Alcoholism is a chronically relapsing disorder that develops over time and is characterized by the transition from recreational alcohol use to abuse and dependence. Negative emotional states, such as post- traumatic stress disorder (PTSD) or anxiety, influenced by genetic factors or determined by environmental conditions contribute to shaping this transition. On the other hand, chronic exposure to alcohol is a major determinant for the occurrence of mood disorders (e.g., anxiety, depression, PTSD) and negative emotional states (i.e., dysphoria, irritability). The amygdalar nuclei [both the central nucleus of the amygdala (CeA) and basolateral amygdala (BLA)] are considered a hub for negative emotional circuitry, and the role of the stress peptide corticotropin-releasing factor (CRF) in this brain structure is critical for both development of alcohol dependence and mood disorders/negative affect. During the previous funding period we provided essential new insight into the relationship between innate overexpression of the CRF1 receptor system, stress hypersensitivity and excessive ethanol consumption in genetically selected Marchigian Sardinian (msP) rats. Our most recent results show that enhanced CRF signaling in msP rats is responsible for increased hydrolytic activity of fatty acid amide hydrolase (FAAH) and blunted endocannabinoid (eCB) signaling in the CeA/BLA, leading to enhanced GABA and glutamate transmission in the amygdala. Our hypothesis is that such alterations contribute to enhance stress sensitivity and to exacerbate anxiety-like symptoms in the msP rats, which may increase drinking to alleviate these negative conditions. Understanding the mechanisms through with innate and environmental factors act/interact to dysregulate CRF/eCB transmission in the BLA and CeA will provide new insight into the etiopathology of alcoholism, aiding the development of new therapeutics for this still largely untreated medical condition. The research plan for this competitive renewal is to investigate how alteration of eCB signaling in the amygdala triggered by innate (in msP rats) or EtOH-induced (post-dependent Wistars) upregulation of the CRF1 system contributes to excessive alcohol drinking and exacerbates maladaptive conditioned fear responses, similar to symptoms of PTSD in humans. The ability to restore normal eCB function by FAAH inhibition, and therefore to counteract excessive drinking and normalize fear responses, will be also studied. A better understanding of the molecular mechanism underlying genotypic differences of the msP compared to outbred Wistar rats and of neuroadaptations following exposure to alcohol, will provide novel insight into the innate susceptibility to develop Alcohol Use Disorder and will be useful toward the development of new therapeutic agents to alleviate alcohol dependence. The key personnel involved in the present study possess all the necessary expertise needed to accomplish this multidisciplinary program. In particular, Dr. R. Ciccocioppo will supervise behavioral experiments, breeding programs and animal selections. Dr. M. Roberto will be dedicated to the electrophysiology experiments and the research program coordination. Dr. L. Parsons will perform the neurochemistry experiments, and will also perform behavioral tests at TSRI to ensure cross-lab reproducibility and provide the animals for electrophysiology. These three key personnel each have extensive publication histories in their respective areas of expertise, and have ongoing collaborative interactions, documented by common publications, that will be invaluable for the successful completion of the proposed experiments.

Public Health Relevance

The Marchigian Sardinian alcohol-preferring (msP) rats represent an unique rat model in which genetic selection for high alcohol preference has led to co-segregation of elevated sensitivity to stress and anxiety. The goal of this project is to provide a systematic investigation at the molecular, neurochemical and behavioural levels of the impact of these heritable factors and biological mechanisms in the etiology of anxiety and alcohol drinking behaviour. These studies may help identify biological targets for the development of pharmacological treatment for alcoholism and the frequent co-occurrence anxiety related disorders, such as post-traumatic stress disorder (PTSD).

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AA017447-06A1
Application #
9191298
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Grandison, Lindsey
Project Start
2009-09-10
Project End
2021-06-30
Budget Start
2016-09-01
Budget End
2017-06-30
Support Year
6
Fiscal Year
2016
Total Cost
$396,900
Indirect Cost
$166,500
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
McClatchy, Daniel B; Yu, Nam-Kyung; Martínez-Bartolomé, Salvador et al. (2018) Structural Analysis of Hippocampal Kinase Signal Transduction. ACS Chem Neurosci :
Berger, Anthony L; Henricks, Angela M; Lugo, Janelle M et al. (2018) The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System. Biol Psychiatry 84:611-623
Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W et al. (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840-1850
Egervari, Gabor; Ciccocioppo, Roberto; Jentsch, J David et al. (2018) Shaping vulnerability to addiction - the contribution of behavior, neural circuits and molecular mechanisms. Neurosci Biobehav Rev 85:117-125
Kirson, Dean; Oleata, Christopher Shaun; Parsons, Loren Howell et al. (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676-688
Roberto, Marisa; Spierling, Samantha R; Kirson, Dean et al. (2017) Corticotropin-Releasing Factor (CRF) and Addictive Behaviors. Int Rev Neurobiol 136:5-51
Natividad, Luis A; Buczynski, Matthew W; Herman, Melissa A et al. (2017) Constitutive Increases in Amygdalar Corticotropin-Releasing Factor and Fatty Acid Amide Hydrolase Drive an Anxious Phenotype. Biol Psychiatry 82:500-510
Varodayan, Florence P; Bajo, Michal; Soni, Neeraj et al. (2017) Chronic alcohol exposure disrupts CB1 regulation of GABAergic transmission in the rat basolateral amygdala. Addict Biol 22:766-778
Natividad, Luis A; Steinman, Michael Q; Laredo, Sarah A et al. (2017) Phosphorylation of calcium/calmodulin-dependent protein kinase II in the rat dorsal medial prefrontal cortex is associated with alcohol-induced cognitive inflexibility. Addict Biol :
Cippitelli, Andrea; Domi, Esi; Ubaldi, Massimo et al. (2017) Protection against alcohol-induced neuronal and cognitive damage by the PPAR? receptor agonist pioglitazone. Brain Behav Immun 64:320-329

Showing the most recent 10 out of 33 publications