Our longitudinal design of alcohol self-administration in the non-human primate has yielded evidence of stress axis risk factors associated in the development of heavy alcohol drinking as well as an impairment in brain regions involved in the control of voluntary actions. In this proposal, we will examine the ability of manipulating stress circuitry by inhibiting glucocorticoid receptors to decrease heavy ethanol drinking and relapse. We will also test the hypothesis that heavy alcohol drinking leads to impairments of the neural control of voluntary actions that involves a relative shift in activation of cortico-basal ganglia circuitry between the associative and sensorimotor subcircuits in response to context, contingencies and the predicted outcome of the action. The associative circuitry, involving prefrontal cortical projections to the caudate nucleus, is implicated in flexible adjustments to behavior. The sensorimotor circuitry, on the other hand, involves sensorimotor and motor cortical projections to the putamen and controls habitual behaviors. We will use baseline resting-state functional connectivity with MRI to investigate if individual differences in cortico-basal ganglia connectivity are associated with performance on a self-paced set shifting task as well as heavy alcohol consumption. Designer receptors exclusively activated by designer drug (DREADDs) will be implemented to alter cortico-basal ganglia circuits and examine effects on cognitive flexibility and heavy ethanol drinking. Resting-state fMRI will then be used to verify the changes in connectivity strength by the activation of DREADDs, so that this less invasive method can be positioned to identify abnormal functioning of cortico-basal ganglia subcircuits. This highly innovative research in macaque monkeys will advance the application of neurotechnologies to understand and modulate addiction, a maladaptive behavior.

Public Health Relevance

Stress is considered a risk factor in the development of addiction and in addiction relapse, while addiction is also associated with a dissociation between environmental consequences and behavior. There is a huge need to develop novel approaches to treating these disorders. The proposed research using new neuroscience technologies in primates with sophisticated behavioral assessments will open a new pathway for developing treatments by manipulating the stress system or brain circuitry involved in flexible behaviors.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1)
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Powell, Elizabeth
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Oregon Health and Science University
Other Basic Sciences
Schools of Medicine
United States
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Iancu, Ovidiu D; Colville, Alexander; Walter, Nicole A R et al. (2018) On the relationships in rhesus macaques between chronic ethanol consumption and the brain transcriptome. Addict Biol 23:196-205
Alexander, Nancy J; Rau, Andrew R; Jimenez, Vanessa A et al. (2018) SNARE Complex-Associated Proteins in the Lateral Amygdala of Macaca mulatta Following Long-Term Ethanol Drinking. Alcohol Clin Exp Res 42:1661-1673
Allen, Daicia C; Gonzales, Steven W; Grant, Kathleen A (2018) Effect of repeated abstinence on chronic ethanol self-administration in the rhesus monkey. Psychopharmacology (Berl) 235:109-120
Boule, Lisbeth A; Ju, Cynthia; Agudelo, Marisela et al. (2018) Summary of the 2016 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 66:35-43
Barr, Tasha; Sureshchandra, Suhas; Ruegger, Paul et al. (2018) Concurrent gut transcriptome and microbiota profiling following chronic ethanol consumption in nonhuman primates. Gut Microbes 9:338-356
Cuzon Carlson, Verginia C; Grant, Kathleen A; Lovinger, David M (2018) Synaptic adaptations to chronic ethanol intake in male rhesus monkey dorsal striatum depend on age of drinking onset. Neuropharmacology 131:128-142
Jimenez, Vanessa A; Allen, Daicia C; McClintick, Megan N et al. (2017) Social setting, social rank and HPA axis response in cynomolgus monkeys. Psychopharmacology (Berl) 234:1881-1889
Cervera-Juanes, R; Wilhelm, L J; Park, B et al. (2017) Alcohol-dose-dependent DNA methylation and expression in the nucleus accumbens identifies coordinated regulation of synaptic genes. Transl Psychiatry 7:e994
Cervera-Juanes, Rita; Wilhelm, Larry J; Park, Byung et al. (2017) Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking. Alcohol 60:103-113
Jimenez, Vanessa A; Grant, Kathleen A (2017) Studies using macaque monkeys to address excessive alcohol drinking and stress interactions. Neuropharmacology 122:127-135

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