This is a 5 year competitive renewal that builds upon nearly a decade of previously funded research that has identified the projection from the prefrontal cortex to the nucleus accumbens, and then to the ventral pallidum as a key brain circuit underlying relapse to cocaine use. Relapse is modeled in rats trained to self-administer cocaine and then undergone extinction training, and is defined as the reinstatement of cocaine seeking in response to a conditioned cue, a noncontingent injection of cocaine, or after inhibition of the infralimbic cortex that is hypothesized to disinhibit extinguished responding. In the first aim of the present proposal we will use the recent development of genetically targeted light- activated proteins to validate the role of this circuitry in the reinstatement of cocaine seeking. Previous pharmacological or electrical stimulation techniques used to define brain circuitry suffer caveats such affecting fibers of passage and/or multiple projections from a given nucleus, and these weaknesses are largely circumvented using in vivo light activation of virally transfected channels or transporters. Thus, the first aim is devoted to refining this new technology and validating, or not, previous circuitry studies by our group and others identifying the PFC-accumbens-pallidal circuit as important in relapse. The remaining 3 aims focus on our recent finding that dendritic spine morphology in the nucleus accumbens undergoes rapid and profound changes during a cocaine-primed reinstatement of drug seeking. Firstly, in Aim 2 we will fully characterize these morphological changes in both the core and shell subcompartments of the accumbens in response to different modalities of inducing cocaine seeking (e.g. cue, cocaine and inhibition of infralimbic cortex). Then in Aim 3 we will determine which afferents to the nucleus accumbens are mediating the reinstatement-associated morphological changes, with a focus on glutamatergic inputs from the prefrontal cortex and amygdala, and dopaminergic inputs from the ventral tegmental area. Finally in Aim 4 we conduct experiments to determine if the changes in spine morphology are necessary for reinstating cocaine seeking, or if they are protective and inhibit reinstatement. Accordingly, we will test the capacity of 3 different inhibitors of actin dynamics to simultaneously inhibit primed reinstatement and reinstatement-associated spine morphology. Interestingly, preliminary data presented in the proposal indicates that the rapid morphological changes may be protective rather than causal in reinstating cocaine seeking.
The social and criminal ramifications of psychostimulant abuse are an enormous problem in North America. This project defines the circuitry underlying relapse to cocaine use in an animal model using new genetically targeted light-activated protein technology. Furthermore, neuronal plasticity in relapse circuitry will be examined to determine if the changes in brain structure accompanying chronic cocaine use are protective and helping to inhibit relapse or if they are causal and facilitating relapse.
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|Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin 3rd, William C et al. (2017) Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking. J Neurosci 37:757-767|
|Kupchik, Yonatan M; Kalivas, Peter W (2017) The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think. Neuropsychopharmacology 42:369-370|
|Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624|
|Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386|
|Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756|
|Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812|
|Back, Sudie E; McCauley, Jenna L; Korte, Kristina J et al. (2016) A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders. J Clin Psychiatry 77:e1439-e1446|
|Mulholland, Patrick J; Chandler, L Judson; Kalivas, Peter W (2016) Signals from the Fourth Dimension Regulate Drug Relapse. Trends Neurosci 39:472-85|
|Kalivas, Benjamin C; Kalivas, Peter W (2016) Corticostriatal circuitry in regulating diseases characterized by intrusive thinking. Dialogues Clin Neurosci 18:65-76|
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