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Investigating the Mechanisms of Aversive Effects Produced by Cannabinoid 1 Receptor Agonism

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Title: Investigating the Mechanisms of Aversive Effects Produced by Cannabinoid 1 Receptor Agonism
Author: DeVuono, Marieka
Department: Department of Psychology
Program: Psychology
Advisor: Parker, LindaLeri, Francesco
Abstract: Cannabis is one of the most commonly used recreational drugs, but research regarding its rewarding effects is inconsistent. Many aversive effects, including the phenomenon of cannabinoid hyperemesis syndrome (CHS), are reported and may mask rewarding effects when tested in animals. The main psychotropic constituent, Δ9-tetrahydrocannabinol (THC), acts on the cannabinoid 1 (CB1) receptor of the endocannabinoid system. Aversive effects of CB1 receptor agonists are thought to arise from impaired stress homeostasis caused by endocannabinoid system dysregulation. Therefore, we aimed to elucidate the role of the endocannabinoid and stress systems in place aversion and nausea produced by CB1 receptor agonism in Sprague-Dawley rats. Using an unbiased place conditioning paradigm, acute footshock stress reduced the place aversion and locomotor suppressing effects of THC, confirming the interplay between stress and CB1 receptor agonism. Using the taste reactivity paradigm, high but not low doses of THC and the full CB1 receptor agonist, JWH-018, produced conditioned gaping, a measure of nausea in rats. Conditioned gaping was blocked with pretreatment of the CB1 receptor inverse agonist/antagonist, rimonabant, indicating that the effect is CB1 receptor mediated. High doses of THC and JWH-018 both increased levels of the stress hormone corticosterone (CORT). A high dose of THC also altered mRNA gene expression of the endocannabinoid degrading enzymes in the hypothalamus, supporting the involvement of stress. To further investigate the mechanisms of THC-induced nausea, we investigated the ability of several drugs that interfere with stress to interfere with THC induced-nausea. Indeed, increasing levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and blocking corticotropin releasing hormone, β-adrenergic or serotonin 5-HT1A receptors interfered with THC-induced conditioned gaping. Lastly, a non-intoxicating cannabis component, cannabidiol (CBD), inhibited THC-induced conditioned gaping via a 5-HT1A receptor mechanism and blocked the CORT increase produced by high dose THC. Results with CBD are consistent with its ability to reduce CB1 receptor agonist aversion. Interactions of the endocannabinoid system, stress, nausea, and the influence of CB1 receptor agonism are discussed. Overall, the results of this dissertation support the involvement and interaction between the stress response and the endocannabinoid system mediating the aversive effects of CB1 receptor agonism.
Date: 2021-03
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Related Publications: DeVuono, M. V, Wills, K. L., MacPherson, D. V, Hrelja, K. M., & Parker, L. A. (2017). Effect of footshock stress on place conditioning produced by delta9-tetrahydrocannabinol and the fatty acid amide hydrolase (FAAH) inhibitor, URB597, in sprague-dawley rats. Psychopharmacology, 234(21), 3229–3240., M. V., Hrelja, K. M., Sabaziotis, L., Rajna, A., Rock, E. M., Limebeer, C. L., Mutch, D. M., & Parker, L. A. (2018). Conditioned gaping produced by high dose Δ9-tetrahydrocannabinol: Dysregulation of the hypothalamic endocannabinoid system. Neuropharmacology, 141, 272–282., M. V., Hrelja, K. M., Petrie, G. N., Limebeer, C. L., Rock, E. M., Hill, M. N., & Parker, L. A. (2020). Nausea-induced conditioned gaping reactions in rats produced by high dose synthetic cannabinoid, JWH-018. Cannabis and Cannabinoid Research, 5(4), 298–304., M. V., La Caprara, O., Sullivan, M. T., Bath, A., Petrie, G. N., Limebeer, C. L., Rock, E. M., Hill, M. N., & Parker, L. A. (2020). Role of the stress response and the endocannabinoid system in Δ9-tetrahydrocannabinol (THC)-induced nausea. Psychopharmacology, 237, 2187–2199., M. V., La Caprara, O., Petrie, G. N., Limebeer, C. L., Rock, E. M., Hill, M. N., & Parker, L. A. (2020). Cannabidiol (CBD) interferes with the establishment of Δ9-Tetrahydrocannabinol (THC)-induced nausea through a 5-HT1A mechanism. Cannabis and Cannabinoid Research.

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