Drug addiction in humans is characterized by compulsive drug taking and has been conceptualized as an increased motivation to seek drugs. Still largely unknown are what neurochemical/neurocircuitry changes occur that provide the motivational basis for vulnerability to escalation in drug intake over time. During the previous funding period, an animal model of escalation of cocaine intake was established using prolonged access to cocaine that provides heuristic value for exploring the neurobiological changes that may lead to vulnerability to escalation in cocaine intake and relapse. Neuropharmacological studies during the previous funding period have pointed to changes in reward neurotransmitter neurocircuitry (dopamine and opioid peptides) and changes in brain stress systems as contributing to the escalation process. The purpose of the present proposal is to systematically explore the neurobiological mechanisms responsible for expression of cocaine escalation. The overall hypothesis under test is that sufficient exposure to cocaine leads to changes in specific elements of the neurocircuitry of the extended amygdala to produce progressive elevation in drug intake. A subhypothesis is that the neurobiological basis of this transition to drug escalation reflects compromised dopamine and opioid peptide function and a recruitment of the brain corticotropin-releasing factor (CRF) and norepinephrine systems in different elements of the extended amygdala. The purpose of the proposed studies is to explore the role of specific dopamine receptor subtypes (Specific Aim 1), the role of opioid peptides and specific opioid receptor subtypes (Specific Aim 2), the role of the CRF systems and specific CRF receptor subtypes (Specific Aim 3), and the role of the norepinephrine systems and specific norepinephrine receptor subtypes (Specific Aim 4) in the expression of cocaine escalation in specific subregions of the extended amygdala. These experiments will provide critical information about the brain changes that accompany the transition from stable, limited-access cocaine intake to prolonged access, escalated cocaine intake. Such information is critical for the development of new treatments for cocaine addiction as well as for the development of strategies to identify individuals vulnerable for the development of cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA004398-18
Application #
6772827
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Lynch, Minda
Project Start
1987-04-25
Project End
2009-03-31
Budget Start
2004-04-07
Budget End
2005-03-31
Support Year
18
Fiscal Year
2004
Total Cost
$375,400
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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