Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity

Mason, Natasha L.; Theunissen, Eef L.; Hutten, Nadia R. P. W.; Tse, Desmond H. Y.; Toennes, Stefan W.; Stiers, Peter; Ramaekers, Johannes G.

doi:10.1016/j.euroneuro.2018.12.003

Cited by 55 publications

(78 citation statements)

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“…amygdala, medial orbital frontal cortex, hippocampus) (43, 44). Importantly, decrements in FC between the NAc and regions such as the thalamus and frontal cortex have been suggested to reflect increase s in dopaminergic neurotransmission throughout the circuit (10, 29, 30). Specifically, the NAc receives dopaminergic input from the VTA, which is under inhibitory control of GABA interneurons on which presynaptic CB1 receptors (CB1R) are located.…”

Section: Discussionmentioning

confidence: 99%

“…Blood samples were centrifuged and serum was frozen at −20 °C until analyses for pharmacokinetic assessments. Cannabinoid concentrations were determined using a validated and proficiency test approved forensic routine method consisting of an automated solid-phase extraction and gas chromotrography with tandem mass spectrometric detection with a limit of quantification of 0.3 ng/ml or less (10).…”

Section: Methodsmentioning

confidence: 99%

“…Accumulating evidence suggests that the main psychoactive component of cannabis [delta-9-tetrahydrocannabinol (THC)] binds to cannabinoid (CB1) receptors located on GABAergic and glutamatergic neurons distributed throughout the brain, with high densities found in limbic-reward structures (4). Subsequently, THC has been found to acutely activate the reward circuitry, increasing dopamine (5–9) and glutamate (10, 11) concentration levels in key brain areas including the striatum, nucleus accumbens (NAc) and prefrontal cortex (PFC); a pattern implicated in both the rewarding and impairing effects of drugs of abuse (12, 13).…”

Section: Introductionmentioning

confidence: 99%

“…Ultra-High Field (7T) proton magnetic resonance spectroscopy ( 1 H MRS), a non-invasive imaging technique that allows reliable in vivo measurement of neurometabolites and neurotransmitters, was used to assess glutamate, gamma-aminobutyric acid (GABA), NAA, Cho, and mI levels in the striatum and ACC. Resting state functional magnetic resonance imaging (fMRI) data were acquired to determine functional connectivity between the regions of interest (ROI) in the NAc and remote cortical areas, as an indirect measure of dopaminergic stimulation (10, 29, 30). Furthermore a priori ROI-to-ROI analysis assessed differences in connectivity strength between areas of the reward circuit.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore a priori ROI-to-ROI analysis assessed differences in connectivity strength between areas of the reward circuit. Finally, subjective high and sustained attention, two outcome variables shown to be modulated by (acute) cannabis exposure (10, 31, 32), were assessed.…”

Section: Introductionmentioning

confidence: 99%

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Reduced responsiveness of the reward system underlies tolerance to cannabis impairment in chronic users

Mason

Theunissen

Hutten

et al. 2019

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words)Cannabis is the most commonly used illicit drug in the world. However due to a changing legal landscape, and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly, cannabis impairment. Importantly, a growing body of evidence suggests regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug.However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo controlled, cross-over study assessed the acute influence of cannabis on brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional (OUs) and 12 chronic (CUs) cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, and underwent ultra-high field functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS). In OUs, cannabis induced significant neurometabolic alterations in reward circuitry, namely decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in CUs. The finding that cannabis altered circuitry and distorted behavior in OUs, but not CUs, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment. regions of interest (ROI) in the NAc and remote cortical areas, as an indirect measure of dopaminergic stimulation (10, 29, 30). Furthermore a priori ROI-to-ROI analysis assessed differences in connectivity strength between areas of the reward circuit. Finally, subjective high and sustained attention, two outcome variables shown to be modulated by (acute) cannabis exposure (10, 31, 32), were assessed.The second goal was exploratory in nature, to evaluate long-term effects of repeated cannabis exposure, by comparing the placebo condition of each group. Overall, we hypothesized that THC would induce behavioral, functional, and metabolic changes in the OUs, but not the CUs, indicative of (neuroadaptive) tolerance. Furthermore, based on previous studies with chronic cannabis users, we hypothesized that during placebo, CUs would show decreased concentrations of metabolites compared to OUs. MethodsParticipants. In total, 27 healthy cannabis users entered the study. Three participants were excluded due to poor fMRI data, resulting in a total of 12 occasional and 12 chronic users (male N= 14, female N= 10). For further details see SI Methods.This study was conducted according to the code of ethics on human experimentation established by the declaration of Helsinki (1964) and amended in Fortaleza (Brazil, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and was approved by the Academic Hospital and University's Medical Ethics committee. All participants were full...

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