Defining the effects of cocaine delivery speed on the encoding of drug-cue associations

Vanderbilt University, Nashville TN

Investigators

Abstract

PROJECT SUMMARY AND ABSTRACT Cocaine use disorder (CUD) is a significant public health crisis with no FDA-approved pharmacotherapies. Routes of administration that deliver cocaine to the brain most rapidly, such as inhalation and intravenous (IV) injection, have a greater likelihood of abuse and dependence compared to slower routes like intranasal use. Indeed, even at the same equivalent dose, inhalation of crack cocaine is associated with greater risk for addiction than insufflation of powder cocaine. Thus, the speed of cocaine administration is a key factor that determines its addiction potential. The goal of this proposal is to define how faster infusion of the same dose of cocaine results in increased drug taking and seeking. The nucleus accumbens (NAc) is a critical hub within the brain’s reward circuitry for encoding drug-cue associations. This region is composed of two non-overlapping populations of medium spiny neurons (MSNs) based on their expression of D1 or D2 type dopamine receptors. While D2 MSNs are inhibited by cocaine, D1 MSNs are activated by cocaine and cocaine-predicting cues, undergo robust drug-induced plasticity, and causally drive drug-seeking. Thus, cocaine and cocaine-associated cues selectively recruit specific subsets of NAc neurons (i.e. neuronal ensembles) to mediate addiction-like behaviors. However, it is unknown whether the speed of cocaine delivery alters neural ensemble responses to cocaine and its predictive cues, as well as its role in drug-seeking. There are two key questions that guide this research proposal: 1) Does the speed of cocaine administration influence ensemble activity and drug-cue associations? 2) Does the speed of cocaine administration influence how associated cues drive drug-seeking? I hypothesize that fast cocaine delivery enhances drug-cue associations by more robustly activating D1 MSNs in the NAc, increasing drug-cue ensemble stability and driving drug-seeking. In Aim 1 of this proposal, we will use in vivo cellular resolution calcium imaging to record neural responses to fast and slow cocaine infusions to determine how cocaine infusion speed alters the activity of cocaine ensembles. In Aim 2, we will use calcium imaging to track the same cells over time to determine how cocaine infusion speed alters the development and stability of drug-cue ensembles. Finally, in Aim 3, we will optically stimulate cue-ensembles associated with either fast or slow cocaine infusion to assess their role on the reinstatement of drug-seeking. The training plan in this fellowship will build upon my background in systems neuroscience by providing rigorous training in in vivo cellular resolution calcium imaging, behavioral models of addiction, and viral and genetic approaches for cell-type specific manipulation. Altogether, this project will answer a fundamental question in the addiction field, while also providing exceptional training in my development as an independent physician-scientist.