Pharmacokinetic and Pharmacodynamic Characterization of Tetrahydrocannabinol-Induced Cannabinoid Dependence After Chronic Passive Cannabis Smoke Exposure in Rats

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 and Methods:

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 and Conclusions:

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.

Get full access to this article

View all access options for this article.

References

Rebecca

Ahrnsbrak

, Bose

, Hedden

, et al. Key substance use and mental health indicators in the United States: results from the 2016 National Survey on Drug Use and Health. 2017. Available at www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2016/NSDUH-FFR1-2016.htm (last accessed October 25, 2019).

Panlilio

, Justinova

, Goldberg

. Animal models of cannabinoid reward. Br J Pharmacol. 2010; 160:499–510.

Benjamin

, Fossler

. Edible cannabis products: it is time for FDA oversight. J Clin Pharmacol. 2016; 56:1045–1047.

Zgair

, Wong

JCM

, Sabri

, et al. Development of a simple and sensitive HPLC–UV method for the simultaneous determination of cannabidiol and 9-tetrahydrocannabinol in rat plasma. J Pharm Biomed Anal J Pharm Biomed. 2015; 114:145–151.

Zgair

, Wong

JCM

, Lee

, et al. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines. Am J Transl Res. 2016; 8:3448–3459.

Valiveti

, Agu

, Hammell

, et al. Intranasal absorption of Δ9-tetrahydrocannabinol and WIN55,212-2 mesylate in rats. Eur J Pharm Biopharm. 2007; 65:247–252.

Justinova

, Tanda

, Redhi

, et al. Self-administration of Δ9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl). 2003; 169:135–140.

Tanda

, Munzar

, Goldberg

. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci. 2000; 3:1073–1074.

Zangen

. Two brain sites for cannabinoid reward. J Neurosci. 2006; 26:4901–4907.

10.

Spencer

, Neuhofer

, Chioma

, et al. A model of Δ9-tetrahydrocannabinol self-administration and reinstatement that alters synaptic plasticity in nucleus accumbens. Biol Psychiatry. 2018; 84:601–610.

11.

Wakeford

AGP

, Wetzell

, Pomfrey

, et al. The effects of cannabidiol (CBD) on Δ⁹-tetrahydrocannabinol (THC) self-administration in male and female Long-Evans rats. Exp Clin Psychopharmacol. 2017; 25:242–248.

12.

Panlilio

, Goldberg

, Justinova

. Cannabinoid abuse and addiction: clinical and preclinical findings. Clin Pharmacol Ther. 2015; 97:616–627.

13.

Gardner

, Paredes

, Smith

, et al. Facilitation of brain stimulation reward by delta 9-tetrahydrocannabinol. Psychopharmacology (Berl). 1988; 96:142–144.

14.

Kornetsky

, Esposito

, McLean

, et al. Intracranial self-stimulation thresholds: a model for the hedonic effects of drugs of abuse. Arch Gen Psychiatry. 1979; 36:289–292.

15.

Liu

, Pan

, Gold

, et al. Effects of fentanyl dose and exposure duration on the affective and somatic signs of fentanyl withdrawal in rats. Neuropharmacology. 2008; 55:812–818.

16.

Igari

, Alexander

, Ji

, et al. Varenicline and cytisine diminish the dysphoric-like state associated with spontaneous nicotine withdrawal in rats. Neuropsychopharmacology. 2014; 39:455–465.

17.

Small

, Shah

, Davenport

, et al. Tobacco smoke exposure induces nicotine dependence in rats. Psychopharmacology (Berl). 2010; 208:143–158.

18.

Sambo

, Lin

, Owens

, et al. The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission. Nat Commun. 2017; 8:2228.

19.

Der-Avakian

, Markou

. The neurobiology of anhedonia and other reward-related deficits. Trends Neurosci. 2012; 35:68–77.

20.

Panagis

, Mackey

, Vlachou

. Cannabinoid regulation of brain reward processing with an emphasis on the role of CB1 receptors: a step back into the future. Front Psychiatry. 2014; 5:92.

21.

Wilson

, Varvel

, Harloe

, et al. SR 141716 (Rimonabant) precipitates withdrawal in marijuana-dependent mice. Pharmacol Biochem Behav. 2006; 85:105–113.

22.

Järbe

TUC

, Gifford

, Makriyannis

. Antagonism of Δ9-THC induced behavioral effects by rimonabant: time-course studies in rats. Eur J Pharmacol. 2011; 648:133–138.

23.

Katsidoni

, Kastellakis

, Panagis

. Biphasic effects of Δ9-tetrahydrocannabinol on brain stimulation reward and motor activity. Int J Neuropsychopharmacol. 2013; 16:2273–2284.

24.

Lichtman

, Martin

. Marijuana withdrawal syndrome in the animal model. J Clin Pharmacol. 2002; 42(11 Suppl):20S–27S.

25.

Nguyen

, Aarde

, Vandewater

, et al. Inhaled delivery of Δ9-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology. Neuropharmacology. 2016; 109:112–120.

26.

Lichtman

, Poklis

, et al. The pharmacological activity of inhalation exposure to marijuana smoke in mice. Drug Alcohol Depend. 2001; 63:107–116.

27.

Bruijnzeel

, Qi

, Guzhva

LV.

, et al. Behavioral characterization of the effects of cannabis smoke and anandamide in rats. PLoS One. 2016; 11:1–24.

28.

Cone

, Bigelow

, Herrmann

, et al. Nonsmoker exposure to secondhand cannabis smoke. III. Oral fluid and blood drug concentrations and corresponding subjective effects. J Anal Toxicol. 2015; 39:497–509.

29.

FDA F and DA, Food and Drug Administration. Guidance for Industry: Bioanalytical Method Validation; 2001. Available at www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf (last accessed October 25, 2019).

30.

Ravula

, Chandasana

, Setlow

, et al. Simultaneous quantification of cannabinoids tetrahydrocannabinol, cannabidiol and CB1 receptor antagonist in rat plasma: an application to characterize pharmacokinetics after passive cannabis smoke inhalation and co-administration of rimonabant. J Pharm Biomed Anal. 2018; 160:119–125.

31.

Bruijnzeel

, Zislis

, Wilson

, et al. Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats. Neuropsychopharmacology. 2007; 32:955–963.

32.

, Guzhva

, Yang

, et al. Overexpression of CRF in the BNST diminishes dysphoria but not anxiety-like behavior in nicotine withdrawing rats. Eur Neuropsychopharmacol. 2017; 26:1378–1389.

33.

Blaes

, Orsini

, Holik

, et al. Neurobiology of learning and memory enhancing effects of acute exposure to cannabis smoke on working memory performance. Neurobiol Learn Mem. 2019; 157:151–162.

34.

Bruijnzeel

, Knight

, Panunzio

, et al. Effects in rats of adolescent exposure to cannabis smoke or THC on emotional behavior and cognitive function in adulthood. Psychopharmacology (Berl). 2019. DOI:10.1007/s00213-019-05255-7

35.

Rosenkrantz

, Braude

. Acute, subacute inhalation and 23-day toxicities chronic in the Marihuana. Toxicol Appl Pharmacol. 1974; 441:428–441.

36.

Alexander

, Collins

, Coombs

, et al. Association of Inhalation Toxicologists (AIT) working party recommendation for standard delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals. Inhal Toxicol. 2008; 20:1179–1189.

37.

Strougo

, Zuurman

, Roy

, et al. Modelling of the concentration—effect relationship of THC on central nervous system parameters and heart rate—insight into its mechanisms of action and a tool for clinical research and development of cannabinoids. J Psychopharmacol. 2008; 22:717–726.

38.

Negus

, Moerke

. Determinants of opioid abuse potential: insights using intracranial self-stimulation. Peptides. 2019; 112:23–31.

39.

Bespalov

, Lebedev

, Panchenko

, et al. Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur Neuropsychopharmacol. 1999; 9:377–383.

40.

Heuberger

JAAC

, Guan

, Oyetayo

, et al. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics. Clin Pharmacokinet. 2015; 54:209–219.

41.

Grim

, Wiebelhaus

, Morales

, et al. Effects of acute and repeated dosing of the synthetic cannabinoid CP55,940 on intracranial self-stimulation in mice. Drug Alcohol Depend. 2015; 150:31–37.

42.

Vlachou

, Nomikos

, Panagis

. CB1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat. Psychopharmacology (Berl). 2005; 179:498–508.

43.

Fokos

, Panagis

. Effects of delta9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress. J Psychopharmacol. 2010; 24:767–777.

44.

Vlachou

, Nomikos

, Stephens

, et al. Lack of evidence for appetitive effects of Delta 9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference procedures in rodents. Behav Pharmacol. 2007; 18:311–319.

45.

Chen

, Paredes

, Lowinson

, et al. Strain-specific facilitation of dopamine efflux by Delta9-tetrahydrocann binol in the nucleus accumbens of rat: an in vivo microdialysis study. Neurosci Lett. 1991; 129:136–140.

46.

Tsou

, Patrick

, Walker

. Physical withdrawal in rats tolerant to delta 9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. Eur J Pharmacol. 1995; 280:R13–R15.

47.

Schlosburg

, Carlson

BLA

, Ramesh

, et al. Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J. 2009; 11:342–352.

48.

Hunault

, Böcker

KBE

, Stellato

, et al. Acute subjective effects after smoking joints containing up to 69 mg Δ9-tetrahydrocannabinol in recreational users: a randomized, crossover clinical trial. Psychopharmacology (Berl). 2014; 231:4723–4733.

49.

Awasthi

, An

, Donovan

, et al. Relating observed psychoactive effects to the plasma concentrations of delta-9-tetrahydrocannabinol and its active metabolite: an effect-compartment modeling approach. J Pharm Sci. 2018; 107:745–755.

50.

Mura

, Kintz

, Dumestre

, et al. THC can be detected in brain while absent in blood. J Anal Toxicol. 2005; 29:842–843.