Addictions are among the most heritable of human neuropsychiatric disorders, but human genetic studies have been hampered by the extreme complexity of human genetics, as well as the sheer behavioral complexity of the addictive process, with multiple stages at which humans can exhibit addiction vulnerability ? e.g. initial drug exposure, escalation, relapse, etc. We address these shortcomings by studying heterogeneous stock (HS) rats, which have extremely well characterized genetic profiles, and using behavioral models that examine multiple well-defined time periods in the progression of addictive behaviors. Our preliminary findings show that even though addiction is often viewed as aberrant reward learning, much individual variation in addiction propensity is actually due to differences in avoidance learning. For example, in addition to its well-known rewarding properties, cocaine has aversive effects that show greater individual variability than its rewarding effects, and are stronger predictors of cocaine-seeking. Furthermore, we found that rats differ greatly in ?punishment resistance?, i.e. propensity to seek rewards despite adverse outcomes, which is one of the defining characteristics of addiction. Both cocaine avoidance and punishment resistance are highly heritable in HS rats (h2 = 0.58 and 0.48, respectively), and both are critically regulated by the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons that plays key roles in avoidance learning. Building on these findings, we seek to identify the genetic differences underlying these two distinct addiction vulnerability phenotypes using a genome-wide association screen (GWAS) to identify candidate genes in HS rats, followed by eQTL analysis on gene expression in the RMTg and afferent circuits that drive these behaviors. This project will identify candidate addiction-related genes using a highly innovative combination of powerful behavioral tests, extensive neural circuitry knowledge, and the Palmer lab's groundbreaking sequencing and analytical approaches.

Public Health Relevance

Addiction is characterized by a propensity to seek rewards (e.g. drugs of abuse) despite highly adverse consequences. Although often viewed as a personal choice, addiction is known to run in families, and is strongly influenced by genetic factors, but the search for specific genes has been difficult due to the behavioral and genetic complexity of human addiction. We propose to use animal models to overcome many of the difficulties encountered in human studies, and we particularly will use animal models to learn how adverse consequences (of drug-taking) influence behavior, and why some individuals are able to stop using drugs as the costs of doing so escalate, while others cannot.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01DA044468-01A1
Application #
9521128
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Lossie, Amy C
Project Start
2018-04-15
Project End
2023-01-31
Budget Start
2018-04-15
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403