CTNA3 will test the central hypothesis that the heritable risk for alcoholism reflects dysfunction of corticostriatal-midbrain circuitry, mediated by the interplay of glutamate and dopamine, that biases people to respond to drug-like rewards relative to delayed reward/punishments. This bias to respond to drug-like rewards leads to enhanced learning of alcohol-related associations, and facilitation of the development of habitual alcohol consumption. P2 will test this hypothesis by assessing alcohol induced dopamine (DA) release in the striatum in at risk subjects and in patients with alcoholism to demonstrate that risk is associated with an increased alcohol-induced DA release in the striatum while the transition from risk to habit is associated with a decreased response. Thus DA mediates the propensity to become addicted, and is altered by the process of addiction. SA #1. PET scanning will be performed with the D2/3 receptor radiotracer [[11]C]raclopride in 22 family history positive (FHP) healthy volunteers versus 22 FH negative (FHN) healthy volunteers. Groups will be matched on age, gender, ethnicity, socioeconomic background, and drinking habits. All subjects will be 21 to 25 years of age. [[11]C]raclopride scans will be obtained following the administration of oral alcohol at 0.75 g alcohol per kg body water or a sham drink on two separate days in counterbalanced order. The ventrostriatal [[11]C]raclopride specific to nonspecific equilibrium partition coefficient (BPND) will be measured and compared between the two groups. Alcohol-induced reduction in [[11]C]raclopride BP{ND} (ABP{ND}) will be compared between the two groups. SA#2. In the striatum, alcohol-induced DA intrasynaptic release is decreased in alcoholic subjects (n = 20) compared to matched healthy controls (n = 20). The same experimental design will be used as in SAI. Groups will be matched on age (25 to 45), gender, ethnicity, socioeconomic background, and drinking habits. Subjects will be nontreatment-seeking subjects with alcoholism. Alcohol-induced reduction in [[11]C]raclopride BP{ND} will be compared between the two groups. We will also test if baseline [[11]C]raclopride BP{ND} in FHP subjects (n = 22) is lower compared to FHN subjects (n = 22) (EA3) and explore if the propensity for Pavlovian Instrumental Transfer predicts the propensity to develop alcohol-related habit in all 44 subjects from SA1.

Public Health Relevance

This study builds on our current findings and extends the study of dopaminergic transmission to a high-risk population. It will characterize the biology of vulnerability versus habit. This could lead to developing a biomarker for identifying at risk subjects and possibly designing specific therapeutic strategies for prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
2P50AA012870-11
Application #
8128248
Study Section
Special Emphasis Panel (ZAA1-GG (99))
Project Start
2011-07-15
Project End
2016-05-31
Budget Start
2011-07-15
Budget End
2012-05-31
Support Year
11
Fiscal Year
2011
Total Cost
$254,633
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Polimanti, Renato; Agrawal, Arpana; Gelernter, Joel (2017) Schizophrenia and substance use comorbidity: a genome-wide perspective. Genome Med 9:25
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Polimanti, Renato; Meda, Shashwath A; Pearlson, Godfrey D et al. (2017) S100A10 identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours. J Psychiatry Neurosci 42:252-261

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