica en función de esta diferencia, y los animales presentan una respuesta emocional ante el cambio sorpresivo del reforzador, comúnmente denominada frustración. Algunos de los paradigmas que se utilizan habitualmente para estudiar estos problemas son: el Contraste Sucesivo Negativo consumatorio y la Extinción consumatoria. En esta revisión se describen los principales trabajos realizados para investigar los mecanismos neuroanatómicos y neurofisiológicos involucrados en estos estudios, y aquellos orientados a la manipulación de drogas que modulan la memoria de los cambios sorpresivos del reforzamiento. Neurobiological basis of frustration: The main feature shared by the phenomena involving unexpected changes of reinforcement is that there is a discrepancy between expected and received reward. Consequently, the behavior is modified according to this difference; the animals have an emotional response to the surprising reward change, called frustration. Some of the paradigms that are commonly used to study these problems are: consummatory Successive Negative Contrast and consummatory Extinction. This review describes the major works that investigate the neuroanatomical and neurophysiological mechanisms involved in these studies, and the main tasks related with the administration of drugs that modulate the memory of the surprising reward changes.

Rod and cone photoreceptors possess ribbon synapses that assist in the transmission of graded light responses to second-order bipolar and horizontal cells of the vertebrate retina. Proper functioning of the synapse requires the juxtaposition of presynaptic release sites immediately adjacent to postsynaptic receptors. In this review, we focus on the synaptic, cytoskeletal, and extracellular matrix proteins that help to organize photoreceptor ribbon synapses in the outer plexiform layer. We examine the proteins that foster the clustering of release proteins, calcium channels, and synaptic vesicles in the presynaptic terminals of photoreceptors adjacent to their postsynaptic contacts. Although many proteins interact with one another in the presynaptic terminal and synaptic cleft, these protein–protein interactions do not create a static and immutable structure. Instead, photoreceptor ribbon synapses are remarkably dynamic, exhibiting structural changes on both rapid and slow time scales.

Neurobehavioral disorders, except their most overt form, tend to lie beyond the reach of clinicians. Presently, the use of molecular data in the decision-making processes is limited. However, as details of the mechanisms of neurotoxic action of aluminium become clearer, a more complete picture of possible molecular targets of aluminium can be anticipated, which promises better prediction of the neurotoxicological potential of aluminium exposure. In practical terms, a critical analysis of current data on the effects of aluminium on neurotransmission can be of great benefit due to the rapidly expanding knowledge of the neurotoxicological potential of aluminium. This review concludes that impairment of neurotransmission is a strong predictor of outcome in neurobehavioral disorders. Key questions and challenges for future research into aluminium neurotoxicity are also identified.

Intercellular purinergic signalling, which utilizes ATP as a transmitter, is fundamental for the operation of the autonomic nervous system. ATP is released together with 'classical' transmitters from sympathetic and parasympathetic nerves supplying various peripheral targets, modulates neurotransmission in autonomic ganglia, has an important role in local enteric neural control and coordination of intestinal secretion and motility, and acts as a common mediator for several distinct sensory modalities. Recently, the role of ATPmediated signalling in the central nervous control of autonomic function has been addressed. Emerging data demonstrate that in the brain ATP is involved in the operation of several key cardiorespiratory reflexes, contributes to central processing of viscerosensory information, mediates central CO 2 chemosensory transduction and triggers adaptive changes in breathing, and modulates the activities of the brainstem vagal preganglionic, presympathetic and respiratory neural networks.

The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA is critically implicated also in higher-order cognitive functioning. Many cognitive functions and multiple markers of striatal and extrastriatal DA systems decline across adulthood and aging. Research examining the correlative triad among adult age, DA, and cognition has found strong support for the view that age-related DA losses are associated with age-related cognitive deficits. Future research strategies for examining the DA-cognitive aging link include assessing (a) the generality/specificity of the effects; (b) the relationship between neuromodulation and functional brain activation; and (c) the release of DA during actual task performance. r

We identified CAPS1 (calcium-dependent activator protein for secretion) as a D2 dopamine receptor interacting protein (DRIP) in a yeast two-hybrid screen of a human brain library using the second intracellular domain of the human D2 receptor (D2IC2). CAPS1 is an evolutionarily conserved calcium binding protein essential for late-stage exocytosis of neurotransmitters from synaptic terminals. CAPS1 interaction was confirmed for both the long and short isoforms of the D2 receptor, but not with any other dopamine receptor subtype. Interaction between CAPS1 and the D2 receptor was validated using both pulldown and coimmunoprecipitation assays. Deletion mapping localized the D2 receptor binding site to a segment located within the C-terminal region of CAPS1 as well CAPS2. In PC12 cells, CAPS1 and D2 receptors were found to colocalize within both cytosolic and plasma membrane compartments. Overexpression of a truncated D2 receptor fragment caused a significant decrease in K + -evoked dopamine release from PC12 cells, whereas no effect on norepinephrine or BDNF release was observed. These results suggest that D2 dopamine receptors may modulate vesicle release from neuroendocrine cells via direct interaction with components of the exocytotic machinery #

Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessivecompulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D 2 receptors (D 2-R's), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DA rel) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT 2A receptors (5-HT 2A R), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DA rel was significantly increased in the ventral striatum among subjects with TS. Adults with TS + OCD exhibited a significant D 2-R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS + OCD and TS-OCD). In three subjects with TS + OCD, in whom D 2-R, 5-HT 2A R, and SERT were measured within a 12-month period, there was a weakly significant elevation of DA rel and 5-HT 2A BP, when compared with TS-OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DA rel is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT 2A R in individuals with TS who had increased DA rel , suggest a condition of increased phasic DA rel modulated by low 5-HT in concomitant OCD.

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The effects of ethanol in vitro on calmodulin-dependent Ca2+-activated ATPase (CaM-Ca2+-ATPase) activity were studied in synaptic plasma membranes (SPM) prepared from the brain of normal and chronically ethanol-treated rats. In SPM from normal animals, ethanol at 50-200 mM inhibited the Ca2+-ATPase activity. Lineweaver-Burk analysis indicates that the inhibition was the result of a decreased affinity of the enzyme for calmodulin, whereas the maximum activity of the enzyme was not changed. Arrhenius analysis indicates that the enzyme activity was influenced by lipid transition of the membranes, and ethanol in vitro resulted in a shift of the transition temperature toward a lower value. From animals receiving chronic ethanol treatment (3 weeks), the SPM were resistant to the inhibitory effect of ethanol on the enzyme activity. The resistance to ethanol inhibition was correlated with a higher enzyme affinity for calmodulin and a higher transition temperature, as compared with normal SPM. Since the calmodulin-dependent Ca2+-ATPase in synaptic plasma membranes is believed to be the Ca z+ pump controlling free Ca 2 § levels in synaptic terminals, its inhibition by ethanol could therefore lead to altered synaptic activity. 475 cell types, is dependent upon calmodulin for its activity (4-6). By analogy with the plasma membrane CaZ+-ATPases of other cell types such as erythrocytes, it has generally been agreed that this calmodulin-dependent Ca e+activated ATPase (CaM-CaZ+-ATPase) in SPM also functions as the Ca 2+ pump to regulate intracellular Ca 2+ levels and thus plays a major role in synaptic activity.

In the present study, we report the effect of insular cortex (IC) ablation caused by bilateral microinjection of the non-selective synaptic blocker CoCl 2 on cardiac baroreflex response in unanesthetized rats as well as the involvement of local glutamatergic neurotransmission. Unilateral (left or right) microinjection of CoCl 2 (1 nmol/ 100 nL) did not affect the bradycardiac response to blood pressure increase evoked by intravenous infusion of phenylephrine nor the tachycardiac response to blood pressure decrease caused by intravenous infusion of sodium nitroprusside, 10 min after CoCl 2 . Bilateral microinjection of CoCl 2 into IC decreased the magnitude of reflex bradycardia without affecting tachycardiac responses. Baroreflex activity returned to control values 60 min after CoCl 2 microinjection, confirming its reversible effect. Further we studied the possible involvement of IC-glutamatergic neurotransmission in baroreflex modulation. We observed that bilateral microinjection of the selective NMDA receptor antagonist LY235959 (4 nmol/100 nL) into the IC decreased the magnitude of reflex bradycardia without affecting tachycardiac responses. IC treatment with the selective non-NMDA antagonist NBQX (4 nmol/100 nL) did not affect baroreflex activity. The results suggest that synapses within the IC have a tonic excitatory influence on the baroreflex parasympathetic component. Moreover, the present data suggest that local NMDA-receptors are involved in the ICmediated tonic excitatory influence on baroreflex parasympathetic activity.

The skewed amplitude distribution of spontaneous excitatory junction potentials (sEJPs) in the mouse vas deferens and other electrically-coupled smooth muscle syncytia has been attributed to electrically-attenuated depolarizations resulting from the spontaneous release of quantized packets of ATP acting on remote smooth muscle cells (SMCs). However, in the present investigation surface SMCs of the mouse isolated vas deferens were poorly electrically coupled, with input resistances (176±18 MΩ, range: 141-221 MΩ, n=4) similar to those of dissociated cells. Furthermore, the amplitude of evoked EJPs was more variable in surface compared with deeper SMCs (F test, F=17.4, P<0.0001). Using simultaneous electrophysiology and confocal microscopy to investigate these poorly-coupled cells, it is shown that α-latrotoxin-stimulated sEJPs correlate, in timing (median delay ranged from −30 to −57 ms, P<0.05 in all experiments, n=5) and amplitude (Pearson product moment correlation, ρ>0.55 and P<0.001), with purinergic neuroeffector Ca 2+ transients (NCTs) in SMCs. The temporal correlation between sEJPs of widely ranging amplitude with NCTs in the impaled SMC demonstrates that all sEJPs could arise from neurotransmitter action on the impaled cell and that the skewed distribution of sEJPs can be explained by the variable effect of packets of ATP on a single SMC. The amplitude correlation of sEJPs and NCTs argues against the attenuation of electrical signal amplitude along the length of a single SMC. The skewed sEJP amplitude distribution arising from neurotransmitter release on single SMCs is consistent with a broad neurotransmitter packet size distribution at sympathetic neuroeffector junctions.