Sunday, May 11, 2025
5/11/2025
The role of nucleus accumbens dopamine in incubation of cocaine craving - Project Summary Relapse represents a consistent clinical problem when treating individuals with Substance Use Disorder. To study this, I will use the incubation of craving model to investigate the role of dopamine in the nucleus accumbens (NAc) core subregion (NAcc) in the persistence of cue-induced cocaine craving in rats after protracted abstinence. The procedure begins with extended access cocaine self-administration during which the rat learns to associate a drug infusion with a light cue. This is followed by a period of forced abstinence during which the rat is returned to their home cage and has no exposure to the drug or drug-paired cues. At different time-points during this abstinence period, rats are returned to the operant boxes for cue-induced seeking tests, during which responding on the nose-poke hole that previously delivered drug and cue now delivers only the cue. As the duration of abstinence increases, responding under these conditions, our measure of cue-induced drug seeking or craving, progressively intensifies or ‘incubates’. This model is translationally relevant because incubation of craving also occurs in humans. The Wolf lab and others have demonstrated that incubation requires plasticity of excitatory synaptic transmission in the NAcc allowing for a strengthening of these synapses. However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine plays in the incubation of cocaine craving. I hypothesize that dopamine transients in the NAcc associated with cue-induced drug seeking intensify during incubation and contribute to its expression. In Aim 1, I will use fiber photometry paired with the dopamine biosensor GRAB_DA to measure dopamine responses provoked by the drug paired cue during seeking tests in early abstinence, prior to incubation, and late abstinence, after incubation has plateaued. In Aim 2, I will determine the functional significance of NAcc dopaminergic transmission during incubation by injecting dopamine receptor antagonists into the NAcc before the drug seeking test. I predict that blockade of either D1 dopamine receptors or D2 dopamine receptors will reduce cue-induced cocaine seeking after incubation has occurred, and that this reduction will be less robust in early abstinence. This project will address a current gap in the literature regarding dopamine’s role in the incubation of craving. In addition to scientific advancement, this proposal offers me many opportunities to develop as a scientist. Learning fiber photometry and the other approaches required for this project, and applying these approaches to an established animal model of relapse, are key foundational technical skills that I can build upon during future postdoctoral training. Other goals of this fellowship training are to improve my written and oral communication skills by writing manuscripts and by attending conferences to present my work and network in the field of neuroscience, to improve my ability to design rigorous experiments, and to gain more experience with mentoring and supervising others. These skills will help me become a competitive post-doc candidate and will eventually allow me to become an independent researcher either at the PI level or the staff scientist level.
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