Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects

Ellgren, Maria; Artmann, Andreas; Tkalych, Oleg; Gupta, Achla; Hansen, Harald S.; Hansen, Steen Honoré; Devi, Lakshmi A.; Hurd, Yasmin L.

doi:10.1016/j.euroneuro.2008.06.009

Cited by 194 publications

(185 citation statements)

References 60 publications

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“…It is now well established that the endocannabinoid system plays a significant role in neurogenesis, neural specification, neural maturation, neuronal migration, axonal elongation, and glia formation (Harkany et al, 2007(Harkany et al, , 2008a. Furthermore, CB1R levels peak in adolescence, suggesting that young cannabis users may be particularly vulnerable to the development-altering effects of cannabis (Ellgren et al, 2008;Heng et al, 2011). In support of this idea, cannabis-related decreases in steady-state gamma power have been shown to be more profound in individuals who start using cannabis at an earlier age (Skosnik et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Disrupted Gamma-Band Neural Oscillations During Coherent Motion Perception in Heavy Cannabis Users

Skosnik

Krishnan

D’Souza

et al. 2014

Neuropsychopharmacol

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Previous work in animals and humans has shown that exogenous cannabinoids disrupt time-locked, evoked gamma oscillations . However, no studies to date have examined the effect of cannabis on non-time-locked, induced gamma oscillations during more complex Gestalt perception. The current study therefore utilized electroencephalography (EEG) to examine gamma oscillations during coherent motion perception in heavy cannabis users and controls. Chronic cannabis users (n ¼ 24; 12 h abstinence before study; positive 11-nor-9-carboxy-delta-9-tetrahydrocannabinol urine levels) and cannabis-naive controls (n ¼ 23) were evaluated. Stimuli consisted of random dot kinetograms (RDKs) that subjects passively viewed during three different conditions: coherent motion, incoherent motion, and static. Time Â frequency analysis on EEG data was performed using Fourier-based mean trial power (MTP). Transient event-related potentials (ERPs) to stimulus onset (visual N100 and P200 components) were also evaluated. The results showed that the coherent motion condition produced a robust increase in neural activity in the gamma range (induced power from 40 to 59 Hz) as compared with the incoherent motion and static conditions. As predicted, the cannabis group showed significant reductions in induced gamma power in the coherent condition relative to healthy controls. No differences were observed between the groups in the N100 or P200 components, indicating intact primary sensory processing. Finally, cannabis users showed a trend toward increased scores on the Chapman Perceptual Aberration Scale (PAS) that was positively correlated with total years of active cannabis use. These data suggest that cannabis use may interfere with the generation of induced gamma-band neural oscillations that could in part mediate the perceptualaltering effects of exogenous cannabinoids.

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Section: Discussionmentioning

confidence: 99%

Disrupted Gamma-Band Neural Oscillations During Coherent Motion Perception in Heavy Cannabis Users

Skosnik

Krishnan

D’Souza

et al. 2014

Neuropsychopharmacol

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“…Early adolescence is marked by a decrease in FAAH and an increase in AEA levels, whereas FAAH levels increase and AEA levels decrease toward later adolescence (10,33). CB1 receptor expression peaks with the onset of adolescence (8,9,32,33). The predicted effects of FAAH C385A across development are presented as dotted lines.…”

Section: Faah C385a-associated (Phenotypic) Differences In Frontolimbmentioning

confidence: 99%

“…The onset of adolescence is marked by the highest expression of type 1 cannabinoid receptor (CB1) in both cortical and subcortical brain regions, with CB1 expression declining to adult levels throughout adolescence (8,9). Across the amygdala and prefrontal cortex, fatty acid amide hydrolase (FAAH) expression shows a transient increase from postnatal day 35 (P35) to P45 during adolescence in mice (10).…”

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confidence: 99%

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

Gee

Fetcho

Jing

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3-to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxietyrelated behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.A nxiety disorders typically emerge during adolescence, when the incidence of mental illness peaks (1, 2). The developmental phase of adolescence is characterized by dynamic changes in gene expression, frontolimbic circuitry (3, 4), and overall tone of the endocannabinoid system, which are implicated in anxiety (5-7).The corticolimbic endocannabinoid system undergoes dynamic changes across development. The onset of adolescence is marked by the highest expression of type 1 cannabinoid receptor (CB1) in both cortical and subcortical brain regions, with CB1 expression declining to adult levels throughout adolescence (8, 9). Across the amygdala and prefrontal cortex, fatty acid amide hydrolase (FAAH) expression shows a transient increase from postnatal day 35 (P35) to P45 during adolescence in mice (10). Consistent with the regulatory role of FAAH, anandamide (AEA) levels show an inverse pattern of a peak at P35 and subsequent decrease during adolescence (10, 11). AEA is an endogenous ligand for the CB1 receptor, suggesting that the concurrent changes in AEA and CB1 expression reflect decreasing endocannabinoid signaling during adolescence (12), which may be associated with increasing risk for anxiety (Fig. 1).A common human polymorphism in the gene encoding FAAH (C385A; rs324420), the primary catabolic enzyme of the prototypical endocannabinoid AEA, regulates FAAH activity. The variant FAAH A385 allele destabilizes the FAAH protein, causing lower levels of FAAH enzymatic activity and/or increased levels of AEA in T lymphocytes and brain (13,14). Phenotypic expression of common polymorphism...

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“…In support of the latter possibility, Δ 9 -THC treatment increases circulating levels and brain levels of ECs (AEA, 2-AG) in humans and rodents (17,18). However, nothing is known regarding the impact of Δ human NAFLD (24), especially in human subjects expressing the highly prevalent FABP1 T94A variant (26-38% minor allele frequency; 8.3±1.9% homozygous) (rev.…”

mentioning

confidence: 99%

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

McIntosh

Martin

Huang

et al. 2018

Journal of Lipid Research

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Phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC), bind and activate cannabinoid (CB) receptors, thereby “piggy-backing” on the same pathway’s endogenous endocannabinoids (ECs). The recent discovery that liver fatty acid binding protein-1 (FABP1) is the major cytosolic “chaperone” protein with high affinity for both Δ9-THC and ECs suggests that Δ9-THC may alter hepatic EC levels. Therefore, the impact of Δ9-THC or EC treatment on the levels of endogenous ECs, such as N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), was examined in cultured primary mouse hepatocytes from WT and Fabp1 gene-ablated (LKO) mice. Δ9-THC alone or 2-AG alone significantly increased AEA and especially 2-AG levels in WT hepatocytes. LKO alone markedly increased AEA and 2-AG levels. However, LKO blocked/diminished the ability of Δ9-THC to further increase both AEA and 2-AG. In contrast, LKO potentiated the ability of exogenous 2-AG to increase the hepatocyte level of AEA and 2-AG. These and other data suggest that Δ9-THC increases hepatocyte EC levels, at least in part, by upregulating endogenous AEA and 2-AG levels. This may arise from Δ9-THC competing with AEA and 2-AG binding to FABP1, thereby decreasing targeting of bound AEA and 2-AG to the degradative enzymes, fatty acid amide hydrolase and monoacylglyceride lipase, to decrease hydrolysis within hepatocytes.

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Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects

Cited by 194 publications

References 60 publications

Disrupted Gamma-Band Neural Oscillations During Coherent Motion Perception in Heavy Cannabis Users

Disrupted Gamma-Band Neural Oscillations During Coherent Motion Perception in Heavy Cannabis Users

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

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