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Extended Attenuation of Corticostriatal Power and Coherence after Acute Exposure to Vapourized Δ9-Tetrahydrocannabinol in Rats

Nelong, Tapia Foute1,*; Jenkins, Bryan W. MSc2,*; Perreault, Melissa L. PhD1,#; Khokhar, Jibran Y. PhD2,#

doi: 10.1097/CXA.0000000000000063
ORIGINAL ARTICLES
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Introduction: Over 14% of Canadians use cannabis, with nearly 60% of these individuals reporting daily or weekly use. Inhalation of cannabis vapour has recently gained popularity, but the effects of this exposure on neural activity remain unknown. In this study, we assessed the impact of acute exposure to vapourized Δ9-tetrahydrocannabinol (THC) on neural circuit dynamics in rats.

Objectives: We aimed to characterize the changes in neural activity in the dorsal striatum (dStr), orbitofrontal cortex (OFC), and prefrontal cortex (PFC), after acute exposure to THC vapour.

Methods: Rats were implanted with electrode arrays targeting the dStr, OFC, and PFC. Rats were administered THC (or vehicle) using a Volcano vapourizer and local field potential recordings were performed in a plexiglass chamber in a cross-over design with a week-long washout period.

Results: Decreased spectral power was observed within the dStr, OFC, and PFC in the gamma range (>32–100 Hz) following vapourized THC administration. Most changes in gamma were still present 7 days after THC administration. Decreased gamma coherence was also observed between the OFC–PFC and dStr–PFC region-pairs.

Conclusion: A single exposure to vapourized THC suppresses cortical and dorsal striatal gamma power and coherence, effects that appear to last at least a week. Given the role of gamma hypofunction in schizophrenia, these findings may provide mechanistic insights into the known psychotomimetic effects of THC.

Introduction: Plus de 14% des Canadiens consomment du cannabis, et près de 60% d’entre eux ont déclaré en faire une consommation quotidienne ou hebdomadaire. L’inhalation de vapeurs de cannabis a récemment gagné en popularité, mais les effets de cette exposition sur l’activité neurale restent inconnus. Dans cette étude, nous avons évalué l’impact de l’exposition aiguë au Δ9-tétrahydrocannabinol (THC) sur la dynamique du circuit neural chez le rat.

Objectifs: Nous avons voulu caractériser les changements d’activité neuronale dans le striatum dorsal (dStr), le cortex orbitofrontal (OFC) et le cortex préfrontal (PFC), après une exposition aiguë à la vapeur de THC.

Méthodes: Des réseaux d’électrodes ciblant le dStr, l’OFC et le PFC ont été implantés dans des rats. Les rats ont reçu du THC (ou un véhicule) à l’aide d’un vaporisateur Volcano® et des enregistrements du potentiel de champ local ont été réalisés dans une chambre en plexiglas dans une configuration croisée avec une période de sevrage d’une semaine.

Résultats: Une diminution de la puissance spectrale a été observée dans les niveaux dStr, OFC et PFC dans le registre gamma (> 32–100 Hz) après l’administration de THC vaporisé. La plupart des modifications du gamma étaient toujours présentes 7 jours après l’administration de THC. Une diminution de la cohérence gamma a également été observée entre les dyades de régions OFC-PFC et dStr-PFC.

Conclusion: Une seule exposition au THC vaporisé supprime la puissance et la cohérence des rayons gamma striatals dorsaux et corticaux, effets qui semblent durer au moins une semaine. Étant donné le rôle de l’hypofonction gamma dans la schizophrénie, ces résultats pourraient fournir des connaissances sur le mécanisme des effets psychotomimétiques connus du THC.

1Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada

2Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada. *,#: Both authors contributed equally.

Corresponding Author: Jibran Y. Khokhar, PhD, Assistant Professor, Department of Biomedical Sciences, University of Guelph, 50 Stone Rd E, Guelph, ON, Canada N1G1C5. Tel: +1 519 824 4120x54239; e-mail: jkhokhar@uoguelph.ca

The authors report no conflicts of interest.

Received May 17, 2019

Accepted July 9, 2019

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INTRODUCTION

In 2019, the World Health Organization reported an estimated 147 million users of cannabis globally.1 In Canada, national census data revealed that 15% of individuals aged 15 years and older had consumed cannabis in the third quarter of 2018,2 and the Canadian Centre for Substance Use and Addiction3 reported that nearly 30% of youth in grades 7 to 12 (approximately 12–18 years of age) had reported consuming cannabis in the past 12 months. Considering the prevalence of cannabis and the shifting landscape of legalization for recreational purposes,4 research that aims to elucidate the causal effects of cannabis on brain and behaviour is needed. One emerging trend is the use of alternative routes of administration such as vapourized cannabis; in 2018, the Monitoring the Future survey recently reported that the frequency of “vaping” cannabis had increased by approximately 50% to 60% in high school students since it was first measured in 2017.5

Escalations in the frequency of use and cannabis potency, combined with novel delivery methods, call for a more in-depth understanding of the differential effects of varying routes and durations of exposure to cannabis on brain function and circuitry. The reported and observed cognitive effects of cannabis vary greatly depending on the route of administration, the frequency of use, and the concentration of Δ9-tetrahydrocannabinol (THC) and cannabidiol, 2 of the main phytocannabinoids found in cannabis.6,7 Generally, consuming cannabis results in a “stoned” or “calm and relaxed” feeling; the distinctive “high” experienced by cannabis users.4,8 In contrast, greater amounts of THC in cannabis often produce psychotomimetic feelings of paranoia, anxiety, and may lead to an increased risk for psychiatric illness.8–10

Previous studies have used electrophysiological assessments to explore changes in neural activity following THC or cannabinoid receptor agonist administration (intravenous in humans and intraperitoneal in rodents), reporting acute suppression of gamma and theta signal in hippocampal, parahippocampal, and cortical regions,11–13 suggesting this as a possible mechanism for the psychotomimetic effects of cannabis due to consistent findings in patients with schizophrenia.14 However, human studies often recruit subjects with prior, albeit minimal, cannabis use, making it difficult to assess the acute impacts of THC in cannabis-naïve individuals.9,15,16 Furthermore, the responsiveness of individuals to THC, including the appearance of psychotomimetic effects, varies greatly depending on age,17 sex,18 socioeconomic status,19–21 genetics,22 and education, amongst other environmental measures. These confounding factors make it difficult to assess the causal effects of cannabis constituents on brain circuitry.

To test the effects of acute vapourized THC exposure on neural circuitry in cannabis-naïve animals, we employed an established rodent model of vapourized THC exposure23–25 and acquired electrophysiological recordings of local field potentials (LFPs) from corticostriatal brain circuitry after THC exposure. In this study, we targeted the dorsal striatum (dStr), prefrontal cortex (PFC), and orbitofrontal cortex (OFC) because these regions are often implicated in the cognitive and psychotomimetic effects of THC. Specifically, clinical studies have previously highlighted the impact of cannabis consumption on decision-making,26,27 attention, and memory4,15; cognitive tasks that involve the OFC and PFC, in addition to the psychotomimetic effects correlated with cortical electrophysiology measures mentioned above.13 The dStr was targeted because it is a brain region that is commonly implicated in the rewarding effects of cannabis use and dependency,28,29 and is known to communicate with the PFC and OFC.30,31 We hypothesized that vapourized THC would acutely reduce neural synchrony and power between the dStr and cortical regions (PFC and/or OFC).

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METHODS

Animals

Adult male Sprague Dawley rats weighing approximately 400 g at the start of the experiment were used. Rats were housed individually in polyethylene cages in a colony room maintained on a 12-hour light:dark cycle with ad libitum access to food and water. Rats were handled for 2 minutes daily for 5 days before the start of experiments to habituate them to the experimental manipulations. All treatments were performed during the dark phase of the 12-hour reverse light:dark cycle. All procedures complied with the guidelines described in the Guide to the Care and Use of Experimental Animals (Canadian Council on Animal Care, 1993) and the Animal Care Committee at the University of Guelph.

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Surgeries

Eight rats were anesthetized with isoflurane, administered the analgesic carprofen (5 mg/kg, subcutaneous injection) and secured in a stereotaxic frame. Body temperature was maintained at 37 °C with a warming pad. Electrodes (A-M Systems, Carlsborg, WA) were implanted bilaterally into the dStr (anteroposterior [AP]: +1.9, mediolateral [ML]: ±2.6, dorsoventral [DV]: −4.4), OFC (AP: +3.2, ML: ±2.6, DV: −5.5), and PFC (AP: +3.2, ML: ±0.6, DV: −3.8), and grounded by attaching (using silver paint) a reference wire to a screw fixed into the skull below lambda. Additional anchor screws were attached to the skull and electrodes secured with dental cement to the anchor screws. The animals received an additional injection of carprofen 24 and 48 hours following surgery and recovered individually in their home cage for a minimum of 7 days before the experiments were performed. Electrode placement was validated postmortem with 40-μm brain slices stained using cresyl violet.

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Vapourized THC Administration

Effects of vapourized THC on neural activity were evaluated using a crossover design as has previously been performed in human subjects.9 Rats were randomized to 2 groups (n = 4/group), receiving either vapourized THC or vehicle (1:1:18 TWEEN-80:ethanol:saline) in the first session. After a 7-day washout period, rats that initially received THC were administered vehicle, and rats that initially received vehicle received THC. A Volcano Vapourizer (Storz and Bickel, GmbH and Co., Tuttlingen, Germany) was used as described previously23–25: THC (10 mg/pad; 250 μL of 40 mg/mL solution for 2 rats) was vapourized at approximately 226 °C and channeled into detachable plastic bags (with a total volume of approximately 25 L) through an attached valve. The bags were manually constricted to expel the vapour into an enclosed Plexiglas chamber (with approximate dimensions of 15 × 10 × 15 cm3) using a small port in 1 face of the chamber. It is reported that this method delivers ∼50% of the THC on the wire pad into the bag with a pulmonary uptake similar to smoking cannabis (402 ng/mL/kg in whole blood, 20 min after 10 mg/pad exposure).25 Rats were administered THC or vehicle vapour individually and LFP recordings were collected for 30 minutes beginning 10 minutes post-administration.

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Electrophysiology

All LFPs were acquired using a wireless electrophysiology recording system (W2100, Multichannel Systems, Reutlingen, Germany) and were performed in awake, freely moving animals. Data were recorded for 30 minutes and sampled at a rate of 1000 samples/s. The spectral power of LFP oscillations and coherence was analyzed using routines from the Chronux software package for MATLAB (MathWorks, Natick, MA). LFP data were segmented, detrended and low-pass filtered to remove frequencies greater than 100 Hz. Continuous multitaper spectral power [tapers = (59)] for each region was calculated for each segment in the following frequency bands: delta (1–4 Hz), theta (>4–12 Hz), beta (>12–32 Hz), slow gamma (>32–60 Hz), and fast gamma (>60–100 Hz). The LFP spectral power from each group was normalized to the respective total spectral power for each rat within each treatment.

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Data Analysis

Quantification of LFP power and coherence data at each frequency is reported as the mean ± standard error of the mean (SEM). Comparisons were performed to evaluate between-subject or within-subject changes between THC and VEH treatment groups using a Student's t test or paired t tests, respectively. Computations were performed using the SPSS/PC+ statistical software package (Chicago, IL, USA).

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RESULTS

Exposure to vapourized THC reduced the amplitude of the gamma frequency band in dStr, OFC, and PFC, compared to vehicle (Fig. 1A). Reductions in gamma frequency (>32–100 Hz) spectral power following acute THC exposure were evident in all 3 brain regions (Fig. 1B–D). Quantification of the power spectra demonstrated an approximate 35% decrease in low gamma (>32–60 Hz) power in the dStr and OFC (Fig. 1E and F) with a 22% decrease in the PFC (Fig. 1G). Similarly, a 40% to 50% reduction in high gamma (>60–100 Hz) power following THC administration was observed in each of the 3 brain regions (Fig. 1B–G). We did not observe any cross-over order effect on spectral power at each frequency between the 2 THC-treated groups, in that the group that received THC in week 1 was not different from the group that received THC in week 2 (Fig. 1E–G). However, unlike the 2 THC groups, a cross-over order effect was evident in rats that received THC in week 1 and VEH in week 2, indicative of an extended effect of THC on neural gamma oscillations (Fig. 1H–J). One week after THC administration, only the dStr high gamma deficits appeared to normalize (Fig. 1H), whereas no significant increases in gamma power in any of the other regions was evident (Fig. 1I and J). In order to control for any confounding effects of sedation, we assessed the effects of THC exposure on delta power and delta/gamma correlations, and saw no significant effects of THC on both measures (data not shown).

Fig. 1

Fig. 1

Due to the cross-over order effect observed with the power measures, oscillatory coherence between brain regions was evaluated within-subjects for those animals that received VEH in week 1 and THC in week 2 (n = 4). There were no effects of THC on dStr–OFC coherence (Fig. 2A and B) with changes occurring selectively in dStr–PFC (Fig. 2C and D) and OFC–PFC coherence (Fig. 2E and F). Like the observations in spectral power, THC-induced differences in coherence occurred predominantly within the gamma frequency range. Specifically, analysis of dStr–PFC coherence showed reduced coherence selectively in high gamma (Fig. 2C and D). With OFC–PFC coherence, THC induced a reduction in the low and high gamma ranges, as well as in the theta frequency range (Fig. 2E and F).

Fig. 2

Fig. 2

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DISCUSSION

The results of our study revealed that vapourized THC exposure in rats leads to acute decreases in gamma power within the dStr, OFC, and PFC, and a decrease in gamma coherence between OFC–PFC and dStr–PFC. Interestingly, rats that received THC in week 1 and vehicle in week 2 showed a cross-over effect, indicating that the THC-induced decreases in gamma power last for at least 1 week after exposure. One important caveat in attributing the source of these oscillations to the anatomical targets of electrodes is that there are known limitations in localizing the source of the LFP signal,32,33 which is mitigated by the consistent effects seen across the anatomical targets of the electrodes.

The decrease in gamma signal that was observed in this study is supported by similar observations after cannabinoid exposure in rodents and humans: a decrease in both power and coherence of gamma and theta signals in the rat hippocampus was observed acutely after THC and after a cannabinoid receptor 1 agonist, CP55940, was administered intraperitoneally or intracranially.11,12 Aberrant gamma power and coherence has also been measured after intravenous THC-administration in humans with a history of cannabis use and was associated with a greater score on the Positive and Negative Syndrome Scale, a clinical survey commonly used in the diagnosis of schizophrenia.13 Previously, psychotomimetic behaviours have been associated with a dysfunctional gamma signal: (1) directly, as recorded in patients with schizophrenia compared to healthy controls14,34 and (2) indirectly, through shared behavioural manifestations such as sensorimotor gating deficits in heavy cannabis users35 and in patients with schizophrenia.12 Thus, gamma hypofunction arising from acute THC exposure may explain some of the psychotomimetic effects of THC and provide a potential mechanistic commonality between acute negative consequences of cannabis use (especially high THC dose variants) and schizophrenia phenotypes. Subsequent studies will be designed to explore this relationship and to determine whether gamma hypofunction contributes causally to the psychotomimetic effects of cannabis.

Gamma-band oscillatory activity is thought to result from competing excitatory (i.e., glutamatergic) and inhibitory (i.e., gamma-Aminobutyric acid [GABA]ergic) activity,36 with most research highlighting a strong association between GABA concentrations and gamma activity.37 However, previous research in humans and rodent models has suggested that gamma activity is also associated with glutamate neurotransmitter concentrations in specific brain regions, including the lateral occipital cortex38 and the anterior cingulate cortex.39,40 Glutamate concentrations can affect distal brain structures as well: glutamate activity in the hippocampus was shown to be predictive of theta activity in the PFC.41 Recent studies have revealed that glutamate levels in the striatum decrease after exposure to THC, and relate to the psychotomimetic effects produced by THC.10 Combined with the results of our study, it is plausible that corticostriatal gamma hypofunction resulting from acute THC exposure could possibly be a product of changes in glutamatergic signalling; future studies combining LFP recordings with microdialysis will help to characterize the relationship between glutamatergic and GABAergic signalling with the gamma hypofunction and psychotomimetic effects produced by vapourized THC exposure.

The cross-over effect observed in our animals that received THC 1 week before vehicle indicates that the THC-induced gamma suppression may last at least up to 1 week after a single exposure to vapourized THC in otherwise naïve animals; lasting differences in gamma activity has previously been observed in chronic cannabis users.42 These findings provide important considerations for designing cross-over studies with THC in animals and in humans, and ensuring sufficient washout durations. It is unclear whether this long-lasting suppression is due to pharmacokinetic or pharmacodynamics factors related to vapourized THC. Inhalation of vapourized THC, like smoking, results in rapid increased in plasma THC concentration, with some indications that it produces higher plasma THC levels compared to smoking.43,44 In future studies, we will assess later time points and both plasma and brain levels, to establish the role of pharmacokinetic factors in this long-lasting effect.

Taken together, these studies indicate that acute exposure to vapourized THC in naïve animals can produce lasting changes in brain circuit dynamics, and the overlap between these signatures and those observed in patients with schizophrenia may provide a potential mechanism for the psychotomimetic effects of THC. Future studies, combining electrophysiology with behaviour, will aim to determine how long this gamma suppression lasts, and, using circuit manipulation techniques, whether it serves as a causal factor in the psychotomimetic or cognitive effects of THC; one that could be targeted to develop treatments for acute THC-induced psychosis.

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ACKNOWLEDGEMENTS

We would like to thank Dr Paul Mallet (from Wilfrid Laurier University) for providing the THC vapourization apparatus for use in this study. TFN and BWJ contributed equally to this manuscript, as well as MLP and JYK.

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REFERENCES

1. World Health Organization (2019). Management of Substance Abuse - Cannabis. Accessed April 17, 2019 at https://www.who.int/substance_abuse/facts/cannabis/en/.
2. Statistics Canada. Table 13-10-0383-01 Prevalence of cannabis use in the past three months, self-reported. Accessed April 17, 2019 at https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1310038301.
3. Wallingford S., Konefal S., Young M.M., & Student Drug Use Surveys Working Group (2019). Cannabis use, harms and perceived risks among Canadian students. Ottawa, Ont.: Canadian Centre on Substance Use and Addiction.
4. Blaes SL, Orsini CA, Holik HM, et al Enhancing effects of acute exposure to cannabis smoke on working memory performance. Neurobiol Learn Mem 2018;157:151–162.
5. Hamilton AD, Jang JB, Patrick ME, et al. Age, period and cohort effects in frequent cannabis use among US students: 1991–2018. Addiction May 20, 2019;[Epub ahead of print]. doi: https://doi.org/10.1111/add.14665.
6. Davidson ES, Schenk S. Variability in subjective responses to marijuana: initial experiences of college students. Addict Behav 1994;19:531–538.
7. Feeney DM. The marijuana window: a theory of cannabis use. Behav Biol 1976;18:455–471.
8. Sharma P, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry 2012;7:149–156.
9. Morgan CJA, Freeman TP, Hindocha C, et al Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function. Transl Psychiatry 2018;8:181.
10. Colizzi M, Weltens N, McGuire P, et al. Delta-9-tetrahydrocannabinol increases striatal glutamate levels in healthy individuals: implications for psychosis. Mol Psychiatry February 15, 2019;[Epub ahead of print]. doi: https://doi.org/10.1038/s41380-019-0374-8.
11. Robbe D, Montgomery SM, Thome A, et al Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nat Neurosci 2006;9:1526–1533.
12. Hajos M, Hoffmann WE, Kocsis B. Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia. Biol Psychiatry 2008;63:1075–1083.
13. Cortes-Briones J, Skosnik PD, Mathalon D, et al Delta9-THC disrupts gamma (gamma)-band neural oscillations in humans. Neuropsychopharmacology 2015;40:2124–2134.
14. Spencer KM, Nestor PG, Niznikiewicz MA, et al Abnormal neural synchrony in schizophrenia. J Neurosci 2003;23:7407–7411.
15. D'Souza DC, Perry E, MacDougall L, et al The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 2004;29:1558–1572.
16. Roitman P, Mechoulam R, Cooper-Kazaz R, et al Preliminary, open-label, pilot study of add-on oral delta9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin Drug Investig 2014;34:587–591.
17. De Hert M, Wampers M, Jendricko T, et al Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophr Res 2011;126:270–276.
18. Bassir Nia A, Mann C, Kaur H, et al Cannabis use: neurobiological, behavioral, and sex/gender considerations. Curr Behav Neurosci Rep 2018;5:271–280.
19. Lee JO, Hill KG, Hartigan LA, et al Unemployment and substance use problems among young adults: does childhood low socioeconomic status exacerbate the effect? Soc Sci Med 2015;143:36–44.
20. Bergen SE, Gardner CO, Aggen SH, et al Socioeconomic status and social support following illicit drug use: causal pathways or common liability? Twin Res Hum Genet 2008;11:266–274.
21. Legleye S, Beck F, Khlat M, et al The influence of socioeconomic status on cannabis use among French adolescents. J Adolesc Health 2012;50:395–402.
22. Khokhar JY, Dwiel LL, Henricks AM, et al The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res 2018;194:78–85.
23. Manwell LA, Charchoglyan A, Brewer D, et al A vapourized delta(9)-tetrahydrocannabinol (delta(9)-THC) delivery system part I: development and validation of a pulmonary cannabinoid route of exposure for experimental pharmacology studies in rodents. J Pharmacol Toxicol Methods 2014;70:120–127.
24. Manwell LA, Ford B, Matthews BA, et al A vapourized delta(9)-tetrahydrocannabinol (delta(9)-THC) delivery system part II: comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents. J Pharmacol Toxicol Methods 2014;70:112–119.
25. Hazekamp A, Ruhaak R, Zuurman L, et al Evaluation of a vaporizing device (volcano) for the pulmonary administration of tetrahydrocannabinol. J Pharm Sci 2006;95:1308–1317.
26. Churchwell JC, Lopez-Larson M, Yurgelun-Todd DA. Altered frontal cortical volume and decision making in adolescent cannabis users. Front Psychol 2010;1:225.
27. Grant JE, Chamberlain SR, Schreiber L, et al Neuropsychological deficits associated with cannabis use in young adults. Drug Alcohol Depend 2012;121:159–162.
28. Zhou F, Zimmermann K, Xin F, et al Shifted balance of dorsal versus ventral striatal communication with frontal reward and regulatory regions in cannabis-dependent males. Hum Brain Mapp 2018;39:5062–5073.
29. Goodman J, Packard MG. The influence of cannabinoids on learning and memory processes of the dorsal striatum. Neurobiol Learn Mem 2015;125:1–14.
30. McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci 2019;42:205–220.
31. Bloomfield MA, Ashok AH, Volkow ND, et al The effects of delta(9)-tetrahydrocannabinol on the dopamine system. Nature 2016;539:369–377.
32. Carmichael JE, Gmaz JM, van der Meer MAA. Gamma oscillations in the rat ventral striatum originate in the piriform cortex. J Neurosci 2017;37:7962–7974.
33. Bastos AM, Schoffelen JM. A tutorial review of functional connectivity analysis methods and their interpretational pitfalls. Front Syst Neurosci 2015;9:175.
34. Cohen M, Solowij N, Carr V. Cannabis, cannabinoids and schizophrenia: integration of the evidence. Aust N Z J Psychiatry 2008;42:357–368.
35. Edwards CR, Skosnik PD, Steinmetz AB, et al Sensory gating impairments in heavy cannabis users are associated with altered neural oscillations. Behav Neurosci 2009;123:894–904.
36. Atallah BV, Scanziani M. Instantaneous modulation of gamma oscillation frequency by balancing excitation with inhibition. Neuron 2009;62:566–577.
37. Duncan NW, Wiebking C, Northoff G. Associations of regional GABA and glutamate with intrinsic and extrinsic neural activity in humans—a review of multimodal imaging studies. Neurosci Biobehav Rev 2014;47:36–52.
38. Lally N, Mullins PG, Roberts MV, et al Glutamatergic correlates of gamma-band oscillatory activity during cognition: a concurrent ER-MRS and EEG study. Neuroimage 2014;85 (pt 2):823–833.
39. Walter M, Henning A, Grimm S, et al The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch Gen Psychiatry 2009;66:478–486.
40. Schmaal L, Goudriaan AE, van der Meer J, et al The association between cingulate cortex glutamate concentration and delay discounting is mediated by resting state functional connectivity. Brain Behav 2012;2:553–562.
41. Gallinat J, Kunz D, Senkowski D, et al Hippocampal glutamate concentration predicts cerebral theta oscillations during cognitive processing. Psychopharmacology 2006;187:103–111.
42. Skosnik PD, Krishnan GP, D'Souza DC, et al Disrupted gamma-band neural oscillations during coherent motion perception in heavy cannabis users. Neuropsychopharmacology 2014;39:3087–3099.
43. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 2003;42:327–360.
44. Spindle TR, Cone EJ, Schlienz NJ, et al Acute effects of smoked and vaporized cannabis in healthy adults who infrequently use cannabis: a crossover trial. JAMA Netw Open 2018;1:e184841.
Keywords:

cannabis; circuitry; limbic; psychosis; vapour; cannabis; circuits; limbique; psychose; vapeur

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