1985 — 2001 |
Gillis, Richard Alan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cns Control of Gastrointestinal Function
A major CNS component of CNS control of gastrointestinal (GI) function, specifically CNS control of vagal outflow from the brain is the dorsal motor nucleus of the vagus (DMV). This nucleus contains perikarya of vagal efferent neurons that project to the esophagus, stomach and cecum, and to other organs such as the liver, pancreas and heart. Afferent inputs to this nucleus originate from peripheral sites such as specific areas of the GI tract (stomach, cecum) as well as specific sites in the brain (e.g., nucleus tractus solitaires, nucleus raphe obscurus). To understand how the CNS controls GI function, it is important to first understand how information processing occur in CNS centers such as the DMV. To understand, specifically, information processing in the DMV, it is essential to know the electrophysiological behavior of the DMV motoneurons (which is determined by the presence and distribution of different ionic currents in each neuron), and how the electrophysiological properties of DMV neurons are influenced by the neuroactive substance impinging upon them. Our hypothesis is that DMV is not a diffuse neuronal system that conveys information simultaneously to vast areas of the body (i.e., to the GI tract, liver, pancreas, and heart), but is highly organized neuronal system that conveys specific topographic types of information to targeted areas in the body. The experimental strategy for testing this hypothesis will be use the in vitro rat brain slice preparation and perform whole cell patch-clamp recording of single DMV neurons. With this preparation our specific aims are to: (1) determine whether all DMV neurons are homogenous in terms of their membrane currents, or does a heterogeneity in membrane currents exist that can be related to where DMV neurons project; (2) determine whether all DMV neurons respond in a uniform fashion to putative neurotransmitter thought to control DMV neurons, or is there a heterogeneity of responses of DMV neurons to a specific putative neurotransmitter that can be related to where the DMV neurons projects in the periphery; (3) determine whether stimulation of specific afferent inputs to DMV neurons such as inputs from the nucleus tractus solitaires (e.g. commissural part of the nucleus of the tractus solitaires which contains the A2 catecholaminergic cell group) and the nucleus raphe obscurus engage only a specific population of DMV neurons thus affecting a targeted area of the G.I. tract; and (4) confirm findings obtained using the in vitro brain slice preparation in an iv vivo preparation. Data obtained from pursing these four specific aim will reveal the neuronal currents that exist in DMV neurons, and how these currents are affected by neurotransmitter of brain and peripheral input to DMV neurons. Furthermore, we will have increased our understanding of how interplay between neuronal currents in DMV motoneurons and neurotransmitter released by afferent inputs can result in the pattern of neural activity that is sent to specific sites in the GI tract and to other visceral organs such as the liver, pancreas and heart.
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1987 — 1989 |
Gillis, Richard Alan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cardiorespiratory Effects of Cocaine
The aims of our proposed research are to determine: 1) the spectrum of cardiorespiratory effects that occur with cocaine administration, 2) the effect of cocaine on cardiovascular changes induced by neurally released and injected catecholamines, 3) whether cocaine augments ventricular irritability and increases susceptibility to sudden death, 4) mechanisms whereby cocaine produces changes in cardiorespiratory function, and 5) the most effective drug(s) for counteracting cocaine-induced cardiorespiratory toxicity. For this purpose cocaine will be administered i.v. to chloralose-anesthetized cats in doses ranging from 0.125 to 8 mg/kg while monitoring arterial pressure, tracheal air flow and tidal volume, heart rate, cardiac rhythm, cardiac output, myocardial contractility, myocardial lactate production, and flows from 3 vascular beds (coronary, renal and mesenteric). Cocaine will also be administered in a cat model of sympathetic mediated coronary constriction and in isolated coronary vessels of pigs. In later studies we will test cocaine in an animal model of coronary spasm. Cocaine will be evaluated on cardiovascular responses elicited by neurally-released and injected catecholamines. The role of presynaptic alpha2- adrenoceptors in modifying all of the above responses produced by cocaine will be examined by repeating experiments in animals pretreated with the alpha 2-adrenoceptor blocker, yohimbine. Cat models of ventricular irritability (coronary occlusion and reperfusion-induced changes in cardiac electrical activity, and imbalanced sympathetic cardiac drive) will be used to evaluate arrhythmogenic properties of cocaine. Mouse models of cardiac sudden death will be employed to determine whether cocaine affects coronary thrombosis. We will use sympathetic nerve recordings, intracerebroventricular injections of cocaine and specific drugs to manipulate the function of brain neurotransmitters for the purpose of elucidating the mechanisms whereby cocaine influences cardiorespiratory function. The information gained will be used as a basis for designing studies to assess which drug(s) is/are best able to counteract cocaine- induced cardiorespiratory toxicity. These studies should: 1) define dose-related cardiorespiratory effects of cocaine, 2) elucidate mechanisms whereby cocaine produces cardiorespiratory effects and 3) provide a foundation for developing drug treatments to both prevent and treat cocaine-induced cardiorespiratory toxicity.
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1990 — 1997 |
Gillis, Richard Alan |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Excitatory Amino Acids--Role in Cns Disorders
The long range goal of the program project is to advance current knowledge of the role of excitatory amino acids (EAA) in CNS disorders, and to use this knowledge as a basis for developing new pharmacological agents effective in the treatment of neurological disorders. To achieve this goal, a set of strategies will be used by each principal investigator and these are as follows: (1) New information will be sought on the role of each subtype of EAA in CNS disorders. As yet, each particular EAA receptor subtype cannot be clearly correlated with specific CNS functions or dysfunctions. Clarification of the relationship of NMDA, quisqualate and kainate receptors to specific functions and dysfunctions will provide one basis for new drug development. (2) New information will be sought on the role of the strychnine-insensitive glycine receptor in allosteric modulation of the NMDA receptor. Focusing on this specific allosteric modulatory site represents a point of departure for understanding CNS disorders and for the development of a new generation of drugs for disorders such as epilepsy, muscle spasticity, learning and memory impairments, neuronal death, spinal cord trauma, and diseases of the cardiovascular and respiratory system. (3) New information will be sought on the mechanism of signal transduction at EAA receptors. A feature of EAA receptors is their ability to induce the formation of multiple intracellular messages which may be integrated with other incoming stimuli to produce distinct neuronal responses. Identification of each step in the formation of intracellular messages will help elucidate molecular mechanisms for normal cell function and disordered cell function, and provide a basis for developing drugs that act one or several steps beyond the EAA receptor. (4) New information will be sought on the role of other neurotransmitter systems that can regulate the EAA systems in the brain and spinal cord. Our assumption is that the EAA system may be manipulated by other neurotransmitter systems that either regulate EAA transmission or act independently to produce CNS disorders. Elucidation of these other transmitter systems will provide a basis for the development of new drugs, or a combination of drugs for treating neurological disorders. In summary, concentration on relating disorders of CNS function to a specific EAA receptor, side stepping the primary recognition site and focusing on the modulator site of the NMDA receptor complex, bypassing the EAA receptor by focusing on second messenger systems, and elucidating other neurotransmitter systems that interact with EAA transmitter systems offer the opportunities for the design of new drugs to treat a wide spectrum of CNS disorders.
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1990 — 1998 |
Gillis, Richard Alan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurocardiovascular Effects of Cocaine
The specific aims of our research have been derived from the findings that we have made during the first two and one-half years of NIDA support to study"Cardiorespiratory Effects of Cocaine" Our first aim will be to continue in our pursuit of characterizing the effects of cocaine on the sympathetic nervous system. Hypotheses that will be tested are that cocaine administration: (1) in i.v. doses of 0.0625 to 0.25 mg/kg will augment the effects of cardiac sympathetic nerve stimulation on the heart; however, doses above 2 mg/kg and above will not exhibit an augmenting effect; (2) will result in inhibition of central sympathetic outflow to the heart; and the site of this effect is the ventrolateral medulla (subretrofacial nucleus); (3) will result in inhibition of ganglionic transmission due to inhibition of norepinephrine uptake in the ganglia; (4) will result in selective stimulation of the adrenal medulla, leading to an increase in plasma epinephrine levels; (5) will result in sympathetically- mediated contraction of the isolated coronary artery, as well as sympathetically-mediated release of endothelial relaxing factor; (6) will result in tachyphylaxis to the sympathomimetic effects of the drug and the tachyphylaxis will e reversible after blockade of presynaptic alpha2- adrenoceptors; and (7) in repeated doses over a period of several hours ("run") will result in down regulation of adrenoceptors. Our second aim will be to continue in our pursuit of characterizing the direct effects of cocaine on cardiac and neural tissues. Hypotheses that will be tested are that: (1) cocaine's direct effects on the heart resemble more closely the drug flecainide than the drug lidocaine; (2) cocaine acts directly on cardiac tissue to counteract Ca2+ entry into A-V nodal cells; and (3) cocaine's direct negative inotropic effect is not counteracted by its sympathomimetic effect. Our third aim is to determine whether ethanol and nicotine as well as interference with the activity of plasma cholinesterase will predispose subjects to cocaine-cardiotoxicity. Our fourth aim will be to use information obtained from pursuing Aims 1-3 as a basis for developing drugs that would prevent and/or counteract cardiovascular disorders associated with cocaine abuse. We will also determine whether any deleterious actions occur on the cardiovascular system when drugs that are proposed to interfere with drug taking behavior (e.g., tricyclic experimental animals using standard techniques that are for the most part on-going in our laboratories. Our findings will provide: (1) new information on the pharmacology of cocaine, and information on nay deleterious effects that might occur when drugs which might interfere with drug taking behavior are combined with cocaine. (2) a rationale basis for selecting drugs to counter neurocardiovascular effects of the drug.
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1993 |
Gillis, Richard Alan |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Excitatory Amino Acids: Role in Cns Disorders |
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2000 — 2004 |
Gillis, Richard Alan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brainstem Regulation of Gastric Motility in Diabetes
neuroregulation; gastrointestinal motility /pressure; diabetes mellitus; brain stem; glucose receptor; solitary tract nucleus; dorsal motor nucleus; blood glucose; spinal reflex; vagus nerve; laboratory rat;
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2002 — 2006 |
Gillis, Richard Alan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brainstem Nachr Subtypes &Their Effect On Gi Function
DESCRIPTION (provided by applicant): Administration of nicotine and/or smoking has been shown to have important effects on gastric function. Evidence of others and our own data strongly indicate that these effects are due to nicotine acting on neuronal nicotinic acetylcholine receptors (nAChRs) in the dorsal motor nucleus of the vagus (DMV) and medial subnucleus of the tractus solitarius (mNTS). The goals of our proposed studies are to: (i) investigate the influence of DMV and mNTS nAChRs in the effects of systemically administered nicotine on gastric function and (ii) to use DMV and mNTS nAChRs as model systems to learn more about native CNS nicotinic receptors, their nature, their function and their regulation. The Specific Aims of our research are to: (i) determine the subunit composition of nAChRs in the rat DMV and mNTS that mediate the effects of nicotine on gastric tone and motility; (ii) examine regulation of the function and density of nAChRs in rat DMV and mNTS after chronic administration of nAChR-stimulating doses of nicotine, and the agonist-induced responsiveness of nAChRs in the DMV and mNTS after acute exposure to sub-activating doses of nicotine; and (iii) test the hypothesis that nAChRs observed to exist in the DMV and mNTS as revealed by pursuing Specific Aims 1 & 2 play an important role in the gastric effects (DMV and mNTS) and cardiovascular effects (mNTS) of systemically administered nicotine. To achieve these Specific Aims, a focused but multidisciplinary approach will be used consisting of the following techniques: (i) pharmacological tools applied either in vivo by microinjection of drugs into the DMV and mNTS of anesthetized rats while monitoring gastric tone and motility, or in vitro to rat brain slice preparations containing the DMV and mNTS while monitoring electrophysiological events using the whole-cell patch-clamp recording method; (ii) in vitro autoradiography taking advantage of the high affinity epibatidine binding to nAChRs combined with selective denervation of efferent and afferent vagal fibers; (iii) immunofluorescent identification of nAChR subtypes in DMV and mNTS neurons; (v) fluorescent in situ hybridization technique to identify nAChR subunits associated with DMV neurons projecting to the fundus and antrum, (vi) knockout mice, in which one gene of interest is silenced, and the contribution of a particular nAChR subunit (e.g., a7 subunit) in eliciting a specific gastric response can be assessed. Findings made to date suggest that: (I) there are five different nAChRs in the DMV and mNTS that influence gastric function; (ii) there might be a viscerotopic organization of nAChR subunits on DMV motoneurons. That is a7 containing nAChRs might be located primarily on DMV neurons projecting to the fundus but not on DMV neurons projecting to the antrum; and (iii) iv. administered nicotine might act in the mNTS on a ct4B2-nAChR subtype to inhibit tonic contraction of the fundus. These and future data obtained from pursuing our Specific Aims will extend current understanding of the different receptor mediated effects of nicotine on parasympathetic nervous system control of the upper GI tract.
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