On neurotransmitter mechanisms of reinforcement and internal inhibition

Experiments reported in this study have been performed in order to investigate cholinergic and GABA-ergic neurotransmitter systems and substance P in the realization of internal inhibition and pain reinforcement. This was accomplished during the elaboration of inhibitory and defensive conditioned reflexes to light flashes in alert, nonimmobilized rabbits. Present results together with a review of past research indicate that the cholinergic system is directly involved in transmitting the effects of pain reinforcement to neocortical neurons. Substance P, a neuropeptide, reduces the background activity of neocortical and hippocampal neurons and the response of cortical neurons to pain and positive conditioned stimuli. The cholinergic system and substance P exert a modulating effect on the elaboration of internal inhibition. Phenybut, a GABA derivative capable of penetrating the blood-brain barrier, enhances inhibitory hyperpolarization in the cerebral cortex and improves discrimination between the inhibitory and reinforcing light flashes. It appears, therefore, that the GABA-ergic system plays a leading part in the elaboration of internal inhibition. Neuronal activity and slow potential changes in response to positive conditioned and pain stimuli occur in the same direction after administering the preparations, and the dynamics of these changes is different from that in responses to inhibitory stimuli. It may be supposed on these grounds that the neurotransmitter and neuromodulator systems studied possess a considerable degree of plasticity.     

Activation and inhibitory types of brain neuronal sinchronisation: genesis and functional significance

The generalization of studies of the systemic work of cortical neurons during the information processing initiated in Livanov's laboratory allows us to make the following conclusions in terms of the modem state of the problem. In different brain structures, there is a considerable degree of correlation between neuronal activities and slow potential oscillations. In the state of rest or deep extinction, the synchronization of brain neurons increases by the inhibitory type. In the active state of the brain, the degree of neuronal synchronization increases by the activation type. Both processes are determined by the involvement of the whole brain inhibitory or activation systems, respectively. A relative augmentation of inhibitory processes results in a restriction of information transmission in the cortex and prevents its fixation in memory of the system. A decrease in inhibition facilitates the excitation thransmission in the interconnected brain structures. Synchronous convergence of ordered polse flows ensures the information fixation during learning.     

The Role of Brain Serotonin in the Expression of Genetically Determined Defensive Behavior

The review summarizes the results of long-term studies on the role of the brain neurotransmitter serotonin in genetic predisposition to various types of defensive behavior. The involvement of the serotonergic brain system in the mechanisms of genetic control of both active and passive defensive responses has been established using silver foxes, Norway rats of S₄₀ selection for low and high aggressiveness to humans, aggressive mice with genetic knockout of monoaminoxidase A, and S₄₀ rats selected for predisposition to passive defensive response of freezing (catalepsy). The changes in the serotonergic 5-HT_1A brain receptors of rats genetically predisposed to different strategies of defensive behavior were similar. However, the activity of the key enzyme of serotonin biosynthesis and the brain structures, in which serotonin metabolism was altered, significantly differed with regard to the preferred strategy. The conclusion was drawn that the 5-HT_1A receptors and enzymes of serotonin metabolism in the brain are involved in implementing genetic control of defensive behavior. Expression of the 5-HT_1A brain receptors was suggested to determine the levels of fear and anxiety and, consequently, the predisposition to defensive behavior, whereas the preferred strategy of defensive response (active or passive defensive) depends on genetically determined features of serotonin metabolism in the brain structures.     

老化和精神疾病引起的皮层抑制功能变化

脑神经网络信息加工的实现方式主要依赖于兴奋性和抑制性突触连接.脑内抑制性神经元数量较少,但在信息加工和神经可塑性等方面作用极其重要,而且抑制系统失常与多种脑功能障碍有关联.脑内抑制性神经环路可粗略分为皮层内和皮层间(包括前馈和反馈)两种,分别介导同一脑区内和不同脑区间的抑制作用.本文先围绕中心-外周抑制和运动方向互斥介绍了皮层间、皮层内抑制的行为表现和作用机制,然后以老化和精神疾病为例综述了脑功能障碍与视觉系统皮层抑制功能变化间的联系,希望能对相关研究工作有所助益.     

Functional role of hypothalamic D1 and D2 receptors in organization of some forms of behavior of the common frog

Dopamine is one of the most ancient, widely spread neurotransmitters that performs a great number of neuromodulator effects in the vertebrate CNS. For the last few years there considerably increases an interest in study of functional role of this neurotransmitter in regulation of various forms of behavior of poikilothermal vertebrates. The present work deals with study of the role of the dopaminergic system, specifically of the hypothalamic dophaminergic system in providing some behavioral frog reactions. We studies behavior of the animals in the "open field" before and after administration to them of antagonists of D1 (SCH 23390) and D2 (haloperidol) receptors as well as of animals with destructed anterior and posterior parts of hypothalamis. Administration of SCH 23390 to intact frogs caused a statistically significant decrease of the number of exploratory reactions and goal-oriented jumps, whereas haloperidol only moderately increased the number of the above reactions. Destruction of the posterior part of hypothalamus inhibited essentially all kinds of activity, while destruction of the anterior part suppressed them completely. Antagonists of D1 and D2 receptors of dopamin little changed the initial motor and emotional activity of the operated animals. The obtained data are discussed in the light of evolutionary origin of D1 and D2 receptors in the vertebrate subphylum and allow concluding that D1 and D2 receptors of hypothalamic dophamin of the common frog are located predominantly in the anterior hypothalamic areas and that their effect on behavior can be mediated and is associated with other brain neurotransmitter systems in such brain structures as lateral hypothalamus, locus coereleus, and striatum that provide different aspects of wakefulness.     

c-fos Gene expression in the brain of rats with various exploratory and defensive behavior

Groups of active and passive Wistar rats were revealed in the "open field" and "hole exploration" tests. The pronounced c-fos gene expression was found in different brain structures of rats preliminary subjected to electrodermal stimulation in the "step down" test. Marked differences in c-fos gene expression were observed in brain structures of rats with the active and passive behavior in the "open field", "hole exploration", and "step down" tests. The most pronounced and intensive c-fos gene expression was noticed in the passive rats.     

Controlling synchronization in a neuron-level population model

We have studied coupled neural populations in an effort to understand basic mechanisms that maintain their normal synchronization level despite changes in the inter-population coupling levels. Towards this goal, we have incorporated coupling and internal feedback structures in a neuron-level population model from the literature. We study two forms of internal feedback--regulation of excitation, and compensation of excessive excitation with inhibition. We show that normal feedback actions quickly regulate/compensate an abnormally high coupling between the neural populations, whereas a pathology in these feedback actions can lead to abnormal synchronization and "seizure"-like high amplitude oscillations. We then develop an external control paradigm, termed feedback decoupling, as a robust synchronization control strategy. The external feedback decoupling controller acts to achieve the operational objective of maintaining normal-level synchronous behavior irrespective of the pathology in the internal feedback mechanisms. Results from such an analysis have an interesting physical interpretation and specific implications for the treatment of diseases such as epilepsy. The proposed remedy is consistent with a variety of recent observations in the human and animal epileptic brain, and with theories from nonlinear systems, adaptive systems, optimization, and neurophysiology.     

Primary structure of myoglobins from 31 species of birds

Primary structure of myoglobins (Mbs) from 31 avian species of 15 orders were reported, although portions of the structures in the 2 species could not be determined. At least 68 of the total 153 amino acid sites were invariant all through the avian, reptilian and human Mbs, and 20 of these sites were "internal", forming the internal hydrophobic cavities in which the heme group remains wrapped. Furthermore, at 27 sites, if replaced, the replacements were mostly conservative, and 13 of the conservative sites were "internal". Thus the all 33 "internal" sites, important for structural and functional stability of the protein, have been well preserved, either invariant or conserved, during evolution from reptiles to birds and mammals. The residue 71 (E14) in 4 penguin species was not deleted as previously reported in emperor penguin Mb but occupied by Gln. The residue 121 (GH3) was deleted in all 3 species studied of Falconiformes. Out of 9 anseriforms, 5 species of different genera showed the identical structure. Secondary structures as viewed by hydropathy profiles were highly similar throughout the reptilian, avian and mammalian Mbs.     

Spinal cord thyrotropin releasing hormone receptors of morphine tolerant-dependent and abstinent rats

The effect of chronic administration of morphine and its withdrawal on the binding of 3H-[3-MeHis2]thyrotropin releasing hormone (3H-MeTRH) to membranes of the spinal cord of the rat was determined. Male Sprague-Dawley rats were implanted with either 6 placebo or 6 morphine pellets (each containing 75-mg morphine base) during a 7-day period. Two sets of animals were used. In one, the pellets were left intact at the time of sacrificing (tolerant-dependent) and in the other, the pellets were removed 16 hours prior to sacrificing (abstinent rats). In placebo-pellet-implanted rats, 3H-MeTRH bound to the spinal cord membranes at a single high affinity binding site with a Bmax of 21.3 +/- 1.6 fmol/mg protein, and an apparent dissociation constant Kd of 4.7 +/- 0.8 nM. In morphine tolerant-dependent or abstinent rats, the binding constants of 3H-MeTRH to spinal cord membranes were unaffected. Previous studies from this laboratory indicate that TRH can inhibit morphine tolerance-dependence and abstinence processes without modifying brain TRH receptors. Together with the present results, it appears that the inhibitory effect of TRH on morphine tolerance-dependence and abstinence is probably not mediated via central TRH receptors but may be due to its interaction with other neurotransmitter systems.     

Brain injury: New insights into neurotransmitter and receptor mechanisms

The studies reviewed here represent a continuing search for mechanisms which play a role in neurological disturbances resulting from brain injury. Focal cortical freezing lesions in rats were shown to cause a widespread decrease in local cerebral glucose utilization (LCGU) in cortical areas of the lesioned hemisphere and this was interpreted as reflecting a depression of cortical activity. Such an interpretation was supported by the finding that in lesioned brain reduction of cerebral metabolism by pentobarbital and isoflurane was limited by the metabolic depression that has already occurred as a result of injury and by the demonstration that the energy status and substrate (glucose) supply in the cortical areas in the injured brain have not been compromised at the time when LCGU was decreased. Both the serotonergic and the noradrenergic neurotransmitter systems were implicated in functional alterations associated with injury. Cortical serotonin (5-HT) metabolism was increased throughout the lesioned hemisphere and complete inhibition of 5-HT synthesis withp-chlorophenylalanine ameliorated the decrease in cortical LCGU, interpreted as reflecting cortical functional depression. Cortical norepinephrine metabolism was bilaterally increased in focally injured brain, while prazosin, a selective ₁-noradrenergic receptor blocker, normalized cortical LCGU in the lesioned hemisphere. Low-affinity in vivo binding of [¹²⁵I]HEAT, another selective ₁-receptor ligand, was specifically increased in cortical areas of the lesioned hemisphere at the time of the greatest depression in LCGU, suggesting that ₁-adrenoreceptors may be of functional importance in injured brain. The general conclusion from this series of studies on mechanisms underlying functional disturbances in injured brain is that both the serotonergic and the noradrenergic neurotransmitter systems are involved in the widespread cortical depression which develops with time as a consequence of a focal lesion. The data are compatible with the inhibitory effects of NE and 5-HT in the cortex and with the hypothesis that these two transmitter systems affect cortical information processing.     

Neuromediator mechanisms of wakefulness and the voluntary behavior of cats

Properties were studied of neurotransmitter provision of mechanisms of voluntary food-procuring behavior in cats. It has been shown that functional significance of monoamino- and cholinergic brain structures in these mechanisms are greatly determined by their participation in the control of the alertness level, the raising of which is necessary for solving complicated tasks and mastering new motor habits by animals.     

Involvement of synaptosomal neurotransmitter amino acids in audiogenic seizure-susceptibility and-severity of Rb mice

The involvement of synaptosomal neurotransmitter amino-acids in seizure susceptibility and seizure severity was explored. The amino-acid contents of brain synaptosomes were determined in three sublines of Rb mice differing in their response to an acoustic stimulus: Rb1, clonic-tonic seizure-prone, Rb2, clonic seizure-prone, and Rb3, seizure-resistant. Synaptosomes were prepared from 6 brain areas considered to be involved in seizure activity: olfactory bulbs, amygdala, inferior colliculus, hippocampus, cerebellum, pons-medulla. The steady-state levels of GABA and glycine (Gly), inhibitory amino-acids, of taurine (Tau), an inhibitory neurotransmitter of neuromodulator, of aspartate (Asp) and glutamate (Glu), excitatory amino-acids, as well as of serine (Ser) and glutamine (Gln), two precursors of neurotransmitter amino-acids, were determined by HPLC. Low levels of Tau, GABA, and Ser in hippocampus, Gly in amygdala, Glu in hippocampus, inferior colliculus and pons, Gln and Asp in inferior colliculus appeared to correlate with seizure-susceptibility. GABA and Asp in olfactory bulb, Gln in amygdala, hippocampus and pons, ser in olfactory bulb and pons, appeared to be associated either with seizure-severity or-diversity. A strong involvement of hippocampus (Tau, GABA, Ser, Glu, and Gln) and inferior colliculus (Asp, Glu, Gln) in audiogenic seizure-susceptibility, and of olfactory bulb (GABA, Asp) in seizure-severity and/or-diversity is suggested.Special issue dedicated to Dr. Alan N. Davison.     

Vergleich zweier Modelle für laterale Inhibition

Summary Two semi-linear models for lateral inhibition are discussed. The interaction between receptor units is assumed to be linear, as demonstrated by Hartline and Ratliff in the eye of the horseshoe crab Limulus polyphemus. Yet a model of such an inhibitory system must be nonlinear, since the output values correspond to nerve activities, which cannot be negativ. Models with forward inhibition were used often to describe contrast phenomena in the human nervous system. However, in order to simulate the input-output relation in systems similar to the eye of Limulus, a model with backward inhibition must be constructed. Two important properties of backward inhibition not shared by forward inhibition are: (1) Inhibition in a receptor unit has an influence upon its excitation, as well as upon its ability to inhibit other units (Disinhibition). (2) The range of interaction between sensory units is not necessarily the same as the range of direct cross connections. It is shown in this paper, that also forward inhibition may possess these two properties, provided that it is repeated on subsequent levels. Some properties of systems with backward and forward inhibition are studied and compared in models consisting of three units. The input-output relation for large systems with backward inhibition was calculated under special assumptions concerning the inhibitory coefficients. If the inhibitory coefficients in a system with backward inhibition decrease like a power series, as a function of the distance between receptor units, only neighboring receptors have an effect upon each other. That is, in an equivalent system with forward inhibition the inhibitory interaction is confined to neighbouring receptors. Conversely, when backward inhibition exists only between neighbouring receptors, the inhibitory coefficients in an equivalent system with forward inhibition are described, as a function of the distance between the receptor units, by a power series with alternating sign.     

Fast Micro-iontophoresis of Glutamate and GABA: A Useful Tool to Investigate Synaptic Integration

One of the fundamental interests in neuroscience is to understand the integration of excitatory and inhibitory inputs along the very complex structure of the dendritic tree, which eventually leads to neuronal output of action potentials at the axon. The influence of diverse spatial and temporal parameters of specific synaptic input on neuronal output is currently under investigation, e.g. the distance-dependent attenuation of dendritic inputs, the location-dependent interaction of spatially segregated inputs, the influence of GABAergig inhibition on excitatory integration, linear and non-linear integration modes, and many more.With fast micro-iontophoresis of glutamate and GABA it is possible to precisely investigate the spatial and temporal integration of glutamatergic excitation and GABAergic inhibition. Critical technical requirements are either a triggered fluorescent lamp, light-emitting diode (LED), or a two-photon scanning microscope to visualize dendritic branches without introducing significant photo-damage of the tissue. Furthermore, it is very important to have a micro-iontophoresis amplifier that allows for fast capacitance compensation of high resistance pipettes. Another crucial point is that no transmitter is involuntarily released by the pipette during the experiment.Once established, this technique will give reliable and reproducible signals with a high neurotransmitter and location specificity. Compared to glutamate and GABA uncaging, fast iontophoresis allows using both transmitters at the same time but at very distant locations without limitation to the field of view. There are also advantages compared to focal electrical stimulation of axons: with micro-iontophoresis the location of the input site is definitely known and it is sure that only the neurotransmitter of interest is released. However it has to be considered that with micro-iontophoresis only the postsynapse is activated and presynaptic aspects of neurotransmitter release are not resolved. In this article we demonstrate how to set up micro-iontophoresis in brain slice experiments.     

Effects on sleep of microdialysis of adenosine A1 and A2a receptor analogs into the lateral preoptic area of rats

Evidence suggests that adenosine (AD) is an endogenous sleep factor. The hypnogenic action of AD is mediated through its inhibitory A1 and excitatory A2A receptors. Although AD is thought to be predominantly active in the wake-active region of the basal forebrain (BF), a hypnogenic action of AD has been demonstrated in several other brain areas, including the preoptic area. We hypothesized that in lateral preoptic area (LPOA), a region with an abundance of sleep-active neurons, AD acting via A1 receptors would induce waking by inhibition of sleep-active neurons and that AD acting via A2A receptors would promote sleep by stimulating the sleep-active neurons. To this end, we studied the effects on sleep of an AD transport inhibitor, nitrobenzyl-thio-inosine (NBTI) and A1 and A2A receptor agonists/antagonists by microdialyzing them into the LPOA. The results showed that, in the sleep-promoting area of LPOA: 1) A1 receptor stimulation or inhibition of AD transport by NBTI induced waking and 2) A2A receptor stimulation induced sleep. We also confirmed that NBTI administration in the wake promoting area of the BF increased sleep. The effects of AD could be mediated either directly or indirectly via interaction with other neurotransmitter systems. These observations support a hypothesis that AD mediated effects on sleep-wake cycles are site and receptor dependent.     

The in vivo neurochemistry of the brain during general anesthesia

Anesthesia describes a complex state composed of immobility, amnesia, hypnosis (sleep or loss of consciousness), analgesia, and muscle relaxation. Bottom-up approaches explain anesthesia by an interaction of the anesthetic with receptor proteins in the brain, whereas top-down approaches consider predominantly cortical and thalamic network activity and connectivity. Both approaches have a number of explanatory gaps and as yet no unifying view has emerged. In addition to a direct interaction with primary target receptor proteins, general anesthetics have massive effects on neurotransmitter activity in the brain. They can change basal transmitter levels by interacting with neuronal activity, transmitter synthesis, release, reuptake and metabolism. By that way, they can affect a great number of neurotransmitter systems and receptors. Here, we review how different general anesthetics affect extracellular activity of neurotransmitters in the brain during induction, maintenance, and emergence from anesthesia and which functional consequences this may have. Commonalities and differences between different groups of anesthetics in their action on neurotransmitter activity are discussed. We also review how general anesthetics affect the response dynamics of the neurotransmitter systems after sensory stimulation. More than 30 years of research have now yielded a complex picture of the effects of general anesthetics on brain neurotransmitter basal activity and response dynamics. It is suggested that analyzing the effects on neurotransmitter activity is the logical next step after protein interactions in a bottom-up analysis of anesthetic action in the brain on the way to a unifying view of anesthesia.     

Neurophysiologic mechanisms of internal inhibition

The experimental results obtained in the authors' laboratory as a result of multiple recording of slow biopotentials, the recording of neuronal activity and of mathematical modeling, are reviewed. The authors conclude that the elaboration of internal inhibition is followed, and determined to a great extent, by the restriction in conduction of excitations due to the increase of inhibitory hyperpolarization and discordance in the periodicity of slow potentials, reflecting oscillations in excitability of neuronal populations in the cortex and other brain structures.     

Prenylated flavonoids of the leaves of Macaranga conifera with inhibitory activity against cyclooxygenase-2

Two prenylated flavonoid derivatives, 5-hydroxy-4'-methoxy-2",2"-dimethylpyrano-(7,8:6",5")flavanone (1) and 5,4'-dihydroxy-[2"-(1-hydroxy-1-methylethyl)dihydrofurano]-(7,8:5",4")flavanone (2), were isolated from an ethyl acetate-soluble extract of the leaves of Macaranga conifera using an in vitro activity-guided fractionation procedure based on the inhibition of cyclooxygenase-2. Also obtained were eight known compounds, 5,7-dihydroxy-4'-methoxy-8-(3-methylbut-2-enyl)flavanone (3), lonchocarpol A (4), sophoraflavanone B (5), 5,7-dihydroxy-4'-methoxy-8-(2-hydroxy-3-methylbut-3-enyl)flavanone (6), tomentosanol D (7), lupinifolinol (8), isolicoflavonol (9), and 20-epibryonolic acid (10). The structures of compounds 1 and 2 were determined using spectroscopic methods. All isolates were tested for their inhibitory effects against both cyclooxygenases-1 and -2, and selected compounds were evaluated in a mouse mammary organ culture assay.     

Synaptic Neurotransmitter-Gated Receptors

Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.To understand how neurons communicate with each other requires a fundamental understanding of neurotransmitter receptor structure and function. Neurotransmitter-gated ion channels, also known as ionotropic receptors, are responsible for fast synaptic transmission. They decode chemical signals into electrical responses, thereby transmitting information from one neuron to another. Their suitability for this important task relies on their ability to respond very rapidly to the transient release of neurotransmitter to affect cell excitability.In the central nervous system (CNS), fast synaptic transmission results in two main effects: neuronal excitation and inhibition. For excitation, the principal neurotransmitter involved is glutamate, which interacts with ionotropic (integral ion channel) and metabotropic (second-messenger signaling) receptors. The ionotropic glutamate receptors are permeable to cations, which directly cause excitation. Acetylcholine and serotonin can also activate specific cation-selective ionotropic receptors to affect neuronal excitation. For controlling cell excitability, inhibition is important, and this is mediated by the neurotransmitters GABA and glycine, causing an increased flux of anions. GABA predominates as the major inhibitory transmitter throughout the CNS, whereas glycine is of greater importance in the spinal cord and brainstem. They both activate specific receptors—for GABA, there are ionotropic and metabotropic receptors, whereas for glycine, only ionotropic receptors are known to date.Together with acetylcholine- and serotonin-gated channels, GABA and glycine ionotropic receptors form the superfamily of Cys-loop receptors, which differs in many aspects from the superfamily of ionotropic glutamate receptors. Over the last two decades, our knowledge of the structure and function of ionotropic receptors has grown rapidly. In this article, we summarize our current understanding of the molecular operation of these receptors and how we can now begin to interpret the role of receptor structure in agonist binding, channel activation, and allosteric modulation of Cys-loop and glutamate receptor families. Further details on the regulation and trafficking of neurotransmitter receptors in synaptic structure and plasticity can be found in accompanying articles.     

Androgens coordinate neurotransmitter‐related gene expression in male whiptail lizards

Sex steroid hormones coordinate neurotransmitter systems in the male brain to facilitate sexual behavior. Although neurotransmitter release in the male brain has been well documented, little is known about how androgens orchestrate changes in gene expression of neurotransmitter receptors. We used male whiptail lizards (Cnemidophorus inornatus) to investigate how androgens alter neurotransmitter‐related gene expression in brain regions involved in social decision making. We focused on three neurotransmitter systems involved in male‐typical sexual behavior, including the N‐methyl‐d ‐aspartate (NMDA) glutamate receptor, nitric oxide and dopamine receptors. Here, we show that in androgen‐treated males, there are coordinated changes in neurotransmitter‐related gene expression. In androgen‐implanted castrates compared with blank‐implanted castrates (control group), we found associated increases in neuronal nitric oxide synthase gene expression in the nucleus accumbens (NAcc), preoptic area and ventromedial hypothalamus, a decrease of NR1 gene expression (obligate subunit of NMDA receptors) in the medial amygdaloid area and NAcc and a decrease in D1 and D2 dopamine receptor gene expression in the NAcc. Our results support and expand the current model of androgen‐mediated gene expression changes of neurotransmitter‐related systems that facilitate sexual behavior in males. This also suggests that the proposed evolutionarily ancient reward system that reinforces sexual behavior in amniote vertebrates extends to reptiles.