DOI
https://doi.org/10.25772/W5T8-AS25
Defense Date
2013
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Neuroscience
First Advisor
Sim-Selley Laura
Abstract
The main psychoactive and therapeutic effects of Δ9-tetrahydrocannabinol (THC) are mediated through cannabinoid type 1 receptors (CB1Rs). The therapeutic uses of THC are mitigated by the development of tolerance to these therapeutic effects, whereas tolerance does not readily develop to some of the side-effects of THC, like motor impairment and reward. The development of tolerance occurs through adaptations at CB1Rs, which include desensitization (G-protein uncoupling) and downregulation (receptor degradation). Brain region-dependent differences in THC-mediated adaptations are proposed to explain the differences in tolerance to various THC-mediated effects. These studies focused on whether ΔFosB, a stable transcription factor, could regulate CB1R adaptations since regions resistant to CB1R adaptations, like the basal ganglia, exhibit THC-mediated ΔFosB induction. The studies in this dissertation tested the hypothesis that THC-mediated induction of ΔFosB is regulated through interactions between cannabinoid and dopamine systems and that brain region-dependent differences in ΔFosB transcriptional regulation could explain some aspects of long-term CB1R signaling and CB1R adaptations. Results determined that THC induced ΔFosB primarily in forebrain areas, like striatum, that are innervated by midbrain dopamine neurons. An inverse, brain region-dependent correlation was found between CB1R desensitization and ΔFosB induction. Studies utilizing bitransgenic mice with overexpression of ΔFosB, or its dominant negative ∆cJun, determined that ΔFosB regulates CB1R signaling and reduces CB1R desensitization. Based on this regional profile, studies determined the role of dopamine signaling in THC-mediated ∆FosB induction. Results showed that THC-mediated induction of ΔFosB required dopamine type 1 receptors, but not the dopamine-and cAMP-dependent phosphoprotein of Mr 32kDA. Finally, the functional consequences of THC-mediated ΔFosB induction were assessed by measuring expression of known targets of ΔFosB following both acute and repeated THC administration. Results found that, in prefrontal cortex, known targets of ΔFosB exhibited functionally different signaling expression patterns when comparing acute THC with THC-challenge in THC-experienced mice, which enhanced ΔFosB induction. These studies establish a role for ΔFosB in regulating long-term CB1R signaling/adaptation following repeated THC administration and could have implications for changes in the effects of THC during repeated administration, including the development of differential tolerance to motor-impairing and rewarding effects of THC versus other pharmacological effects.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
10-10-2013