INVESTIGATOR: Natalie Zlebnik, Ph.D.
STUDY LOCATION: University of California, Riverside
PROJECT TITLE: Therapeutic potential of cannabinoids for cocaine relapse
FUNDING SOURCE: Center for Medicinal Cannabis Research
PROJECT TYPE: Pre-Clinical Study
STATUS: Active
ABSTRACT:
Background–Significance–Hypotheses: Cannabis is frequently used as a harm-reduction strategy during cocaine abstinence, and both preclinical and human studies suggest cannabinoids may reduce cocaine craving and relapse. However, the neural mechanisms underlying this effect remain unclear. Endocannabinoids (eCBs) regulate synaptic plasticity in corticostriatal circuits critical for drug- seeking. We hypothesize that prolonged cocaine withdrawal impairs eCB signaling in the medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) pathway, contributing to cocaine craving. Further, we hypothesize that THC treatment during withdrawal restores CB1R-mediated regulation of the mPFC-NAc pathway to attenuate relapse vulnerability.
Innovation: This project employs precision measurement of eCB function, novel GRAB-eCB biosensors for real-time in vivo imaging of eCB dynamics, and conditional CB1R deletion to determine the role of eCB signaling in this pathway. By pairing translationally- relevant THC dosing with circuit-specific manipulation, the proposed research offers a novel mechanistic bridge between cocaine- mediated impairment in eCB function and cannabinoid-based therapeutic strategies to combat relapse.
Design–Methods: Using a mouse model of intravenous cocaine self-administration and relapse, Aim 1 will define expression and function of eCB system components during early and late withdrawal using qRT-PCR and UPLC/MS-MS (Day 1, 21; 10-12/group) and fiber photometric imaging of eCB signaling within the mPFC-NAc pathway (GRAB-eCB, GRAB-eCBmut; 14/group). Aim 2 will determine the therapeutic effects of chronic THC (0, 0.5, 5 mg/kg, i.p.) on cocaine seeking during protracted withdrawal (14/group). Further, we will use an intersectional viral strategy to delete CB1Rs from mPFC neurons projecting to the NAc to probe their role in mediating the treatment effects of THC (CB1R-floxed, cre or control; 14/group). Measures will be analyzed with separate multi- factor mixed analyses of variance, followed by post hoc comparisons corrected for multiple comparisons (alpha = 0.05). Effect sizes and sex differences will be reported throughout.
Implications: This study will identify time-dependent eCB deficits in relapse-relevant circuits and establish their role in incubation of cocaine craving. Findings will provide mechanistic support for cannabinoid-based treatments, offering a foundation for future translational research targeting cannabinoid signaling in addiction.