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Posted ContentDOI

Repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence: Sex differences inacute thermoregulatory tolerance and in feeding during adulthood

25 Sep 2018-bioRxiv (Cold Spring Harbor Laboratory)-pp 426064
TL;DR: It is confirmed that repeated THC vapor inhalation in adolescence results in lasting consequences observable in adulthood, and each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC with THC exhibiting greater potency in females.
Abstract: Many US adolescents are regularly exposed to Δ 9 -tetrahydrocannabinol (THC) via the smoking and more recently, vaping, of cannabis and cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, and decreasing perceptions of harm, make it increasingly important to determine the consequences of frequent adolescent exposure. Male and female Wistar rats were implanted with radio-telemetry devices to monitor body temperature and exposed to twice daily 30 minute inhalation of THC vapor, or the propylene glycol (PG) vehicle, from post-natal day (PND) 35-39 and PND 42-45 using an e-cigarette based system. Responses to THC were re-determined from PND 86-94 and chow intake was assessed in mid adulthood. Blood samples were obtained from additional groups following THC inhalation on PND 31, on PND 39 after a week of twice daily exposure, and during early adulthood. Additional groups of male rats exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults. Female, but not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC with THC exhibiting greater potency in females. Repeated-THC male rats consumed more food than their PG treated control group, in the absence of a significant bodyweight difference, but male rats did not differ in oxycodone self-administration. This study confirms that repeated THC vapor inhalation in adolescence results in lasting consequences observable in adulthood.
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Journal ArticleDOI
TL;DR: Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response to THC.
Abstract: Author(s): Nguyen, Jacques D; Creehan, Kevin M; Kerr, Tony M; Taffe, Michael A | Abstract: Background and purposeAdolescents are regularly exposed to ∆9 -tetrahydrocannabinol (THC) via smoking and, more recently, vaping cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response to THC.Experimental approachesMale and female rats inhaled THC vapour, or that from the propylene glycol (PG) vehicle, twice daily for 30nmin from postnatal day (PND) 35-39 and PND 42-46 using an e-cigarette system. Thermoregulatory responses to vapour inhalation were assessed by radio-telemetry during adolescence and from PND 86-94. Chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after 4ndays of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults.Key resultsFemale, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC. However, enhanced potency was found in females. Repeated THC male rats consumed more food than their PG-treated control group, without significant bodyweight differences. Adolescent THC did not alter oxycodone self-administration in either sex but increased fentanyl self-administration in females.Conclusions and implicationsRepeated THC vapour inhalation in adolescent rats has lasting consequences observable in adulthood.

44 citations


Cites background from "Repeated Δ9-tetrahydrocannabinol (T..."

  • ...Our recent study in adult rats showed tolerance to the hypothermic and antinociceptive responses to THC after twice (female) or three times (male or female) daily inhalation (Nguyen et al., 2018)....

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Journal ArticleDOI
TL;DR: Additive effects of THC and oxycodone are demonstrated and the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids is suggested.

37 citations


Cites background or methods from "Repeated Δ9-tetrahydrocannabinol (T..."

  • ...Rats were administered a conjugate vaccine (Oxy-TT; N=12) or the tetanus toxoid carrier protein only (TT; N= 10) on Weeks 0, 2, and 4, adapted from a vaccination protocol previously reported (Nguyen et al., 2018c); see Supplemental Methods for full details....

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  • ...…however, the key result is that THC was equally effective at reducing the IVSA of oxycodone in each of the adolescent-treatment groups, suggesting no lasting alteration of CB1 function (Nguyen et al., 2018a, 2018b) that was relevant to the interaction of THC with the rewarding effects of oxycodone....

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  • ...We also used two strategies that reduce the oxycodone penetration to the brain for each response, anti-oxycodone vaccination (Nguyen et al., 2018c) and per-infusion dose reduction, thereby requiring increased behavioral output; parallel effects of THC on IVSA would be incompatible with an inference…...

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  • ...…mg/kg, s.c.), THC (5,10 mg/kg, i.p.) or the combination were conducted in a group of adult male (N= 6; 48 wks of age, 665.2, SD 76.2 g) and female (N=8; 48 wks of age, 310.5, SD 44.3 g) Wistar rats that were previously used in experiments of chronic vapor inhalation of THC (Nguyen et al., 2018b)....

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  • ...First, we used an anti-oxycodone vaccine strategy which results in about a 50% reduction in brain levels of oxycodone after a given dose (Nguyen et al., 2018c) and increases the intravenous self-administration of oxycodone under easy access conditions (i.e., a fixed-ratio 1 response contingency),…...

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Journal ArticleDOI
TL;DR: The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD, and produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.
Abstract: Rationale Cannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. Objective To further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. Methods Blood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. Results Vapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. Conclusions The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.

28 citations

Posted ContentDOI
23 Dec 2017-bioRxiv
TL;DR: Additive effects of THC and oxycodone are demonstrated and the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids is suggested.
Abstract: Growing nonmedical use of prescription opioids is a significant global problem which motivates research on ways to reduce therapeutic use and combat addiction. Medical marijuana availability has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of heroin or morphine in animal models. This study was conducted to determine if Δ 9 -tetrahydrocannabinol (THC) enhances the rewarding and/or antinociceptive effects of oxycodone. Male Wistar rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h or 8 h sessions. After acquisition of oxycodone IVSA, rats were exposed to THC by vapor inhalation (0, 100 or 200 mg/mL in the vehicle; 1 h and 8 h groups) or injection (0, 5 or 10 mg/kg, i.p., 8 h group) prior to IVSA sessions. Oxycodone intake was significantly decreased in rats following vaporized or injected THC compared with vehicle treatment prior to the session. Additional groups of male and female Wistar rats were assessed for nociception of a 52 °C hot water bath following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL), the THC/oxycodone combination or the PG vehicle. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive effects on tail withdrawal latency were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). These data show additive effects of THC and oxycodone in rats and suggest the potential use of cannabinoids to enhance therapeutic efficacy and to reduce non-medical opioid abuse.

18 citations

Posted ContentDOI
24 Jul 2019-bioRxiv
TL;DR: Female, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels, and each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC with THC greater potency exhibited in females.
Abstract: Adolescents are regularly exposed to Δ9-tetrahydrocannabinol (THC) via smoking, and, more recently, vaping, cannabis / extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behavior and lasting tolerance in response to THC. Male and female rats inhaled THC vapor, or that from the propylene glycol (PG) vehicle, twice daily for 30 minutes from postnatal day (PND) 35-39 and PND 42-45 using an e-cigarette system. Thermoregulatory responses to vapor inhalation were assessed by radio-telemetry during adolescence and from PND 86-94; chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after four days of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults. Female, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC with THC greater potency exhibited in females. Repeated-THC male rats consumed more food than their PG treated control group, in the absence of a significant bodyweight difference. Adolescent THC did not alter oxycodone self-administration in either sex, but increased fentanyl self-administration in females. Repeated THC vapor inhalation in adolescent rats results in lasting consequences observable in adulthood.

7 citations


Cites methods from "Repeated Δ9-tetrahydrocannabinol (T..."

  • ...The training dose (0.15 mg/kg/infusion; ~0.1 ml/infusion) was selected from prior oxycodone self-administration studies (Nguyen et al, 2018; Wade et al, 2015)....

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References
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Journal ArticleDOI
TL;DR: In this article, the authors present a series of linked editorials in the context of biomedical journal abstracts, including: http://onlinelibrary.wiley.com/doi/10.1111/bph.12954/abstract, http://Onlinelabel. wiley. com/doi /10.12956/ABstract, https://www.wired.org/content/index.cfm/
Abstract: Linked Editorials This Editorial is part of a series. To view the other Editorials in this series, visit: http://onlinelibrary.wiley.com/doi/10.1111/bph.12956/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12954/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12955/abstract and http://onlinelibrary.wiley.com/doi/10.1111/bph.13112/abstract

939 citations

Journal ArticleDOI
TL;DR: This study provides the first complete pharmacokinetic profile of the absorption of THC and appearance of metabolites during marijuana smoking, which has implications for understanding the mechanisms underlying the performance-impairing effects of marijuana, as well as for aiding forensic interpretation of cannabinoid blood levels.
Abstract: delta 9-Tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, is rapidly transferred from lungs to blood during smoking. Oxidative metabolism of THC yields the active metabolite, 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-THC), and the inactive metabolite, 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH). Characterization of THC's absorption phase is important because of the rapidity with which THC penetrates the central nervous system to produce psychoactive effects. This study incorporated a highly automated procedure to sample blood and to capture rapid drug level changes during and following smoking. Human subjects smoked one marijuana cigarette (placebo, 1.75%, or 3.55% THC) once a week according to a randomized, crossover, double-blind Latin square design. Samples were analyzed by GC/MS for THC, 11-OH THC, and THCCOOH. THC levels increased rapidly, peaked prior to the end of smoking, and quickly dissipated. Mean peak 11-OH-THC levels were substantially lower than THC levels and occurred immediately after the end of smoking. THCCOOH levels increased slowly and plateaued for an extended period. The mean peak time for THCCOOH was 113 min and a correspondingly longer time course of detection was observed. This study provides the first complete pharmacokinetic profile of the absorption of THC and appearance of metabolites during marijuana smoking. These findings have implications for understanding the mechanisms underlying the performance-impairing effects of marijuana, as well as for aiding forensic interpretation of cannabinoid blood levels.

459 citations

Journal ArticleDOI
TL;DR: The results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.

317 citations


"Repeated Δ9-tetrahydrocannabinol (T..." refers background in this paper

  • ...This shows the potential risks of repeated THC exposure, however, prior investigations have primarily employed the injected route of administration (Cha et al, 2007; Ellgren et al, 2007; Rubino et al, 2008; Winsauer et al, 2011) which may not match the human condition very well....

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  • ...…THC. Repeated treatment of adolescent rats with THC by injection results in observable lasting effects in adulthood including decreased bodyweight (Rubino et al, 2008), impaired spatial working memory (Rubino et al, 2009), increased heroin self-administration (Ellgren et al, 2007), increased…...

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  • ...Prior studies have identified decreased bodyweight (Rubino et al, 2008), impaired spatial working memory (Rubino et al, 2009), and greater sensitivity to THC on a learning task (Winsauer et al, 2011) in the wake of repeated adolescent THC exposure....

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Journal ArticleDOI
TL;DR: The gateway hypothesis demonstrating that adolescence cannabis exposure has an enduring impact on hedonic processing resulting in enhanced opiate intake is supported, possibly as a consequence of alterations in limbic opioid neuronal populations.

274 citations


"Repeated Δ9-tetrahydrocannabinol (T..." refers background in this paper

  • ...This shows the potential risks of repeated THC exposure, however, prior investigations have primarily employed the injected route of administration (Cha et al, 2007; Ellgren et al, 2007; Rubino et al, 2008; Winsauer et al, 2011) which may not match the human condition very well....

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  • ...Another study injected male Long-Evan rats with THC (1.5 mg/kg, i.p.) every third day from PND 28-49 (Ellgren et al, 2007)....

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  • ...…inhalation in the adult rat in terms of tolerance to acute THC exposure, alterations in weight gain and feeding behavior (Sofia and Barry, 1974) and the propensity to self-administer an opioid drug, oxycodone, as has previously been reported for heroin (Ellgren et al, 2007; Stopponi et al, 2014)....

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  • ...…including decreased bodyweight (Rubino et al, 2008), impaired spatial working memory (Rubino et al, 2009), increased heroin self-administration (Ellgren et al, 2007), increased reinstatement of heroin seeking after a pharmacological stressor (Stopponi et al, 2014) and greater sensitivity to…...

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