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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    771—Neural Mechanisms of Appetitive Behavior

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    771.07: Basolateral amygdala and nucleus accumbens shell are necessary for cue-elicited alcohol seeking

    Location: Halls B-H

    *Z. MILLAN, P. JANAK;
    Univ. of California San Francisco, San Francisco, CA

    Abstract Body: Alcohol-predictive cues and environmental contexts play an important role in the maintenance of alcohol seeking and relapse. Here, we examined a role for basolateral amygdala (BLA) and nucleus accumbens shell (AcbSh) in mediating cue-elicited alcohol seeking across both alcohol- and non-alcohol contexts. Rats were trained in two distinct contexts: Training and Neutral, on alternating days. In context Training, rats received 15x cue (CS+) presentations paired with delivery of alcohol (15% v/v) into a magazine. In context Neutral, both CS+ and alcohol reinforcer were absent. On test, rats were assessed for cue-elicited alcohol seeking under extinction conditions in the alcohol (Training) context and in non-alcohol contexts: Neutral and Novel. We found that across experiments cue-elicited alcohol seeking was consistently elevated in the alcohol-associated Training context. In experiment 1, bilateral BLA inactivation (muscimol/baclofen; 0.1/1.0 mM; 0.5 uL/side) prevented cue-elicited alcohol-seeking across alcohol- and non-alcohol contexts. Moreover, it reduced uncued responding specifically in the Training context, suggesting an additional role for BLA in mediating the impact of alcohol associated contexts on behavior. In experiment 2, bilateral AcbSh inactivation similarly prevented cue-elicited alcohol seeking across alcohol and non-alcohol contexts. However, it also increased uncued alcohol seeking across contexts, suggesting an additional role for AcbSh in regulating behavior during off-cue periods. Together, these results demonstrate that cue-elicited alcohol seeking is context-modulated and dependent on both BLA and AcbSh. Moreover, BLA and AcbSh exert dual contribution to behavior: BLA enables the behavioral impact of both alcohol paired cues and contexts whereas AcbSh mediates the behavioral impact of the alcohol paired cue as well as the regulation of uncued behavior.

    Lay Language Summary: To Seek or Not to Seek? How the Brain Uses Environmental Cues to Control Alcohol Seeking.
    Our research shows that whether to seek or not seek alcohol is controlled by at least two small areas in the brain: the amygdala and the nucleus accumbens. The amygdala sends a “go” signal when alcohol cues (e.g. a wine glass or liquor bottle) are detected in the environment. In contrast, the nucleus accumbens sends a “stop” signal to prevent unnecessary seeking when alcohol cues are absent. These findings have important implications for understanding the basic brain mechanisms affected by addiction; mechanisms that control alcohol pursuit and abstinence.
    Alcohol addiction is a chronic and devastating condition. It is associated with poor physical health; violence and suicide; and reduced mental and emotional well-being. A defining feature is that the addict loses control over their drinking despite negative or potentially life-threatening consequences. This loss of control can be attributed, in part, to long-term changes in the brain’s reward circuit as a result of continued alcohol abuse. These changes affect how the brain responds to objects or places related to alcohol. For example, recovering alcoholics experience significant “craving” when they see images related to alcohol. In recovering addicts, the amygdala and nucleus accumbens are typically dysregulated. Our results show that both these areas of the brain play an important role for environmental cues to control alcohol seeking.
    To investigate whether amygdala or nucleus accumbens was important for environmental cues to trigger alcohol seeking, we modeled cue-triggered drinking in rats by repeatedly pairing a noise stimulus with alcohol delivered into a drinking port. Just as human drinkers associate specific cues (e.g. a liquor store sign) with alcohol, rats are apt at learning about environmental cues that predict alcohol. Thus, in our model, rats learn to approach the drinking port in anticipation of alcohol each time an alcohol cue is sounded. After training, we injected a pharmacological agent to temporarily shut down the amygdala or the nucleus accumbens. We then tested whether the rats would continue to show cue-triggered alcohol seeking, even when no alcohol was available. Removing the alcohol from the test was important to show that environmental cues, by themselves, can trigger alcohol seeking.
    Under normal conditions, the cue effectively triggered alcohol seeking. When the amygdala was shut down, the cue failed to trigger alcohol seeking. In contrast, temporarily shutting down the nucleus accumbens increased seeking behavior only when the cue was absent.
    These results suggest that an important function of the amydala and nucleus accumbens is to guide and regulate alcohol seeking: seek out alcohol when alcohol-predictive cues are present,
    and withhold your seeking efforts when alcohol cues are absent. The amygdala and nucleus accumbens work together to make these behavioral adjustments.
    Recovering addicts struggle with the ability to maintain control over their drug use. Alcohol-related environmental cues are ubiquitous, and are a potent trigger for craving and relapse. Once relapse occurs, a significant amount of time and effort is dedicated to alcohol seeking and drinking. Our results suggest that the loss of control over drinking might be related to alterations in the function of the amygdala and nucleus accumbens: by affecting the significance of alcohol cues in the environment (e.g. triggering craving), as well as increasing the desire to seek out alcohol, even when alcohol cues are not around. Relapse is a major barrier to the long-term success of addiction treatments. Our studies suggest that the function of the amygdala “go” system and the accumbens “stop” system may be an important target in developing therapeutics that help addiction sufferers regain control over their drinking.