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. 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 receptorswith subtype specificity on ethanol reward and reinforcementin 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of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol,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 undercharacterized modulatory receptor system for alcohol abuse and dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Career Transition Award (K99)
Project #
5K99AA016731-02
Application #
7324074
Study Section
Special Emphasis Panel (ZAA1-EE (70))
Program Officer
Grandison, Lindsey
Project Start
2006-12-01
Project End
2009-05-31
Budget Start
2007-12-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$77,575
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Valenza, Marta; DiLeo, Alyssa; Steardo, Luca et al. (2016) Ethanol-related behaviors in mice lacking the sigma-1 receptor. Behav Brain Res 297:196-203
Baiamonte, Brandon A; Valenza, Marta; Roltsch, Emily A et al. (2014) Nicotine dependence produces hyperalgesia: role of corticotropin-releasing factor-1 receptors (CRF1Rs) in the central amygdala (CeA). Neuropharmacology 77:217-23
Dore, Riccardo; Valenza, Marta; Wang, Xiaofan et al. (2014) The inverse agonist of CB1 receptor SR141716 blocks compulsive eating of palatable food. Addict Biol 19:849-61
Dore, Riccardo; Iemolo, Attilio; Smith, Karen L et al. (2013) CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP. Neuropsychopharmacology 38:2160-9
Blasio, Angelo; Iemolo, Attilio; Sabino, Valentina et al. (2013) Rimonabant precipitates anxiety in rats withdrawn from palatable food: role of the central amygdala. Neuropsychopharmacology 38:2498-507
Cottone, Pietro; Wang, Xiaofan; Park, Jin Won et al. (2012) Antagonism of sigma-1 receptors blocks compulsive-like eating. Neuropsychopharmacology 37:2593-604
Iemolo, Attilio; Valenza, Marta; Tozier, Lisa et al. (2012) Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats. Behav Pharmacol 23:593-602
Blasio, Angelo; Narayan, Aditi R; Kaminski, Barbara J et al. (2012) A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT?A/C and 5-HT?A receptor agonists. Psychopharmacology (Berl) 219:377-86
Repunte-Canonigo, Vez; van der Stap, Lena D; Chen, Jihuan et al. (2010) Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake. Brain Res 1339:1-10
Roberto, Marisa; Cruz, Maureen T; Gilpin, Nicholas W et al. (2010) Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence. Biol Psychiatry 67:831-9

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