Drug-associated stimuli (?cues?: sights, sounds, places) have a powerful influence over behavior in addiction1?4. In animal models, cues are typically studied in isolation, but in real life, addicts experience many types of drug- related stimuli at the same time, and little is known about the neural circuits that encode and control multi-cue relationships to guide drug seeking. In previous experiments, I have demonstrated that following intermittent, binge-like cocaine self-administration in rats, a cue associated with general drug availability in the rat?s environment (the availability cue) gates the motivational impact of a cue associated with drug delivery (the drug-delivery cue) to trigger cocaine-seeking actions. This indicates that different types of drug cues can interact in a hierarchical fashion to control drug-seeking motivation. Dopamine signaling has received attention for its role in reward-related processes, including drug seeking1,2,5,6. Ablations of dopamine terminals in the nucleus accumbens (NAc) disrupt drug self-administration7,8, and blocking NAc dopamine receptors attenuates the ability of drug-associated cues to promote drug seeking9. In human addicts, striatal dopamine release in response to drug-associated cues is associated with increased drug craving and future relapse10,11. Though NAc dopamine has been generally implicated in addiction, it is unknown how dopamine signaling 1) is altered by voluntary intermittent, binge-like cocaine use, or 2) encodes hierarchical cue relationships that guide relapse. Fiber photometry, in combination with a fluorescent dopamine sensor, dLight, provides a method to assess these questions by directly measuring in vivo activity changes at dopamine receptors with spatiotemporal precision12. Therefore, in Aim 1, I will utilize fiber photometry to measure changes in NAc dopamine signaling during binge- like cocaine use and subsequent multi-cue-induced relapse. While dopamine may have a role in signaling the motivational value of reward-paired cues, it remains unclear how hierarchical cue information is transmitted to the striatum to gate motivation and control relapse. Projections from the basolateral amygdala (BLA) to the NAc have a role in signaling contextual information that guides reward seeking, suggesting they may be important for gating cue-controlled drug seeking13,14.
In Aim 2, I propose to investigate this by optogenetically inhibiting (Aim 2.1) or exciting (Aim 2.2) the BLA-NAc circuit during single- and multi-cue relapse tests, to determine the necessity and sufficiency of the circuit in mediating hierarchical cue information to control drug seeking.
Addiction, which is characterized by compulsive drug seeking and a high probability of relapse, is a major public health problem in the United States. The goal of this project is to examine the contribution of amygdalostriatal circuitry to binge-like cocaine intake and relapse, with the hope of identifying targets that will foster the development of addiction treatments aimed at preventing relapse in recovering addicts.
