Correlation between the Dose and Development of Acute Tolerance to the Hypothermic Effect of THC

Uran, Berna Nilgün Özgürsoy; Tulunay, F. Cankat; Ayhan, I.H.; Ülkü, Eda; Kaymakçalan, S

doi:10.1159/000137458

Cited by 8 publications

(5 citation statements)

References 7 publications

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“…This is consistent with tolerance we and others have described in mice and rats (Fan et al, 1994; Singh et al, 2011; Uran et al, 1980). Thus, this study extends the generality of this phenomenon to monkeys.…”

Section: Discussionsupporting

confidence: 93%

Blood levels do not predict behavioral or physiological effects of Δ9-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure

Ginsburg

Hrubá

Zaki

et al. 2014

Drug and Alcohol Dependence

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Background Recent changes in the legality of cannabis have prompted evaluation of whether blood levels of Δ9-tetrahydrocannabinol (THC) or its metabolites could be used to substantiate impairment, particularly related to behavioral tasks such as driving. However, because marked tolerance develops to behavioral effects of THC, the applicability of a particular threshold of blood THC as an index of impairment in people with different patterns of use remains unclear. Studies relevant to this issue are difficult to accomplish in humans, as prior drug exposure is difficult to control. Methods Here, effects of THC to decrease rectal temperature and operant response rate compared to levels of THC and its metabolites were studied in blood in two groups of monkeys: one received intermittent treatment with THC (0.1 mg/kg i.v.) and another received chronic THC (1 mg/kg/12 h s.c.) for several years. Results In monkeys with intermittent THC exposure, a single dose of THC (3.2 mg/kg s.c.) decreased rectal temperature and response rate. The same dose did not affect response rate or rectal temperature in chronically exposed monkeys, indicative of greater tolerance. In both groups, blood levels of THC peaked 20–60 min post-injection and had a similar half life of elimination, indicating no tolerance to the pharmacokinetics of THC. Notably, in both groups, the behavioral effects of THC were not apparent when blood levels were maximal (20-min post-administration). Conclusion These data indicate that thresholds for blood levels of THC do not provide a consistent index of behavioral impairment across individuals with different patterns of THC exposure.

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Section: Discussionsupporting

confidence: 93%

Blood levels do not predict behavioral or physiological effects of Δ9-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure

Ginsburg

Hrubá

Zaki

et al. 2014

Drug and Alcohol Dependence

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show abstract

“…Interestingly, unlike rodent studies that have shown tolerance to THC-induced temperature changes with chronic exposure ( Taylor and Fennessy, 1978 ; Uran et al, 1980 ; Tai et al, 2015 ; Nguyen et al, 2018 , 2020a , b ), there was no tolerance to THC’s temperature changes using this e-cigarette vapor inhalation paradigm. The lack of tolerance in the current study could be due to features of the administration route, chosen dose, or an interaction of the two.…”

Section: Discussioncontrasting

confidence: 71%

A Model of Combined Exposure to Nicotine and Tetrahydrocannabinol via Electronic Cigarettes in Pregnant Rats

et al. 2022

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Nicotine and cannabis are two of the most commonly consumed licit and illicit drugs during pregnancy, often consumed together via e-cigarettes. Vaping is assumed to be a safer alternative than traditional routes of consumption, yet the potential consequences of prenatal e-cigarette exposure are largely unknown, particularly when these two drugs are co-consumed. In a novel co-exposure model, pregnant Sprague-Dawley rats received nicotine (36 mg/mL), tetrahydrocannabinol (THC) (100 mg/mL), the combination, or the vehicle via e-cigarettes daily from gestational days 5–20, mimicking the first and second human trimesters. Maternal blood samples were collected throughout pregnancy to measure drug and metabolite levels, and core body temperatures before and after exposure were also measured. Pregnant dams exposed to combined nicotine and THC had lower plasma nicotine and cotinine levels than those exposed to nicotine alone; similarly, the combined exposure group also had lower plasma THC and THC metabolite (THC-OH and THC-COOH) levels than those exposed to THC alone. Prenatal nicotine exposure gradually decreased initial core body temperatures each day, with chronic exposure, whereas exposure to THC decreased temperatures during the individual sessions. Despite these physiological effects, no changes were observed in food or water intake, weight gain, or basic litter outcomes. The use of this model can help elucidate the effects of co-exposure to THC and nicotine via e-cigarettes on both users and their offspring. Understanding the effects of co-use during pregnancy is critical for improving education for pregnant mothers about prenatal e-cigarette use and has important implications for public policy.

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“…In addition, THC is a highly oxidizable substance and could lose its biological activity within 7-8 days, even in a cold (+4°C) and dark environment (preliminary studies in this work). This factor could contribute, at least to some extent, to the well-known tolerance of various physiological effects of THC described in animals (Uran, 1980) but not evident in humans with marijuana smoking. Finally, drug action in humans is typically defined by its subjective effects, but in animals it relies exclusively on alterations in physiological and behavioral parameters.…”

Section: Discussionmentioning

confidence: 97%

Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats

Smirnov

Kiyatkin

2008

Brain Research

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Marijuana smoking dramatically alters responses to various environmental stimuli. To study this phenomenon, we assessed how delta-9-tetrahydrocannabinol (THC), a primary psychoactive ingredient of marijuana, affects locomotor and brain (nucleus accumbens or NAcc), muscle and skin temperature responses to natural arousing stimuli (one-min tail-pinch and one-min social interaction with another male rat) and iv cocaine (1 mg/kg) in male rats. THC was administered at three widely varying doses (0.5, 2.0 and 8.0 mg/kg, ip), and the drug-induced changes in basal values and responses to stimuli were compared to those occurring following ip vehicle injections (control). Each stimulus in control conditions caused acute locomotor activation, a prolonged increase in brain and muscle temperature (0.6-1.0°C for 20-50 min) and transient decrease in skin temperature (−0.6°C for 1-3 min). While THC at any dose had a tendency to decrease spontaneous locomotion as well as brain and muscle temperatures, true hypothermia and hypoactivity as well as clearly diminished locomotor and temperature responses to all stimuli were only seen following the largest dose. In this case, temperature decreases in the NAcc were stronger than in the muscle, suggesting metabolic brain inhibition as the primary cause of hypoactivity, hypothermia and hyporesponsiveness. While weaker in strength and without associated vasodilatation, this response pattern is mimicked by general anesthetics, questioning to what extent the hypothermic action of THC is specific (i.e., mediated via endogenous cannabinoid receptors) or non-specific, reflecting drug interaction with membrane lipids or other receptors. In contrast, weaker behavioral and temperature effects of THC at lower doses resemble those of diazepam, whose locomotion-and temperature-decreasing effects are evident only in activated conditions, when rats are moving and basal temperatures are elevated. Keywords brain metabolism; brain and body temperature; cannabinoids natural arousing stimuli; intravenous cocaine; vasoconstriction

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Correlation between the Dose and Development of Acute Tolerance to the Hypothermic Effect of THC

Cited by 8 publications

References 7 publications

Blood levels do not predict behavioral or physiological effects of Δ9-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure

Blood levels do not predict behavioral or physiological effects of Δ9-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure

A Model of Combined Exposure to Nicotine and Tetrahydrocannabinol via Electronic Cigarettes in Pregnant Rats

Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats

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