1985 — 1987 |
Stone, Eric A |
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. |
Neurochemical Mechanisms of Resistance to Stress
The objective of this research is to identify central neurochemical changes that occur during stress and to determine if these changes aid in the development of adaptation and resistance to stress. In previous work on this project we have found that chronic stress in rats leads to a reduction in the sensitivity of brain norepinephrine (NE) receptors. Since there is evidence that subsensitivity to NE is one of the factors leading to resistance to stress and is also an important factor in antidepressant therapy, the present research will be directed toward a further study of this phenomenon. The first aim of the proposed research is to obtain basic information on the mechanism of stress-induced subsensitivity which will facilitate subsequent investigation of its function. This will be accomplished (a) by determining the minimum amount of stress necessary to induce subsensitivity, (b) by studying the physiological and endocrinological events that lead to this change, and (c) by defining the molecular basis of this phenomenon. Data obtained from these studies will be used to develop methods to experimentally manipulate subsensitivity in order to test its role in adaptation. The second aim of the project is to determine if stress-induced subsensitivity is an adaptive response which aids in the development of resistance to stress. This will be studied (a) by determining if subsensitivity to NE occurs during the development of resistance to various forms of stress, and (b) by determining if animals who are made subsensitive to NE prior to stress by pretreatment with antidepressant drugs, stress hormones or adrenergic blocking agents show an increased resistance to subsequent stress. In addition to providing basic information on stress adaptation the present research will also provide data on the related hypothesis that adaptation to stress and antidepressant therapy are analagous phenomena both mediated by the same set of central neurochemical changes. The latter hypothesis will stimulate research on the development of new therapeutic approaches to depression involving stress hormones and adaptation to mild stressors such as exercise.
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0.958 |
1988 |
Stone, Eric A |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Measurement of Brain Receptor Function in Vivo
The objective of the proposed research is to further investigate a new biochemical technique for measuring the activity of brain beta adrenergic receptors in vivo in awake, behaving animals so as to facilitate future research on the role of the central noradrenergic system in behavioral disorders. The technique is based on the collection by microdialysis of the second messenger, cyclic AMP (cAMP), which is formed in the brain in response to beta receptor activation. The central noradrenergic system is known to be an integrative system which appears to play an important role in the regulation of responses to stress and also in the mechanism of action of various antidepressant drugs. Research on the function of this system, however, has been hampered by the lack of a suitable biochemical technique for measuring the function of its postsynaptic receptors in vivo in the brains of awake animals. Recent studies in our laboratory, however, have indicated that a new technique involving intracerebral microdialysis may enable one to obtain a biochemical measure of the activity of these receptors in the rat brain. We have found in preliminary studies using implanted microdialysis probes that increases in cAMP efflux reflecting the activation of brain noradrenergic receptors can be detected in response to intracerebral infusions of norepinephrine. The aim of the proposed research is to follow up these preliminary findings and determine under what conditions the new technique is effective in studying these receptors. This will be accomplished by measuring in vivo cAMP responses to various treatments that cause activation of beta receptors by both exogenous and endogenous norepinephrine. In order to determine if the technique can be used to study the relationship between presynaptic neurotransmitter release and receptor activation simultaneous assays of norepinephrine release and cAMP efflux will be attempted. The proposed research can therefore provide a new and powerful tool for studying how neurotransmission in the central noradrenergic system and other cAMP-linked systems is altered by processes such as adaptation to stress and antidepressant drugs which are involved in the etiology and treatment of psychiatric disorders.
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0.958 |
1989 — 2004 |
Stone, Eric A |
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. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Regulation of Brain Noradrenergic Neurotransmission
The purpose of the present proposal is to conduct basic research on the neurobiology and pharmacology of the central noradrenergic system, a brain system thought to play an important role in central responses to stress and in mechanisms of antidepressant drug action. Research on the behavioral functions of this system has been hampered by the lack of a suitable means to study the activity of its receptors in the brains of conscious, freely moving animals. Recent studies in our laboratory however have indicated that a new technique involving the detection by implanted microdialysis probes of increases in the level of the second messenger, cyclic AMP (cAMP), in the brain in vivo in response to infusion of catecholamines now makes possible the study of these receptors in the intact brain. The purpose of the proposed research is to further develop this technique and to use it to study the in vivo regulation of central noradrenergic receptor function by pharmacological processes which are related to various aspects of stress and depression. The first aim of the project is to determine the sensitivity of the microdialysis-cAMP method in detecting experimental alterations in brain receptor function and in detecting ongoing neurotransmission at these receptors. This will be accomplished a) by determining if the technique can detect the chronic desensitization and sensitization of cAMP responses to catecholamines caused by chronic administration of an antidepressant drug or a central noradrenergic lesion, and b) by determining if it can detect cAMP responses to endogenous norepinephrine released by various procedures including stress, amphetamine infusion and stimulation of the locus coeruleus. The second aim of the project is to utilize the microdialysis method to investigate physiological factors that modulate the output of noradrenergic receptors in vivo. The studies will focus on the adrenocortical system, a system known to be active during stress and thought to have regulatory effects on noradrenergic receptors and will determine if corticosterone alters the action of catecholamines on these receptors or protects them from desensitization during prolonged catecholamine exposure. The above research therefore has the potential for providing a new tool that will facilitate investigations of the role of the noradrenergic system in stress and antidepressant drug actions and of providing insight into the physiological regulation of noradrenergic receptors during stress and during psychopathological conditions in which the level of adrenocortical function is increased (e.g., endogenous depression).
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0.958 |
2006 — 2010 |
Stone, Eric A |
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. |
Alpha-1 Adrenergic System in Activity and Depression @ New York University School of Medicine
DESCRIPTION (provided by applicant): The present proposal is a revision of a previous grant, MH45265, whose aim was to elucidate the neurobiology of positively motivated behaviors that are deficient in depressive illness. The goal of the project is to identify more precisely how these behaviors are disrupted during this disorder. Previous work on this grant has shown that brain epinephrine (EPI) and central alpha-1 adrenoceptors, both of which have been neglected in prior research on depression, play key roles in positively motivated behaviors in animals and are altered by stressors that are known to induce depressive behavior. Specifically these studies have suggested the hypotheses that brain EPI is the endogenous neurotransmitter for behaviorally activating alpha-1 receptors and that this "EPI/alpha-1 system" is specifically involved in positively- rather than negatively-motivated behaviors. These hypotheses will be tested in the present proposal by a combination of neuropharmacological, behavioral, immunohistochemical and neurochemical experiments that will assess the role of brain EPI as the endogenous stimulant of this system and the role of the system in various positively-motivated activities including self-stimulation of the lateral hypothalamus, conditioned approach and avoidance of positive and negative reinforcers, and effortful operant behavior. The research will likely identify the EPI/alpha-1 system as a new and important target for antidepressant and antistress medications
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0.958 |