Drug addiction is associated with poor decision making and elevated risk taking in both males and females. Elevated risk taking may contribute to addiction and poor life outcomes by rendering individuals more likely to engage in drug use as well as other risky behaviors. The causal relationships between drug use and elevated risk taking, as well as the neural mechanisms which might mediate such relationships, are unclear. However, a better understanding of these mechanisms could lead to novel approaches for treating addiction. The long- term goal of this research program is to understand the behavioral and neural mechanisms underlying elevated risk taking associated with drug use in both males and females. Important to this long-term goal, preliminary work with a novel rat model of risky decision making shows that elevated risk taking is predictive of subsequent cocaine self-administration, and that chronic cocaine self-administration in turn causes lasting elevations in risk taking, indicating a bidirectional relationship between risk taking and cocaine use. Additiona preliminary data indicate that elevated risk taking in drug-na?ve rats is associated with lower levels of striatal D2 receptor expression, and that activation of these receptors can reduce risk taking. Building on these preliminary findings, the objective of this proposal is to fully characterize the relationships between elevated risk taking and cocaine self-administration, and to determine whether these relationships are mediated by alterations in D2 and D3 dopamine receptor signaling. Our central hypothesis is that elevated risk taking is mediated by low levels of striatal D2 receptors and high levels of striatal D3 receptors, either as a pre-existing conditin or resulting from chronic cocaine self-administration. We further predict that normalizing the activity or expression of these receptors will be efficacious for reducing risk taking. Using an integrative approach in which we combine behavioral assessment of risk taking with cocaine self-administration and pharmacological, molecular, and anatomical assays, we will test our central hypothesis by: 1) characterizing the bidirectional relationship between elevated risk taking and cocaine self-administration in both males and females, and determining if cocaine-induced increases in risk taking are associated with alterations in striatal D2 and D3 receptors; 2) determining if alterations in striatal D2 and D3 receptors are sufficient to cause elevated risk taking, and if acute targeting of these receptors can reverse cocaine-induced elevations in risk taking; 3) determining if chronic environmental or pharmacological normalization of striatal D2 and D3 receptors can reverse cocaine- induced elevations in risk taking. A better understanding of the role of striatal dopamine signaling in risk taking will provide foundational knowledge necessary to develop intervention strategies targeting elevated risk taking in order to reduce drug use.

Public Health Relevance

Cocaine use is associated with high levels of risk taking, which may contribute to addiction and poor life outcomes by rendering individuals more likely engage in drug use as well as other risky behaviors. The experiments in this proposal will use a rat model to determine the neural mechanisms underlying the relationships between risk taking and cocaine use, and to investigate potential therapeutic targets for reducing risk taking. Knowledge gained from these experiments will be useful for development of novel treatments to reduce drug use and enhance quality of life for addicted individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA036534-05
Application #
9625773
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Grant, Steven J
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Psychiatry
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Orsini, Caitlin A; Heshmati, Sara C; Garman, Tyler S et al. (2018) Contributions of medial prefrontal cortex to decision making involving risk of punishment. Neuropharmacology 139:205-216
Orsini, Caitlin A; Hernandez, Caesar M; Bizon, Jennifer L et al. (2018) Deconstructing value-based decision making via temporally selective manipulation of neural activity: Insights from rodent models. Cogn Affect Behav Neurosci :
Orsini, Caitlin A; Colon-Perez, Luis M; Heshmati, Sara C et al. (2018) Functional Connectivity of Chronic Cocaine Use Reveals Progressive Neuroadaptations in Neocortical, Striatal, and Limbic Networks. eNeuro 5:
Blaes, Shelby L; Orsini, Caitlin A; Mitchell, Marci R et al. (2018) Monoaminergic modulation of decision-making under risk of punishment in a rat model. Behav Pharmacol 29:745-761
Deng, Jay V; Orsini, Caitlin A; Shimp, Kristy G et al. (2018) MeCP2 Expression in a Rat Model of Risky Decision Making. Neuroscience 369:212-221
Orsini, Caitlin A; Mitchell, Marci R; Heshmati, Sara C et al. (2017) Effects of nucleus accumbens amphetamine administration on performance in a delay discounting task. Behav Brain Res 321:130-136
Orsini, Caitlin A; Setlow, Barry (2017) Sex differences in animal models of decision making. J Neurosci Res 95:260-269
Orsini, Caitlin A; Hernandez, Caesar M; Singhal, Sarthak et al. (2017) Optogenetic Inhibition Reveals Distinct Roles for Basolateral Amygdala Activity at Discrete Time Points during Risky Decision Making. J Neurosci 37:11537-11548
Orsini, Caitlin A; Willis, Markie L; Gilbert, Ryan J et al. (2016) Sex differences in a rat model of risky decision making. Behav Neurosci 130:50-61