Pharmacokinetic and Pharmacodynamic Characterization of Tetrahydrocannabinol-Induced Cannabinoid Dependence After Chronic Passive Cannabis Smoke Exposure in Rats.
Cannabis Cannabinoid Res
; 4(4): 240-254, 2019.
Article
em En
| MEDLINE
| ID: mdl-32042924
ABSTRACT
Introduction:
Cannabis is the most widely used illicit drug in the US, and cannabis use among young adults continues to rise. Previous studies have shown that chronic administration of delta 9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, induces dependence in animal models. Because smoking is the most frequent route of THC self-administration, it is critical to investigate the effects of cannabis smoke inhalation. The goal of the current study was to develop a rat model to characterize the pharmacokinetics (PKs) of THC after cannabis smoke inhalation, and to determine if chronic cannabis smoke inhalation leads to the development of cannabis dependence. Materials andMethods:
For the PK study, male Wistar rats were administered THC intravenously (1 mg/kg) or exposed to smoke from 5 or 10 sequentially smoked cannabis cigarettes (5.3% THC) in an automated smoking machine. Plasma samples were collected from 10 min to 10 hours post smoke exposure (or intravenous administration) and analyzed using liquid chromatography-mass spectrometry to characterize the PK of THC. A three-compartment PK model was used to characterize the PKs. In a separate study, three groups of male Wistar rats were trained in an intracranial self-stimulation (ICSS) procedure, and exposed to smoke from burning 5 or 10 cannabis cigarettes (or clean air control conditions), 5 days/week for 4 weeks. Discussion andConclusions:
Across exposure days, the change from baseline in ICSS thresholds for cannabis smoke-exposed groups was significantly lower and response latencies were significantly faster in the cannabis smoke-exposed groups compared to controls, suggesting that chronic cannabis smoke exposure has rewarding properties. Acute administration of the CB1 receptor antagonist rimonabant (0.3, 1.0, 3.0 mg/kg) induced a dose-dependent increase in ICSS thresholds in the smoke-exposed rats, suggestive of dependence and withdrawal. Finally, an effect compartment PK-pharmacodynamic model was used to describe the relationship between THC concentrations and changes in ICSS thresholds after cannabis smoke exposure.
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MEDLINE
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Ano de publicação:
2019
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Article