Environmental cues associated with alcohol are more likely to precipitate relapse if experienced in an environmental context associated with past alcohol consumption, as opposed to a context in which alcohol was never consumed. Here we will study contextual modulation of responding to alcohol-conditioned cues in behavioral models of relapse in which rats are trained in a distinctive context to discriminate between one auditory stimulus paired with alcohol (CS+) and a second (CS-) that is never paired with alcohol;conditioned responding is measured as increased entries into the alcohol delivery port during the CS+ relative to the CS-. After extinction of responding in a different context, placement back into the original alcohol training environment enhances CS+-driven alcohol-seeking behavior ('relapse'). Using this paradigm, we propose to investigate the neural circuitry underlying the modulation of cue-induced alcohol-seeking by context using techniques of site-specific microinjections and in vivo electrophysiology. Specifically, we hypothesize that reinstatement of responding to a discrete alcohol-predictive cue requires excitatory projections from the basolateral amygdala (BLA) to the nucleus accumbens core (NACc), whereas the augmentation of this behavior by an alcohol context requires efferents from the ventral hippocampus (vHipp) to the BLA.
In Aim 1 we will examine the independent roles of the BLA and NACc, as well as the BLA-NACc pathway, in cue- induced alcohol-seeking.
Aim 2 will determine if contextual control over alcohol-seeking occurs via vHipp efferents to the BLA.
Aim 3 will further define the neural mechanisms involved by examining neuronal responses to alcohol-predictive cues in the BLA, their modulation by context. Collectively, these studies will refine our understanding of the neural underpinnings of contextual modulation of alcohol-seeking, and may give rise to new therapeutic treatments for relapse in alcoholism.

Public Health Relevance

Exposure to stimuli that have been associated with past alcohol use is thought to contribute to propensity to relapse in human alcoholics. The environment in which alcohol was habitually consumed may be a particularly potent relapse cue. The studies in this proposal are designed to reveal neurobiological mechanisms that underlie the ability of alcohol-associated contexts to trigger relapse. Project Narrative Exposure to stimuli that have been associated with past alcohol use is thought to contribute to propensity to relapse in human alcoholics. The environment in which alcohol was habitually consumed may be a particularly potent relapse cue. The studies in this proposal are designed to reveal neurobiological mechanisms that underlie the ability of alcohol-associated contexts to trigger relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014925-10
Application #
8726887
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Vandaele, Youna; Janak, Patricia H (2017) Defining the place of habit in substance use disorders. Prog Neuropsychopharmacol Biol Psychiatry :
Millan, E Zayra; Kim, H Amy; Janak, Patricia H (2017) Optogenetic activation of amygdala projections to nucleus accumbens can arrest conditioned and unconditioned alcohol consummatory behavior. Neuroscience 360:106-117
Corbit, Laura H; Fischbach, Sarah C; Janak, Patricia H (2016) Nucleus accumbens core and shell are differentially involved in general and outcome-specific forms of Pavlovian-instrumental transfer with alcohol and sucrose rewards. Eur J Neurosci 43:1229-36
Corbit, Laura H; Janak, Patricia H (2016) Changes in the Influence of Alcohol-Paired Stimuli on Alcohol Seeking across Extended Training. Front Psychiatry 7:169
Sangha, Susan (2015) Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction. Front Behav Neurosci 9:354
Janak, Patricia H; Tye, Kay M (2015) From circuits to behaviour in the amygdala. Nature 517:284-92
Sciascia, Joanna M; Reese, Rebecca M; Janak, Patricia H et al. (2015) Alcohol-Seeking Triggered by Discrete Pavlovian Cues is Invigorated by Alcohol Contexts and Mediated by Glutamate Signaling in the Basolateral Amygdala. Neuropsychopharmacology 40:2801-12
Saunders, Benjamin T; Richard, Jocelyn M; Janak, Patricia H (2015) Contemporary approaches to neural circuit manipulation and mapping: focus on reward and addiction. Philos Trans R Soc Lond B Biol Sci 370:20140210
Keiflin, Ronald; Janak, Patricia H (2015) Dopamine Prediction Errors in Reward Learning and Addiction: From Theory to Neural Circuitry. Neuron 88:247-63
Millan, E Zayra; Reese, Rebecca M; Grossman, Cooper D et al. (2015) Nucleus Accumbens and Posterior Amygdala Mediate Cue-Triggered Alcohol Seeking and Suppress Behavior During the Omission of Alcohol-Predictive Cues. Neuropsychopharmacology 40:2555-65

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