2010 — 2012 |
Briand, Lisa A |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
The Role of Creb in Stress-Induced Reinstatement @ University of Pennsylvania
DESCRIPTION (provided by applicant): Although cocaine addiction is a major public health problem, currently no effective pharmacological treatment options exist. With relapse rates estimated at around 40-60%, developing a better understanding of the mechanisms underlying relapse could provide us with the means to develop better treatment options. Stress has been shown to elicit relapse to cocaine seeking in human addicts and reinstatement of drug seeking in animals models;however, the molecular mechanisms by which stress leads to relapse is unknown. Recent work in our lab has demonstrated that cAMP response element binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned place preference using mice with a constitutive deletion of CREB. Currently, it is unclear which aspects of the neural circuitry depend on CREB to drive stress-induced reinstatement of cocaine seeking. Utilizing behavioral, immunohistochemical, and neuropharmacological approaches, this grant aims to examine the role of CREB in stress-induced reinstatement of cocaine conditioned place preference. Initially, we will examine the role of behavioral coping strategies in response to stress will be examined by examining the ability of stressors that do not engage altered behavioral responding in CREB deficient mice to lead to resinstatement of conditioned reward. Additionally, we will examine differences between both naive and cocaine-experienced wildtype and CREB deficient mice in the ability of stress to engage neurobiological circuitry implicated in stress-induced reinstatement. Finally, interactions between CREB and corticotropin-releasing factor (CRF) will be elucidated by local infusions of CRF into the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA) prior to reinstatement. The goal of this research is to gain a better understanding of how stressful experiences can lead to drug relapse. By investigating the role of CREB in both the behavioral responses to stress as well as the molecular mechanisms underlying the interactions between stress and drug seeking we can identify new therapeutic targets for drug discovery
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1 |
2013 — 2017 |
Briand, Lisa A |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Ampa Receptor Trafficking and Cocaine Reinstatement @ University of Pennsylvania
DESCRIPTION (provided by applicant): Cocaine abuse is a major public health problem in the United States. In the latest national study, the number of people over the age of 12 who are current cocaine users is estimated at 1.6 million, or 0.7% of the total population. In recent years extensive research has demonstrated that cocaine addiction is associated with neuroadaptations and consequent pathology of reward learning. Chronic cocaine exposure leads to alterations in glutamatergic synapses, including changes in glutamate release, gene and protein expression, and synaptic plasticity. Further elucidating the mechanisms underlying these changes and how they lead to relapse is the goal of this grant application. More specifically, work utilizing both in vitro slice physiology and in vivo field recordings indicate tat repeated exposure to cocaine leads to a decrease in long-term depression within the nucleus accumbens (NAc). Although the exact mechanisms underlying this effect are unclear, existing evidence from the learning and memory field indicates that PKC-mediated AMPA receptor endocytosis is necessary for long-term depression. Our preliminary results show that blocking this endocytosis, utilizing a transgenic mouse lacking the PKC phosphorylation site on the AMPA receptor GluA2 subunit, leads to increased reinstatement of drug seeking behavior. The specific aims for the mentored component of the proposed grant are designed to use this genetic mouse to probe the molecular mechanisms underlying cocaine reinstatement. Aim 1 focuses on delineating the mechanisms responsible for reinstatement promoted by cocaine-associated cues using patch clamp electrophysiology. Aim 2 expands this work to include stress- induced reinstatement of cocaine seeking. Aims proposed for the independent (R00) phase of the grant will investigate further the individual components of AMPA receptor trafficking, examining the role of the novel PKC isoform, PKM?, in the ability of cues and stress to elicit reinstatement. Thus, the overall goal of the proposed experiments is to determine the role of AMPA receptor trafficking in cocaine-induced changes in synaptic plasticity and whether these changes in plasticity are required for two distinct forms of cocaine reinstatement, an animal model of relapse. My research so far in the field of cocaine addiction has given me a solid foundation in behavioral and molecular approaches. However, the specialized training proposed in electrophysiology during the K99 phase of this award will broaden my knowledge base and allow for a truly multi-disciplinary approach in my future career. Furthermore, this training and individualized research project will serve me well as I prepare for a future academic tenure-track position.
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1 |
2019 — 2021 |
Briand, Lisa 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. |
Examining Mechanisms Underlying Drug-Associated Memory Erasure by Zeta-Inhibitory Peptide @ Temple Univ of the Commonwealth
. Examining mechanisms underlying drug-associated memory erasure by zeta-inhibitory peptide. Project Summary: Cocaine abuse is a major public health problem in the United States with high rates of relapse and a lack to pharmacological treatment options. We have recently demonstrated that zeta-inhibitory peptide (ZIP) infused into the nucleus accumbens blocks cocaine reinstatement, an animal model of relapse. Further, ZIP's effects persist up to 1 week after the peptide is cleared from the brain and ZIP does not alter food reinstatement. Recent evidence has called the mechanism of action of ZIP into question. Therefore, the goal of this proposal is to examine mechanisms by which ZIP affects cocaine-induced behavioral, synaptic and structural plasticity. We, and others, have shown that cocaine self-administration leads to impaired NMDA-dependent long-term depression (LTD) within the accumbens. Future learning, such as the extinction of drug-associated cues, could be occluded without the ability to rescale these synapses. As LTD is dependent upon the removal of GluA2- containing AMPARs, we hypothesize that ZIP may restore the capacity for LTD following cocaine by preventing PKC-mediated removal of GluA2-containing AMPARs. Changes in AMPAR trafficking are dynamic and alterations in structural plasticity, such as changes in spine density, provide a mechanism for persistent changes at the receptor level. In fact, chronic cocaine has been shown to lead to structural plasticity within the nucleus accumbens and manipulations that disrupt this structural plasticity decrease cocaine reward behaviors, including reinstatement behavior. As structural plasticity is dependent upon actin polymerization and cocaine has been shown to alter this process, we propose that ZIP may reverse cocaine-induced structural plasticity via disruption of actin dynamics. As the ability of ZIP to eliminate cocaine reinstatement could provide an avenue to designing potential therapeutics, understanding the mechanism by which these effects occur is critical. Aim 1 focuses on determining how ZIP administration in the nucleus accumbens affects synaptic plasticity and AMPAR trafficking. Additionally, this aim will determine whether the effects of ZIP on cocaine reinstatement are dependent upon the ability to blunt LTD the necessity of the ability of ZIP to reverse this plasticity in its behavioral effects. Aim 2 will focus on the potential affects of ZIP on cocaine-induced structural plasticity. Aim 3 focuses on determining whether the effects of ZIP are dependent upon another atypical PKC, PKC?/?. Thus, the overall goal of the proposed experiments is to elucidate the mechanisms by which ZIP may disrupt cocaine-induced plasticity at the level of the receptor and the dendrite.
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0.903 |