This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This proposed research will examine PET measures of the dopamine (DA) system in relationship to Hypothalamic-pituitary-adrenal (HPA) axis dynamics. Converging evidence suggests that drugs of abuse act through mechanisms involving the brain neurotransmitter, DA. Although drugs of abuse influence several different neurotransmitter systems in the brain, many of these 'primary' responses lead to secondary effects involving DA. Numerous studies have emphasized the interplay of genetic and environmental determinants in establishing this vulnerable substrate. Rodent studies have suggested a link between stress and mesolimbic mesoDA generation. Glucocorticoids released during stress increase mesolimbic mesoDA generation. It has been suggested that the ability of stress to increase mesoDA results in altered reward from drugs of abuse. In this application we propose to measure mesoDA release in alcohol dependent subjects withdrawn from alcohol on the JHU GCRC. Following supervised withdrawal, alcoholics and controls will undergo assessment of brain dopamine release (DArel) measured by PET as well as assessment of their HPA axis. Hypotheses: Hypothesis 1: Alcohol dependent subjects will have impaired dopamine release, compared to age-matched, social drinkers. Additionally, high-risk alcoholics (family history, trait anxiety and novelty seeking) will have more impaired dopaminergic function compared to low risk alcoholics.Hypothesis 2: Dopamine release will correlate negatively with measures of craving and mood obtained in alcoholics during alcohol withdrawal. Hypothesis 3: Alcohol dependent subjects will have lower cortisol responses to naloxone or psychological stress compared to age-matched, social drinkers. Additionally, high-risk alcoholics (family history, trait anxiety and novelty seeking) will have lower cortisol responses compared to low risk alcoholics.Hypothesis 4: The magnitude of cortisol responses will correlate negatively with measures of craving obtained acutely within test sessions and chronically over the GCRC stay. Hypothesis 5: PET determined dopamine release will predict time to relapse. Hypothesis 6: Cortisol production in response to Naloxone or psychological stress will predict time to relapse. Hypothesis 7: All subjects will demonstrate a relation between COMT polymorphism and cognitive function such that those with the LL variant will demonstrate the best performance; those with the HH variant will demonstrate the poorest performance, and those with the HL or LH variant will perform in the intermediate range. Furthermore, we expect this relation to be more pronounced in the alcoholic subjects than in the normal control subjects.
Specific Aims : 1. To examine PET derived measures of dopamine release as a function of alcohol dependence status and risk factors for alcoholism (family history of alcoholism (FHP), trait anxiety and novelty seeking). 2. To examine the relationship between dopaminergic measures (PET and genetic) and alcohol craving and mood during acute alcohol withdrawal on the GCRC.3. To examine the relationship between dopaminergic measures (PET and genetic) and time to relapse following discharge from the GCRC. 4. To examine HPA axis activation by opioid blockade and by psychological stress as a function of alcohol dependence status and risk of alcoholism. 5. To examine the relationship between dopamine release and cortisol production. 6. To examine cortisol production in relation to time to alcohol relapse following GCRC discharge as a function of risk status.7. To investigate the relation between COMT polymorphisms and cognitive functioning among healthy control subjects and those with alcohol dependence.Background and Significance: It is estimated that approximately 14% of men and 5% of women in the United States will experience the symptoms of alcohol abuse or dependence sometime in their lives (Grant, 1994). There is clear evidence that alcohol use disorders have complex genetic and environmental determinants. In recent years, there has been considerable interest in the role of the various neurotransmitter systems in alcohol reward and associated risk for the development of alcoholism. Converging evidence suggests that drugs of abuse act through mechanisms involving the brain neurotransmitter DA and the neural systems that it regulates (Wise and Rompre, 1989; Koob, et al., 1994 and 1998). Alcohol administration increases synaptic DA accumulation within this important brain region; this action is thought to contribute to its rewarding properties (Dichiara and Imperato, 1988). This ethanol-induced release of nucleus accumbens DA is blocked by opioid antagonists, implicating opioidergic activity as an intermediary between ethanol administration and DArel (Benjamin, et al., 1993; Gonzales, et al., 1998).Dopamine receptors and alcohol dependence: Central DA receptors display a decreased response to DA in subjects with alcohol abuse (Markianos et al., 2000; Schmidt et al., 2001) and a compensatory increase in DA receptor activity (Rommelspacher et al., 2001). Central DA receptors display a normal response to DA in subjects with alcohol abuse after detoxification (Markianos et al., 2000).The susceptibility to alcohol dependence and abuse is associated with lower platelet monoamine oxidase B (MAO-B) activity (Eriksson et al., 2000) and with genes coding for DA receptors (Thome et al., 2000), particularly the DA D2 receptor gene (Blomqvist et al., 2000). The severity of alcohol dependence is associated with the A1 allele of the DA D2 gene (DRD2) (Connor et al., 2002). The gene coding for the second DA receptor is implicated in severe, comorbid alcohol dependence (Gorwood, 2000). The TaqI A1 allele of the D2 DA receptor gene is more common in people with alcohol dependence and somatic, social, and professional complications, comorbid substance dependence (Gorwood et al., 2000a), and conduct disorder (Lu et al., 2001). Nevertheless, the TaqI A1 allele of the D2 DA receptor gene is unassociated with the age of onset of alcohol dependence (Anghelescu et al., 2001). However, the A1 allele of the D2 DA receptor gene does not account for an association of alcohol dependence and bipolar disorder (Gorwood et al., 2000b). Among families with alcohol dependence, the DA D2 receptor gene is not associated with habitual smoking (Bierut et al., 2000). The gene coding for the DA receptor D3 is not associated with alcohol dependence (Gorwood et al., 2001).Dopamine release is modulated by neurotensin (Vanakoski et al., 2000) and cholecystokinin (CCK) (Vanakoski et al., 2001). However, alcohol dependence is unassociated with the proneurotensin 479A>G polymorphism (Vanakoski et al., 2000) and the CCK and CCKB receptor genes (Vanakoski et al., 2001).Alterations in the metabolism of DA occur in the ventral tegmental area of mice for two months after the end of the chronic administration of ethanol (Bailey et al., 2000). Because alcohol dependence is associated with the DA system (Radel and Goldman, 2001; Schmidt and Smolka, 2001), pharmacological modulations of the DA receptor may be effective interventions for alcohol dependence (Anton, 2001; Boening et al., 2001; Heinz, 2002; Schmidt et al., 2002; Wiesbeck et al., 2001).Dopamine transporters and alcohol dependence: Dopamine transporter (DAT) gene polymorphisms are associated with alcohol dependence (Vandenbergh et al., 2000). A genotype of the DAT gene is implicated in the nature of alcohol withdrawal (Gorwood, 2000). Alcohol dependence is associated with dysfunction of the DAT in the dopaminergic neurons of the nucleus accumbens (Yoshimoto et al., 2000).
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