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Review
. 2016 Nov 17;539(7629):369-377.
doi: 10.1038/nature20153.

The effects of Δ9-tetrahydrocannabinol on the dopamine system

Michael A P Bloomfield  1   2   3   4   5 , Abhishekh H Ashok  1   2   4 , Nora D Volkow  6 , Oliver D Howes  1   2   4
Affiliations
Review

The effects of Δ9-tetrahydrocannabinol on the dopamine system

Michael A P Bloomfield et al. Nature. .

Abstract

The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.

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Conflict of interest statement

statement. Dr Bloomfield conducts research funded by the Medical Research Council (UK), the National Institute of Health Research (UK) and the British Medical Association. Dr Ashok conducts research funded by the Medical Research Council (UK) and Kings College London. Dr Volkow is Director of the National Institute on Drug Abuse (USA). Professor Howes conducts research funded by the Medical Research Council (UK), the National Institute of Health Research (UK) and the Maudsley Charity. Professor Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Astra-Zeneca, BMS, Eli Lilly, Jansenn, Lundbeck, Lyden-Delta, Servier, and Roche. Neither Professor Howes nor his family have been employed by or have holdings/a financial stake in any biomedical company.

Figures

Fig. 1
Fig. 1. THC binds to CB1 receptors on glutamatergic and GABAergic neurons disrupting normal endocannabinoid retrograde signalling from dopaminergic neurons.
Endocannabinoids (eCBs) influence ventral tegmental area (VTA) synaptic signalling. 2-Arachidonoylglycerol (2-AG) is synthesised by diacylglycerol lipase (DAGL) in dopaminergic VTA neurons and, once released, retroactively acts on endocannabinoid type 1 receptors (CB1Rs) on nearby glutamatergic and γ-aminobutyric acid (GABA)-ergic terminals. CB1Rs mediate robust inhibition of GABA inputs onto VTA dopamine cells, termed retrograde suppression of inhibition. CB1Rs are also localized on glutamatergic terminals synapsing on VTA dopamine neurons where eCBs mediate retrograde suppression of excitation. Thus, eCBs fine-tune the activity of the mesolimbic dopamine projections through modulating both excitatory and inhibitory signalling. THC disrupts this finely tuned system.
Fig. 2
Fig. 2. Summary of the acute effects of THC on dopaminergic function.
In animal models acute THC challenge is associated with increased dopaminergic cell firing, increased dopamine synthesis and increased dopamine release.
Fig. 3
Fig. 3. Cannabis use in humans is associated with reduced dopamine in the striatum. PET studies have shown lower striatal dopamine synthesis and release capacity in cannabis users.
Lower dopamine synthesis capacity in the dorsal striatum is directly associated with reduced motivational levels and reduced dopamine release in the ventral striatum is directly associated with negative emotion levels and addiction severity
See this image and copyright information in PMC

References

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