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Mar 31

Subcellular specificity of cannabinoid effects in stratonigral circuits

Edgar Soria-Gomez publishes this article in Neuron, started back in his postdoc in Bordeaux

The recreational and therapeutic uses of cannabinoid compounds are increasing around the world. They have been proposed to control pain sensitivity in clinical settings. However, due to significant side effects, such as cognitive impairments and motor dysfunctions, the medicinal exploitation of these drugs and the safety of their recreational use are under intense debate.  The main psychoactive component of the cannabis sativa (marijuana) plant is delta-9 tetrahydrocannabinol or THC, which, in the brain, acts mainly by activating cannabinoid receptors type-1 (CB1).  The pharmacological activation of the CB1 receptor affects motor control in experimental animals, while in humans the cataleptic effects are considered one of the main causes of traffic accidents due to cannabis use.  Therefore, understanding the mechanisms of cannabinoid-induced therapeutic and adverse effects is vital for the safest use of these compounds, but the underlying cellular and molecular mechanisms are poorly understood.

Subcellular specificity of cannabinoid effects in stratonigral circuits

The CB1 receptor is widely distributed throughout the brain and in different cell types and cellular compartments (for example, in the mitochondria). We have recently shown that mitochondrial CB1 (mtCB1) participates in learning processes and social behavior. This study reveals that cannabinoids produce adverse (catalepsy) and beneficial (antinociception) effects through the regulation of specific cellular molecular pathways in the brain circuit formed by the striatum and the substantia nigra (striatonigral circuit). In this circuit, we demostrated that the activation of CB1 receptors located in the mitochondria is responsible for the cataleptic effects induced by cannabinoids. On the other hand, CB1 receptors localized in the plasma membrane (pmCB1), reduces sensitivity to pain. All this, by modulating different signaling and neurotransmission pathways. In short, mtCB1 controls GABAergic transmission, and pmCB1 regulates substance P release.

These results not only reveal new cellular mechanisms responsible for the action of cannabinoids but also represent a new conceptual framework in neuroscience. Formerly it was believed that the shape of the skull determined personality traits, later it was established that different brain structures were in charge of specific functions; recently the focus has turned to the study of neural circuits as responsible for behavior. In this study we go one step further, showing that a protein (in this case the CB1 receptor) in different subcellular regions (mitochondria vs plasma membrane) within the same brain circuit (striatonigral circuit) modulates different behaviors. That is, we revealed a subcellular specificity of behavioral control.

https://doi.org/10.1016/j.neuron.2021.03.007