Addictive urges often have several specific motivation features: the motivational urge is a) highly intense, b) narrowly focused on the addicted target (e.g., drugs), and c) sometimes seemingly `irrational', in the sense of not being explainable by past or expected reinforcement values even for the addicts themselves. For example, relapse can occur even when the addict is no longer in withdrawal, and knows from past experience that the available drug is not very pleasant, and does not expect the future drug to be very pleasant. Here we use optogenetic tools to study brain mechanisms that generate these powerful motivation features. This proposal takes advantage of our recent discovery that optogenetic stimulation of amygdala-related circuitry creates powerful motivational urges for cocaine or sucrose rewards that are a) narrowly focused, b) highly intense, and c) irrational in the sense of exceeding the sum of component reinforcements. This manipulation recreates in the laboratory the same features of motivation that need understanding in addiction. Experiment 1 will identify the crucial anatomical site within amygdala, and identify the particular neuron subpopulations, responsible for generating this intense yet narrow urge for a particular reward, even at the expense of other rewards. Experiment 2 will examine larger brain interactions of the amygdala with mesolimbic circuits, to identify the responsible larger brain circuitry. Experiment 3 will examine how drug-induced mesolimbic sensitization interacts with this circuitry to exacerbate these three features of addictive-like motivation. Altogether, these studies will help clarify how brain mechanisms generate excessive yet narrow, and even irrational, urges (similar to the addictive urges that make drug addicts relapse).
DA015188) Relapse in addiction is a major problem that persists even after treatment, and is often triggered by factors such as drug cues and stress. Relapse is caused by urges that are intense and narrowly focused on the addicted reward, while other rewards and life goals may be wanted less at that moment. Sometimes addicts themselves become confused by the seeming irrationality of their intense urge (for example, when they are no longer in withdrawal, they don't expect the drug to be very pleasant, etc.). The studies proposed here use optogenetic tools to reveal how brain circuitry generates such narrow, intense and irrational urges. These experiments will identify the brain mechanisms (connecting amygdala to mesocorticolimbic circuitry) that can generate these features of narrow intense motivation, which become so problematic in addiction. This optogenetic-induced urge is intense, narrowly focused on its single reward target, and disproportionately higher in motivation magnitude than the actual value of the reward. Understanding the brain circuitry mechanisms that produce these addictive features of urges, through the results of experiments proposed here, is a necessary step for the future development of improved therapies for addiction.
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