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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
7R01AA014925-09
Application #
8675123
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grakalic, Ivana
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$333,319
Indirect Cost
$121,014
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Maddux, Jean-Marie; Lacroix, Franca; Chaudhri, Nadia (2014) A procedure to observe context-induced renewal of pavlovian-conditioned alcohol-seeking behavior in rats. J Vis Exp :51898
Remedios, Jessica; Woods, Catherine; Tardif, Catherine et al. (2014) Pavlovian-conditioned alcohol-seeking behavior in rats is invigorated by the interaction between discrete and contextual alcohol cues: implications for relapse. Brain Behav 4:278-89
Sparks, Lindsay M; Sciascia, Joanna M; Ayorech, Ziada et al. (2014) Vendor differences in alcohol consumption and the contribution of dopamine receptors to Pavlovian-conditioned alcohol-seeking in Long-Evans rats. Psychopharmacology (Berl) 231:753-64
Sciascia, Joanna M; Mendoza, Jose; Chaudhri, Nadia (2014) Blocking dopamine d1-like receptors attenuates context-induced renewal of pavlovian-conditioned alcohol-seeking in rats. Alcohol Clin Exp Res 38:418-27
Chaudhri, N; Woods, C A; Sahuque, L L et al. (2013) Unilateral inactivation of the basolateral amygdala attenuates context-induced renewal of Pavlovian-conditioned alcohol-seeking. Eur J Neurosci 38:2751-61
Janak, Patricia H; Chaudhri, Nadia (2010) The Potent Effect of Environmental Context on Relapse to Alcohol-Seeking After Extinction. Open Addict J 3:76-87
Chaudhri, Nadia; Sahuque, Lacey L; Schairer, William W et al. (2010) Separable roles of the nucleus accumbens core and shell in context- and cue-induced alcohol-seeking. Neuropsychopharmacology 35:783-91
Chaudhri, Nadia; Sahuque, Lacey L; Janak, Patricia H (2009) Ethanol seeking triggered by environmental context is attenuated by blocking dopamine D1 receptors in the nucleus accumbens core and shell in rats. Psychopharmacology (Berl) 207:303-14
Chaudhri, Nadia; Sahuque, Lacey L; Janak, Patricia H (2008) Context-induced relapse of conditioned behavioral responding to ethanol cues in rats. Biol Psychiatry 64:203-10
Chaudhri, Nadia; Sahuque, Lacey L; Cone, Jackson J et al. (2008) Reinstated ethanol-seeking in rats is modulated by environmental context and requires the nucleus accumbens core. Eur J Neurosci 28:2288-98

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