A major and growing problem in the field of drug abuse is prescription opioid abuse and dependence, which has reached epidemic proportions. A major question is whether there are any unique pharmacodynamics or neuroadaptations to explain this epidemic. One largely unexplored hypothesis to explain the high abuse potential of the prescription opioid medicines such as oxycodone is that there are neurobiological vulnerabilities in response to chronic administration of these drugs that predispose individuals to addiction on such opioids and that these neurobiological vulnerabilities are exaggerated by the pharmacodynamics of certain synthetic opioids. To test this hypothesis, in the present proposal, individual differences in compulsive drug seeking and dependence will be correlated with individual neuroadaptational changes in brain stress systems known to drive dependence.
In Specific Aim 1, animal models of compulsive drug seeking and dependence will be developed for oxycodone and compared to drug seeking for heroin and buprenorphine. Using such animal models, individual differences in compulsive drug seeking, withdrawal and re-escalation of compulsive drug seeking will be characterized. In parallel, in Specific Aim 2 dysregulation of neural systems known to drive the development of compulsive opioid seeking will be characterized. These include alteration of the brain corticotropin releasing factor (CRF) systems and brain dynorphin kappa systems in brain reward and stress circuits. Finally, in Specific Aim 3 microinjection of antagonists of the CRF system and the kappa system in specific brain regions and gene silencing of specific CRF and dynorphin neurocircuits will be employed to reverse neuroadaptive changes and consequent re-escalation of drug seeking in subgroups of rats with high levels of compulsive drug seeking. The present proposal will go far towards elucidating the neurobiological systems within specific neurobiological circuits of the ventral striatum and extended amygdala, which are critical for the motivational aspects of prescription opioid abuse and dependence. The present proposal also will provide important information for identifying novel non- mu opioid treatments for opioid addiction.

Public Health Relevance

Prescription opioid abuse has reached epidemic proportions and supports the need for understanding the etiology and vulnerability to prescription opioid abuse and dependence. The present proposal will develop an animal model of re- engagement of excessive/compulsive prescription opioid self-administration to investigate individual differences in neurobiological mechanisms in the brain stress/aversive systems (corticotropin releasing factor and dynorphin), systems hypothesized to drive the development of compulsive opioid seeking. Knowledge of the neurobiological bases individual differences in vulnerability to prescription opioid medications will provide insights into prevention of future opioid abuse and development of novel treatments for prescription opioid abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA035281-01A1
Application #
8657415
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (02))
Program Officer
Pilotte, Nancy S
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$426,375
Indirect Cost
$201,375
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037