Pietro Cottone, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The application proposes a career development plan for Dr. Pietro Cottone, a pharmacologically trained post-doctoral fellow committed to a research career in understanding the molecular bases of food and drug addiction. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of dependence and drug withdrawal and co-mentored by Dr. Eric Zorrilla in issues related to feeding, stress neurochemistry, and anxiety-like behavior and by Dr. Pietro Sanna in biochemical and neuroanatomical techniques. The project will be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego. The proposal hypothesizes that neuroadaptations in CRF systems of the extended amygdala mediate negative affective consequences of palatable food withdrawal and thereby come to compel palatable food intake via a negative reinforcement mechanism. Studies use a novel animal model based on "intermittent, but extended, access to palatable food that shares conceptual underpinnings with drug dependence-models and which emphasizes the "dark side" of food addiction, an understudied, innovative area of research. Preliminary studies with the model found that consummatory and affective dependence on palatable food develop with intermittent access and suggest that palatable food may come to be eaten compulsively for acquired negative reinforcing properties, as has been proposed for abused drugs. Additional behavioral and electrophysiological preliminary studies suggest a key role for CRF1 receptor in the alterations observed during withdrawal from preferred food in this model. Specific Aims 1 and 2 combine sophisticated behavioral techniques (progressive ratio reinforcement schedules, intracranial self-stimulation, elevated plus maze) with complementary neuropharmacologic and brain site-specific lentiviral siRNA knockdown approaches to determine the role of CRF1 receptors in the hypophagia, motivational deficits, and anxiogenic-like behavior that is seen upon withdrawal from palatable food. Specific Aim 3 identifies molecular changes in mRNA and protein expression of CRF/CRF1 systems in discrete regions of the central extended amygdala that are observed during withdrawal from chronic, intermittent palatable food access. Relevance: The project seeks to define the role and potential therapeutic relevance of stress-related CRF systems on food addiction. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Epidemic eating disorders and obesity, like drug addiction, can be conceptualized as chronic relapsing conditions with alternating periods of abstinence (e.g., dieting to avoid forbidden foods) and relapse (uncontrollable eating of palatable foods) that continue despite negative consequences. The increased availability of palatable foods and dieting are believed to be risk factors. Eating disorders and obesity very frequently occur comorbidly with anxiety and mood disorders but the neurobiological link between the two pathological conditions is poorly understood. The applicant has recently proposed a new interpretation of the etiology of compulsive eating and comorbid anxiety and affective disorders: overeating may be generated by the negative emotional state associated with its absence (analogous to excessive intake of drugs and relapse). In this context, there is increasing evidence that the endocannabinoid system plays a role in hedonic feeding and it is believed that its activation is part of a negative feedback system that opposes anxiety. Our preliminary evidences show that the endocannabinoid system in the extended amygdala is recruited during abstinence from palatable food. Therefore, the general hypothesis here is that neuroadaptations in the endocannabinoid system in the extended amygdala sustain palatable food intake via a negative reinforcement mechanism and oppose the negative affective consequences of palatable food withdrawal. The present application uses an integrative behavioral, pharmacological and molecular approach to study i) the role of the endocannabinoid system in the consummatory and motivational components of compulsive eating, ii) the mechanisms which link compulsive eating to anxiety and depressive disorders and the role played by the endocannabinoid system in this context, iii) the neuroadaptational changes in the endocannabinoid machinery in the extended amygdala which contribute to the negative reinforcement mechanisms of compulsive eating. PUBLIC HEALTH RELEVANCE: These experiments will provide critical information about the brain changes that accompany compulsive eating of palatable food and their relevance in the development of comorbid anxiety and mood disorders. Such information is important for the development of more efficacious treatments for eating disorders and obesity.

DESCRIPTION (provided by applicant): In the last decades, the epidemic spreading of eating disorders and obesity has raised the question whether certain highly palatable foods may be responsible for the development of a food dependence. In fact, epidemic eating disorders and obesity, like drug addiction, can be conceptualized as chronic relapsing conditions with alternating periods of abstinence (e.g., dieting to avoid forbidden foods) and relapse (uncontrollable eating of palatable foods) that continue despite negative consequences. Eating disorders and obesity very frequently occur comorbidly with anxiety and mood disorders; however the neurobiological link between the two pathological conditions is poorly understood. We have recently proposed a new reliable animal model of palatable food dependence which contributes to the understanding of the etiology of compulsive eating and comorbid anxiety and affective disorders. Compulsive eating may be generated by the recruitment of the extrahypothalamic corticotropin-releasing factor (CRF) brain stress systems and by the emergence of a negative emotional state during abstinence, analogous to withdrawal from abused drugs. Therefore, relying on the general hypothesis that withdrawal generates palatable food overeating as a form of self-medication, the proposed application will investigate the relationship between compulsive eating and comorbid anxiety and mood disorders. Specifically, the experiments of the proposed Specific Aims use a combined behavioral, pharmacological and molecular approach to elucidate: i) the brain sites important for the pharmacological effects of CRF1 receptor antagonists on the consummatory, emotional and motivational components of compulsive eating; ii) the effects of acute mild stress on food consumption, affectivity, and HPA and CRF responses, in animals with a history of palatable diet-cycling during protracted abstinence; iii) the role of the CRF/CRF1 system in the adaptations of the brain reward system and in the depressive-like behavior induced by the palatable diet alternation. This proposal will elucidate the neurobiological relationship between compulsive eating and comorbid anxiety and mood disorders through the lens of negative reinforcement. A better understanding of the etiology of compulsive eating would help prevent the onset of eating disorders and obesity, and would increase the potential for pharmacological intervention for tens of millions of people.

ABSTRACT Alcohol is the most common addictive substance in the world. Alcohol-use disorders, which affect 17 million people in the United States alone, represent a major health issue and a considerable cost to society. One of the major challenges in the alcohol research field is to understand the neurobiological bases of the progressive transition from low/moderate social drinking to the heavy alcohol use which characterizes alcohol dependence. Repeated intoxications and withdrawal produce profound neuroadaptations in specific brain regions critical for the reinforcing effects of alcohol, such as the extended amygdala. In particular, chronic alcohol exposure causes neuroadaptations in the bed nucleus of the stria terminalis (BNST), a brain area which plays a key role in chronic, pathological ethanol use and in withdrawal-induced negative emotional states. The BNST is very rich in a neuropeptide called pituitary adenylate cyclase-activating polypeptide (PACAP), which is considered a master regulator of the major stress circuits in the brain. We have observed that excessive intermittent alcohol consumption causes a marked increase in PACAP levels in the BNST of both male and female mice, compared to control mice, suggesting that PACAP in the BNST may play a key role in regulating high levels of alcohol drinking. The central hypothesis of this application is that PACAP neurons of the BNST represent a major system responsible for the transition to heavy alcohol use and alcohol dependence. We will test these hypotheses by means of a combined behavioral, neuroanatomical, molecular, and chemogenetic approach, which involves the use of PACAP-Ires-Cre mice. Specific Aim 1 will further validate the PACAP-Ires-Cre mouse line, characterize BNST PACAP neurons by examining its co-expression with other neuropeptide markers abundant in this brain region, and characterize BNST PACAP projection targets by means of an adeno-associated virus (AAV) expressing a Cre-dependent fluorescent reporter gene. Specific Aim 2 will then determine the functional role of PACAP neurons of the BNST in the transition to alcohol dependence and heavy alcohol drinking, using a chemogenetic approach. If successful, these experiments will lay the foundation for more extensive studies which may lead to the identification of a neuropeptide system with a critical role in heavy alcohol drinking and in the transition to dependence. A deeper understanding of the neuroadaptations produced by chronic alcohol will be essential for the discovery of novel therapeutic agents to alleviate alcoholism.