2006 — 2010 |
Riegel, Arthur C |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Cellular Mechanisms Regulating Vta Dopamine Neurons @ Oregon Health and Science University
[unreadable] DESCRIPTION (provided by applicant): The applicant's long-term career goal is to develop into an independent investigator studying the mechanisms underlying drug abuse and addiction. In order to achieve this objective, the applicant (Dr. Arthur Riegel) has prepared a Mentored Research Scientist Development Award (K01) designed to: 1) acquire important technical and theoretical training in state-of-the-art neuroimaging techniques, while investigating the dendritic physiology of dopamine neurons; and 2) prepare a competitive R01 grant proposal in order to establish an independent research program. The training proposed in this K01 application will be conducted in the context of a Career Development Plan. This Career Plan incorporates mentoring from an established neurophysiologist (Dr. John Williams), as well as important training opportunities for practical career development skills, didactic instruction and Responsible Conduct of Research. The applicant has the commitment of resources and expertise from the Vollum Institute, one of the finest cellular neuroscience environments in the country. The research element of the Career Plan investigates neuroadaptations in dendritic physiology following chronic exposure to morphine. Dr. Riegel's immediate goals are to develop an expertise in 2-photon microscopy, spinning confocal microscopy, photolysis, focal electrical stimulation, focal iontophoresis, and experimental models of chronic opioid administration. These techniques will be used to investigate preliminary data demonstrating that forskolin-activation of adenylyl cyclase (AC) enhances the mGluR-mediated activation of the sK-channel. The proposed specific aims will test the hypothesis that there exists a novel AC/PKA-dependent signaling cascade, which regulates the sK-channel current and is upregulated during chronic morphine treatment. The results from these experiments are expected to increase our understanding of the impact of sK-channel function on dopamine neuron excitability during addiction. With regard to public health, the relevance for the proposed research is that a better understanding of the cellular mechanisms underlying sK-channel function will lead to the development of neuropharmacological tools to exploit this channel as a therapeutic target. The training incorporated in this Career Plan will provide a solid basis upon which to develop a R01 proposal in Year-3. [unreadable] [unreadable] [unreadable]
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0.964 |
2012 — 2017 |
Riegel, Arthur C |
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. |
Relapse to Cocaine-Seeking: Cellular Adaptations in the Ventral Tegmental Area @ Medical University of South Carolina
DESCRIPTION (provided by applicant): Estimates indicate that drug abuse and addiction cost the U.S. economy nearly one half-trillion dollars per year. Addiction to cocaine is characterized by compulsive drug taking behavior, despite adverse consequences. The mechanisms driving this behavior are not well understood, but involve stress, which can trigger craving. In animal models this is attributed to an interaction between the neuropeptide corticotropin releasing factor (CRF) and glutamate in the Ventral Tegmental Area (VTA). However, there remains a lack of understanding of the cellular mechanism underlying this interaction. This hampers the development of effective pharmacological treatment strategies for drug abuse and addiction. The long-term objective of this proposal is to identify cellular abnormalities in the VTA that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In dopamine neurons, firing patterns are regulated in part by activation of metabotropic glutamate receptors (mGluRs), which mediate a firing 'pause' through activation of calcium activated potassium (sK) channels. The goal of this proposal is to demonstrate that cocaine-induced changes in neuroplasticity in VTA dopamine neurons result from a deficiency in post-synaptic glutamatergic neurotransmission. To explore the interaction between CRF and glutamate-inhibition in dopamine neurons, we will record currents mediated by mGluRs that are coupled to inhibitory sK channels. Patch-clamp recordings will be performed in acute brain slices from rats trained to self-administer cocaine and control (yoked saline) rats, before or afte yohimbine-induced reinstatement. The functional impact of and the mechanism underlying the CRF-R2/mGluR receptor interaction is unknown and will be investigated in Aim-1 and Aim-2. Aim-3 will manipulate cellular targets in vivo and validate the changes in cocaine-reinstatement and the underlying mGluR/sK channel inhibition. The hypothesis that is central to this proposal is that the CRF-R2 signaling cascade is upregulated by chronic cocaine self-administration and depresses mGluR mediated inhibition during reinstatement, and that amelioration of this cocaine-induced pathology will inhibit cocaine-seeking. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat stress-related drug-seeking behaviors.
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0.964 |
2013 — 2017 |
Riegel, Arthur C |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Selective Restoration of Kcnq Channel Inhibition in the Pfc to Inhibit Cue-Induc @ Medical University of South Carolina
Estimates indicate that addiction cost the U.S. economy neariy one half-trillion dollars per year. The mechanisms driving this behavior are unclear, but involve drug-conditioned cues. In animal models this is attributed to an interaction between dopamine and glutamate neurons In the prefrontal cortex (PFC). However, there remains a lack of understanding ofthe cellular mechanism underiying this interaction. This hampers the development of effective pharmacological treatment strategies for addiction. The long-term objective of this proposal is to identify cellular abnormalities in the PFC that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In pyramidal neurons, firing patterns during drug self-administration are regulated in part by dopamine activation of beta-adrenergic receptors (?- AR), which increase intracellular calcium. This activates KCNQ channels to control spike frequency adaptation, which limits the frequency of action potential firing. The central hypothesis of this proposal Is that the ?-AR -signaling cascade is upregulated by chronic cocaine self-administration and depresses KCNQ- mediated inhibition during cue-induced reinstatement of cocaine seeking. To explore the interaction between dopamine and KCNQ-inhibition in PFC neurons, we will record currents mediated by KCNQ that are coupled to of ?-ARs. Patch-clamp recordings will be performed in acute brain slices from rats trained to self- administer cocaine and control (yoked saline) rats, before or after cue-induced reinstatement. The mechanism and functional impact ofthe dopamine-suppressed KCNQ signal on reinstatement is unknown and will be examined in the first two specific aims of this proposal. While activation ofthe prelimbic PFC (PL) initiates cocaine seeking, the projection from the infralimbic PFC (IL) inhibits cocaine seeking. Thus, Aim-2 will examine whether dopamine-suppressed KCNQ signaling is specific to the PL, or also occurs in the IL. Aim-3 will evaluate if manipulation of ?-AR signaling normalizes the KCNQ adaptation during relapse. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat drug-seeking behaviors.
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0.964 |
2018 — 2021 |
Riegel, Arthur C |
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. |
The Role of Ryanodine Receptors in Drug Seeking @ Medical University of South Carolina
There currently exist no effective pharmacological treatment options to prevent relapse to cocaine and heroin seeking. This is due to a principal lack of understanding of the underlying maladaptive cellular mechanisms driving this behavior. Considerable evidence suggests that the pre-frontal cortex (PFC) projection to the nucleus accumbens core (NAcore) represents a principle common pathway for triggering relapse. Recently, we found in rats that cocaine or heroin SA induces persistent hyper-excitability in PFC pyramidal neurons. The hyperexcitability is related to elevated intracellular Ca2+ that likely arises from malfunctioning ryanodine receptors (RYRs). Excess Ca2+ suppresses inhibitory Kv7 ion channels that serve to limit neuronal firing. Notably, this drug-induced malfunction in cell signaling persists even after extended extinction of the drug- reinforced behavior. As a result, a subpopulation of PFC neurons remains hyper-excitable and likely hypersensitive to drug-associated cues. In hippocampal neurons, excessive stimulation by stress is associated with phosphorylation and oxidation of RYR2 and depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the channel complex, resulting in intracellular Ca2+ leak through RYRs and cognitive dysfunction. A novel RYR-targeted small molecule Rycal (S107) that stabilizes the RYR2 closed states of PKA hyperphosphorylated, and oxidized/nitrosylated channels, prevents intracellular Ca2+leak and prevented the stress-induced cognitive defects. Our preliminary data indicate that S107 treatment also reduces cue-induced cocaine seeking in rats. The long-term goal of this project is to understand the cellular signaling and physiological mechanisms by which RYRs regulate relapse behavior in hopes of identifying better therapeutic strategies for the treatment of drug addiction. Our central hypotheses are that: (1) cocaine- and heroin- produces pathological destabilization of RYR via redox post-translational modification, 2) causing RYR- dependent Ca2+ leak within activated PFC neurons projecting to the nucleus accumbens core (NAcore), and 3) that the anti-relapse effects of the RYR stabilizer S107 are due, at least in part, to its ability to reduce RYR Ca2+ ?leak?. To better understand the cellular origin of the enduring adaptations in PFC inhibition, we propose to examine: the redox state of RYR and a battery of biochemical changes in both RYR and FKBP12.6 in Aim 1, RYR changes in specific subpopulations of neurons in Aim 2, and lastly translational strategies aimed at reducing cued reinstatement of drug seeking in Aim 3. Together, these studies will extend our extensive preliminary findings that link the RYR redox state and the candidate addiction therapeutic, S107 to regulation of relapse-like behaviors that drive the long-lasting changes observed in the PFC. We will determine if disruption of the PFC RYR2 and/or FKBP12.6 by cocaine and heroin is necessary for relapse and will provide mechanistic preclinical data in support of a novel target for drug development to treat heroin and cocaine addiction.
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