2007 — 2011 |
Sabino, Valentina |
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. |
Role of Sigma Receptors in Ethanol Reinforcement @ Scripps Research Institute
[unreadable] DESCRIPTION (provided by applicant): Summary: The application proposes a career development plan for Dr. Valentina Sabino, a pharmacologically-trained post-doctoral fellow committed to a research career in ethanol addiction aimed towards understand its molecular basis. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of alcoholism and co-mentored by Dr. Pietro Sanna in immunohistochemical and molecular techniques. The project, to be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego, concerns sigma receptors, unique mammalian binding sites that modulate other neurotransmitter systems and which are richly expressed in limbic brain structures. Pharmacological studies indicate that sigma receptors modulate actions of cocaine and methamphetamine. Recently, sigma receptors also have been proposed to modulate motivating properties of ethanol, consistent with findings of sigma receptor polymorphisms in human alcoholism. [unreadable] [unreadable] Until very recently, however, the understanding of sigma receptor systems had been hampered by the unavailability of specific, subtype-selective ligands or of mutant mouse models that lack sigma receptor subtypes. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacologic, and molecular techniques to determine the modulatory role of sigma receptors with subtype specificity on ethanol reward and reinforcement in distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethanol self-administration will be pharmacologically modulated (in Specific Aim 1), through the administration of novel a receptor ligands, and molecularly (in Specific Aim 2), through the use of o-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on o receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3. Relevance: The project will define the physiologic and potential therapeutic relevance of an under characterized modulatory receptor system for alcohol abuse and dependence. [unreadable] [unreadable] [unreadable]
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0.957 |
2012 — 2016 |
Sabino, Valentina |
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. |
Role of Neuropeptides in Anxiety @ Boston University Medical Campus
DESCRIPTION (provided by applicant): Anxiety disorders are the most common form of mental disorders in the United States, affecting nearly 40 million American adults and more efficacious pharmacological treatments are needed. This project, to be conducted at Boston University in the rich neuroscience community of Boston, concerns the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin/glucagon/VIP superfamily, and a pleiotropic molecule with remarkable central actions on neuroendocrine and behavioral systems. Although the interest towards this fascinating polypeptide continues to increase exponentially, the role of this neuropeptide in the modulation of stress response and its function in the extended amygdala, a key brain site for the behavioral manifestations of stress, are yet to be elucidated. Continued existence of this gap represents an obstacle to the potential benefits that can derive by understanding the role of PACAP in stress and anxiety disorders. Our preliminary data suggest a role for PACAP in the modulation of behavioral response to stress, which seems to be mediated by the receptors of the major brain stress peptide, corticotropin-releasing factor (CRF). Our long-term goal is therefore to elucidate the role of neuropeptide systems in the neurobiology of stress- related disorders. The objective of this application is to understand how the PACAP system is involved in the behavioral response to stress, with the long-term goal to provide novel therapeutic strategies for the management of stress and anxiety disorders. The central hypothesis under test in this proposal is that the endogenous PACAP system in the extended amygdala is recruited following exposure to stress and that PAC1 receptor antagonists exert an anxiolytic-like action. A sub-hypothesis is that the anxiogenic effects of PACAP are mediated by the recruitment of the extra-hypothalamic CRF system. This hypothesis will be tested by pursuing three specific aims; the brain sites important for the anxiogenic effects of PACAP will be characterized in Specific Aim 1, using intracranial microinjection of PACAP-38. The role of endogenous brain PACAP system in anxiety-like behavior will be explored in Specific Aim 2, through the investigation of the potential anxiolytic effect of a PAC1 antagonist and of the effects of stressors on PACAP and PAC1 receptor levels in discrete brain regions. Finally Specific Aim 3 will investigate the role of hypothalamic and extrahypothalamic CRF in the effects of PACAP using a pharmacological and molecular approach. The results of the proposed experiments, through this multidisciplinary approach, will provide novel insights into this neuropeptide system as a mechanism for modulating anxiety-like behavior, and may ultimately lead to the a new class of therapeutic agents for the treatment of anxiety-like disorders.
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0.957 |
2016 — 2020 |
Sabino, Valentina |
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. |
Prefrontal Cortex in Excessive Alcohol Drinking: Role of Sigma Receptors @ Boston University Medical Campus
ABSTRACT Alcohol dependence is a chronic relapsing disorder characterized by compulsive alcohol use and deficits in cognitive and executive functions. The emerging picture of alcohol addiction is that of a disease of disrupted control and compulsion, rather than merely of the pursuit of pleasure. Indeed, alcoholic patients exhibit deficits in cognitive functions governed by prefronto-cortical regions of the brain; these impairments manifest as increased risk taking, poor decision making, and loss of inhibitory control and they are thought to promote further excessive drinking. While evidence shows that chronic alcohol exposure results in loss of behavioral control, little is known about how neurotransmitter systems in prefronto-cortical regions are adversely impacted by alcohol and how they contribute to the susceptibility to drink excessively. This project, to be conducted at Boston University in the rich neuroscience community of Boston, concerns Sigma-1 receptor (Sig-1R), a molecular chaperone highly expressed in the central nervous system. We have shown that blockade of Sig-1R reduce excessive drinking in animal models of alcoholism, while they do not reduce responding for ethanol in control rats or the intake of sweet solutions. We have also found that activation of Sig-1R increases the reinforcing efficacy of alcohol, inducing binge-like drinking. Sig-1Rs are highly expressed in the prefrontal cortex, a brain area which normally exerts ?top-down? inhibitory control over behavior; importantly chronic intermittent alcohol causes a dramatic up-regulation of Sig-1R protein in prefrontal regions, suggesting that hyperactivity of this system may have a key role in excessive drinking and in the neuroplasticity observed in alcohol addiction. The central hypothesis of this proposal is that hyperactivity of Sig-1R in prefronto-cortical regions mediates the chronic alcohol-induced high susceptibility to drink excessively. A secondary hypothesis is that these neuroadaptations of the Sig-1R system mediate chronic alcohol-induced cognitive deficits and the long-lasting modifications of prefronto-cortical glutamatergic transmission and dendritic spines. Aim 1 will identify changes in Sig-1R levels associated with ethanol-dependence and ethanol drinking, and will determine whether Sig-1R in prefronto-cortical areas mediates excessive alcohol intake and motivation to drink. Aim 2 will determine whether Sig-1R mediates chronic alcohol-induced alterations in cognitive function, synaptic glutamate NMDA receptor expression, and dendritic spines in prefronto-cortical areas. If the aims are achieved, our understanding of the neurobiological adaptations driving excessive alcohol intake would significantly increase and new avenues of investigation towards the pharmacological treatment of alcohol use disorders would open.
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0.957 |
2017 — 2021 |
Sabino, Valentina |
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. |
Involvement of Neuropeptide Systems in Excessive Alcohol Drinking @ Boston University Medical Campus
ABSTRACT Approximately 18 million people (1 in every 12 adults) in the USA abuse or are dependent on alcohol. The etiology of alcohol use disorders is complex; heritable susceptibility factors interact with environmental factors to produce and maintain the disease state. One goal of current neuroscience research is, therefore, to identify the neuroadaptations mediating the propensity to consume high amounts of alcohol, of either innate or environmental origin. In particular, dysfunctions of prefronto-striatal projections have been proposed to play a critical role in alcohol addiction. This project concerns pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved 38 amino acid neuropeptide, and its receptor PAC1R. Studies in flies, rodents and humans have started to reveal a crucial role for the PACAP/PAC1R system in motivated behaviors and in the actions of drugs of abuse. The lack of studies exploring its role in alcohol addiction constitutes a barrier to the advancement of the field. Our preliminary data strongly suggest that neuroadaptions in the PACAP/PAC1R system of the nucleus accumbens core (NAcc Core) mediate the susceptibility to drink excessively. Our long-term goal is to unravel the molecular mechanisms underlying the genetic propensity to drink excessively and the transition to alcohol dependence. The overarching hypothesis of this proposal is that hyperactivation of the PACAP/PAC1 system in the medial prefrontal cortex -NAcc Core pathway mediates excessive drinking and the long-lasting neuroplastic changes observed in alcohol dependence. We will test our hypotheses using a multidisciplinary approach which includes the use of chemogenetic, pharmacological, neurochemical, and molecular techniques. The results of the proposed experiments will provide key insights into the neuroadaptive changes responsible for excessive drinking.
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0.957 |
2018 — 2019 |
Russek, Shelley J (co-PI) [⬀] Sabino, Valentina |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Does Rest Make You Resilient? @ Boston University Medical Campus
ABSTRACT Growing evidence suggests that aberrant transcriptional regulation is a key component of the pathogenesis of multiple neuropsychiatric disorders, which are thought to stem from an individual's inability to cope with stressful and traumatic events. Indeed, while traumatic events are very common, only susceptible individuals go on to develop psychopathologies, while others have the ability to cope and therefore remain resilient. Research into the genetic and epigenetic mechanisms underlying the pathological response to stress is crucial for the development of effective treatments to either mitigate susceptibility or enhance resilience. The mechanisms underlying resilience to stress remain not fully understood. This project concerns the transcriptional repressor RE1-Silencing Transcription factor (REST), also known as neuron-restrictive silencer factor (NRSF). REST is expressed in the central nucleus of the amygdala (CeA), a key brain site for the behavioral and endocrine responses of stress. Recent studies have suggested that REST may be a protective factor which would make neurons more resistant to stressors via the repression of downstream genes. Interestingly, we have found that REST levels are significantly elevated in the CeA of rats which are resilient to the effects of chronic social defeat stress (SDS). Several gaps still exist: i) Although REST is elevated in the amygdala of SDS resilient rats, whether the increased levels reflect increased binding of REST to target genes is unknown, as well as whether such binding alters gene expression in a region-specific manner. ii) Furthermore, it is unknown whether REST has a role in the development of behavioral vulnerability to chronic stress. The provocative, high risk/high reward hypothesis of this application is that increased function of the REST transcriptional repressor in the CeA underlies the resilience to the adverse effects of chronic stress. This hypothesis will be tested by combining an established animal model with state-of-the-art molecular and epigenetic techniques to pursue the following specific aims: Aim 1 will determine whether elevated levels of REST in the CeA of SDS resilient rats reflect increased binding of REST to endogenous NRSE sites and the transcriptional repression of REST target genes in CeA neurons, by using chromatin immunoprecipitation assays followed by high density sequencing (ChIP-Seq), and RNA-seq. Aim 2 will determine whether CeA REST mediates resilience to chronic social defeat stress, by overexpressing REST in the CeA in vivo using an adeno-associated viral (AAV) vector in SDS animals, and qPCR to validate REST-mediated repression of specific gene targets in the CeA that are stress responsive. The proposed experiments lay the foundation for highly relevant studies to test the hypothesis that CeA REST is a substrate that confers resilience to stress-induced psychopathologies. This research may lead to a breakthrough in our understanding of the role of REST in the adult brain and of stress-related disorders.
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0.957 |