The convergence of the impulsivity trait with the dynamic state of cue reactivity is a synergy that contributes to greater vulnerability to relapse. A shared theme in the Translational Addiction Sciences Center (TASC) is that disrupted homeostasis in serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2cR neurotransmission in the prefrontal-striatal-thalamic circuit drives impulsivity and cue reactivity and that medications that normalize the 5-HT2AR:5-HT2CR imbalance will be especially efficacious to prevent relapse. This hypothesis is compellingly argued by clinical (Project 1) and preclinical (Project 2) observations, and our innovative strategy is to directly test the hypothesis that a 5-HT2AR:5-HT2CR imbalance in corticostriatal function drives impulsivity and cue reactivity employing validated behavioral models, intracranial microinjections, measures of receptor and cellular activation, receptor immunohistochemistry and genetic manipulations. The research proposed in four specific aims will discover the nature of 5-HT2AR:5-HT2CR imbalance and the integrity of the neurochemical circuit underlying these two phenotypes, site the control of 5-HT2AR and 5-HT2cR to a specific cortical subregion, and demonstrate effective pharmacological strategies to suppress impulsivity and cue reactivity based upon new chemical entities (Project 3). Lastly, our exciting discovery that 5-HT2AR and 5- HT2cR assemble into a heteromer in cells and brain provides an exploratory opportunity with Core B and Project 3 to identify the biological contribution of 5-HT2A+2CR heteromers to neuronal and behavioral function. This project is significant in that we will identify how unique signaling attributes for these two receptors and their balance contribute to the dynamic events underlying persistence of maladaptive behaviors associated with cocaine dependence. Completion of the proposed aims will link 5-HT2AR and 5-HT2cR homeostasis to two key phenotypes that precipitate relapse, and uncover pharmacological strategies to normalize system function and minimize vulnerability to relapse.

Public Health Relevance

The outlined strategy will elucidate the key components of serotonergic neurobiology that drive relapse with the ultimate goal of optimizing novel serotonergic medications that maintain abstinence. These experiments will lend support to the prospects that these compounds may be useful to reduce phenotypic vulnerability to relapse, and set the stage for the use of such compounds therapeutically in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA033935-02
Application #
8725109
Study Section
Special Emphasis Panel (ZDA1-EXL-T)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$301,642
Indirect Cost
$101,641
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Azadeh, Shabnam; Hobbs, Brian P; Ma, Liangsuo et al. (2016) Integrative Bayesian analysis of neuroimaging-genetic data with application to cocaine dependence. Neuroimage 125:813-24
Swinford-Jackson, S E; Anastasio, N C; Fox, R G et al. (2016) Incubation of cocaine cue reactivity associates with neuroadaptations in the cortical serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system. Neuroscience 324:50-61
Howell, Leonard L; Cunningham, Kathryn A (2015) Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev 67:176-97
Hamilton, Kristen R; Littlefield, Andrew K; Anastasio, Noelle C et al. (2015) Rapid-response impulsivity: definitions, measurement issues, and clinical implications. Personal Disord 6:168-81
Hamilton, Kristen R; Mitchell, Marci R; Wing, Victoria C et al. (2015) Choice impulsivity: Definitions, measurement issues, and clinical implications. Personal Disord 6:182-98
Ma, Liangsuo; Steinberg, Joel L; Cunningham, Kathryn A et al. (2015) Inhibitory behavioral control: A stochastic dynamic causal modeling study comparing cocaine dependent subjects and controls. Neuroimage Clin 7:837-47
Anastasio, Noelle C; Stutz, Sonja J; Fink, Latham H L et al. (2015) Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity. ACS Chem Neurosci 6:1248-58
Ma, Liangsuo; Steinberg, Joel L; Moeller, F Gerard et al. (2015) Effect of cocaine dependence on brain connections: clinical implications. Expert Rev Neurother 15:1307-19
Liu, Shijing; Maili, Lorena; Lane, Scott D et al. (2015) Serotonin transporter gene promoter polymorphism predicts relationship between years of cocaine use and impulsivity. Psychiatr Genet 25:213-4
Ma, Liangsuo; Steinberg, Joel L; Cunningham, Kathryn A et al. (2015) Inhibitory behavioral control: a stochastic dynamic causal modeling study using network discovery analysis. Brain Connect 5:177-86

Showing the most recent 10 out of 16 publications