Cannabinoids contribute to cocaine addiction

Cocaine triggers cells in the brain’s pleasure center to release membrane-bound packages of endocannabinoids.
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Mouse midbrain dopamine neurons. Image credit: Nakamura, Dryanovski et al. (CC BY 4.0)

The cannabis plant contains hundreds of different chemicals, including more than sixty types of cannabinoids. By binding to specific sites on brain cells, cannabinoids change how cells communicate with one another. This in turn triggers widespread alterations in brain activity, which can affect mood, appetite, coordination and perception.

But not all cannabinoids come from plants. The brain also produces its own versions, known as endocannabinoids (or eCBs for short). These bind to the same sites on brain cells as the plant-derived chemicals. Changes in endocannabinoid activity have been implicated in various brain disorders. These include Alzheimer's disease, epilepsy and stress disorders. They may also have a role in drug addiction. Exposing rats to cocaine causes endocannabinoid levels to increase in areas of the brain that process pleasurable sensations. This suggests that the release of endocannabinoids may contribute to cocaine addiction. But how cocaine triggers this release has been unclear.

By studying brain tissues and cells kept alive in petri dishes, Nakamura, Dryanovski et al. show that cocaine drives cells to release endocannabinoids via a process called extracellular vesicle release. In essence, cocaine causes cells to make endocannabinoids that are then enclosed inside membrane-bound packages. These packages – or extracellular vesicles – can then fuse with the cell’s outer membrane. Multiple proteins must interact with each other for cells to assemble and release extracellular vesicles. Nakamura, Dryanovski et al. show that disrupting these interactions prevents vesicles from forming, and also prevents cocaine from triggering endocannabinoid release. Blocking extracellular vesicle release prevents cocaine from altering communication between brain cells.

Cocaine thus drives endocannabinoid release in the brain’s pleasure centers via the assembly of extracellular vesicles. Using other drugs to manipulate the protein interactions that underlie vesicle assembly could provide a new way to counter cocaine addiction.