Defense Date

2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Aron H Lichtman

Second Advisor

Poklis Alphonse

Abstract

CP47,497 and other synthetic cannabinoid compounds were incipiently synthesized as research tools to investigate the mechanisms by which marijuana affects the brain and to aid in the development of therapeutic agents. Recently, these cannabinoid compounds have resurfaced in the designer drug market, marketed as “herbal incense products” (HIPs). Their popular use has resulted in an alarming rate of reported adverse effects and toxicities. Current legislation classified CP47,497 and several other synthetic cannabinoids compounds as Schedule I agents, but abuse of these compounds persists with serious consequences to public health and safety. In vivo studies examining the behavioral consequences of abused synthetic cannabinoids are limited. As a result, the goals of this research were to elucidate the acute and chronic pharmacological effects of CP47,497 and to develop a bioanalytical method for CP47,497 drug detection in mice. Cannabimimetic effects were evaluated in well-established in vivo models, the tetrad paradigm and drug discrimination assay. The tetrad test is comprised of four outcome measures sensitive to the primary psychoactive cannabinoid present in marijuana, delta-9-tetrahydrocannabinol (THC): catalepsy (bar test), antinociception (tail withdrawal latency), hypothermia, and decreases in spontaneous locomotor activity. While many pharmacological agents can produce one or a subset of these tetrad effects, drugs that activate CB1 receptors produce characteristic effects in all four parameters. An HPLC/MS/MS method was developed and confirmed the presence of CP47,497 in brain. We investigated whether CB1 receptors mediate the pharmacological effects of CP47,497. Cumulative dose-response experiments determined CP47,497 is more potent than THC in vivo in using multiple behavioral assays. Complementary pharmacological (CB1 receptor antagonist, rimonabant) and genetic (CB1 (-/-) mice) approaches were used to investigate whether CB1 receptors mediate the effects of CP47,497. Rimonabant (3 mg/kg or 10 mg/kg, depending on independent measure) blocked all cannabinoid-like pharmacological effects of CP47,497. Supporting these findings, CB1(-/-) mice were resistant to cannabimimetic effects of CP47,497. CP47,497 fully substituted for THC in the drug discrimination assay, with a potency of more than 5 times that of THC. Collectively, these results indicate that CP47,497 is markedly more potent (i.e. 5-8 fold) than THC, and its repeated administration produces tolerance to the cataleptic, antinociceptive, hypothermic and hypolocomotor effects in mice, with significant presentation of somatic withdrawal signs (paw flutter and head shakes) upon drug cessation. These findings are consistent with the high incidence of adverse events in humans abusing synthetic cannabinoids.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2014

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