New Harmful Side Effects of Marijuana Discovered – Developing Brain Needs Cannabinoid Receptors After Birth

Cannabinoid Receptor Dopamine Neurons

Cannabinoid receptor 1, the cell-surface receptor that mediates the psychoactive effects of marijuana, is essential for normal development of the dopamine system. Images of the midbrain show that dopamine-producing neurons (light blue) extend dendrites that are tightly bundled with input axons from striosomes (co-labeling shown in bright green) in normal mice (left), but that these structures are malformed in knockout mice that lack cannabinoid receptor 1 (right).
Credit: Jill R. Crittenden, Ara Mahar, and Tomoko Yoshida

Cannabinoid receptors help the brain’s dopamine system establish key connections after birth, a new mouse study suggests.

Doctors warn that marijuana use during pregnancy may have harmful effects on the development of a fetus, in part because the cannabinoid receptors activated by the drug are known be critical for enabling a developing brain to wire up properly. Now, scientists at MIT’s McGovern Institute for Brain Research have learned that cannabinoid receptors’ critical role in brain development does not end at birth.

In the March 31, 2022, online issue of eNeuro, scientists led by McGovern investigator Ann Graybiel report that mice need the cannabinoid receptor CB1R to establish connections within the brain’s dopamine system that take shape soon after birth. The finding raises concern that marijuana use by nursing moms, who pass the CB1R-activating compound THC to their infants when they breastfeed, might interfere with brain development by disrupting cannabinoid signaling.

“This is a real change to one of the truly important systems in the brain — a major controller of our dopamine,” says Graybiel, who is an Institute Professor and a faculty member in the Department of Brain and Cognitive Sciences. Dopamine exerts a powerful influence over our motivations and behavior, and changes to the dopamine system contribute to disorders from Parkinson’s disease to addiction. Thus, the researchers say, it is vital to understand whether postnatal drug exposure might put developing dopamine circuits at risk.

Cannabinoid receptors in the brain are important mediators of mood, memory, and pain. Graybiel’s lab became interested in CB1R due to their dysregulation in Huntington’s and Parkinson’s diseases, both of which impair the brain’s ability to control movement and other functions. While investigating the receptor’s distribution in the brain, they discovered that in the adult mice, CB1R is abundant within small compartments within the striatum called striosomes. The receptor was particularly concentrated within the neurons that connect striosomes to a dopamine-rich area of the brain called the substantia nigra, via structures that Graybiel’s team has dubbed striosome-dendron bouquets.

Striosome-dendron bouquets are easy to overlook within the densely connected network of the brain. But when the cells that make up the bouquets are labeled with a fluorescent protein, the bouquets become visible — and their appearance is striking, says Jill Crittenden, a research scientist in Graybiel’s lab.

Striosomal neurons form these bouquets by reaching into the substantia nigra, whose cells use dopamine to influence movement, motivation, learning, and habit formation. Clusters of dopamine-producing neurons form dendrites there that intertwine tightly with incoming axons from the striosomal neurons. The resulting structures, whose intimately associated cells resemble the bundled stems of a floral bouquet, establish so many connections that they give striosomal neurons potent control over dopamine signaling.

By tracking the bouquets’ emergence in newborn mice, Graybiel’s team found that they form in the first week after birth, a period during which striosomal neurons are ramping up production of CB1R. Mice genetically engineered to lack CB1R, however, can’t make these elaborate but orderly bouquets. Without the receptor, fibers from striosomes extend into the substantia nigra, but fail to form the tightly intertwined “bouquet stems” that facilitate extensive connections with their targets. This disorganized structure is apparent as soon as bouquets arise in the brains of young pups and persists into adulthood. “There aren’t those beautiful, strong fibers anymore,” Crittenden says. “This suggests that those very strong controllers over the dopamine system function abnormally when you interfere with cannabinoid signaling.”

The finding was a surprise. Without zeroing in on striosome-dendron bouquets, it would be easy to miss CB1R’s impact on the dopamine system, Crittenden says. Plus, she adds, prior studies of the receptor’s role in development largely focused on fetal development. The new findings reveal that the cannabinoid system continues to guide the formation of brain circuits after birth.

Graybiel notes that funds from donors including the Broderick Fund for Phytocannabinoid Research at MIT, the Saks Kavanaugh Foundation, the Kristin R. Pressman and Jessica J. Pourian ‘13 Fund, Mr. Robert Buxton, and the William N. and Bernice E. Bumpus Foundation enabled her team’s studies of CB1R’s role in shaping striosome-dendron bouquets.

Now that they have shown that CB1R is needed for postnatal brain development, it will be important to determine the consequences of disrupting cannabinoid signaling during this critical period — including whether passing THC to a nursing baby impacts the brain’s dopamine system.

Reference: “Cannabinoid receptor 1 is required for neurodevelopment of striosome-dendron bouquets” by Jill R. Crittenden, Tomoko Yoshida, Samitha Venu, Ara Mahar and Ann M. Graybiel, 31 March 2022, eNeuro.
DOI: https://doi.org/10.1523/ENEURO.0318-21.2022

10 Comments on "New Harmful Side Effects of Marijuana Discovered – Developing Brain Needs Cannabinoid Receptors After Birth"

  1. “…the dopamine system function[s] abnormally when you interfere with cannabinoid signaling.”

    Pregnant and nursing women should avoid all powerful drugs, especially alcohol, cocaine, amphetamines and tobacco. Maybe also Fox News. But does this study support the headline claim of “new harmful side effects”? The “side effects” cited in the study are described as neural malformations: whether these are in fact harmful — and if so to what extent — was not established by the study. “Harmful” can only be assumed at this point, since the mice were genetically engineered to lack all CB1R. … I am reminded of the old joke about the engineer, the physicist, the philosopher and the black sheep.

    • We know for a fact delta 9 thc, the most commonly used exogenous cb1 agonist, has negative effects on developing organisms, and reduces cb1 protein expression and mrna.

  2. What a science stretch! Removing the receptors caused brain growth anomalies. I bet it does. But how is stimulating the receptor with cannabis going to cause brain damage? Not shown here, but thanks for the warning…

  3. Jerold Toomey | April 11, 2022 at 12:51 am | Reply

    It’s been long known that cannabis shouldn’t be used until adulthood.
    I learned of this on the 1960s.

  4. This articles title is highly misleading and the content only speaks to a still to be proven study that hasn’t been done yet.
    According to the above article the title of this article is only a unproven hypothesis.
    The mice were geneticly modified to not produce the substance needed to create the dopamine pathways and on that the hypothesis is MAYBE THC would interfere with this in developing brains.
    I usually love your articles,but this one was a huge disappointment.

    • You must not have read it correctly because it clearly says that they were genetically modified to not produce cb1 receptors. Delta 9 thc reduces cb1 protein expression and cb1 mrna aka reduced cb1 receptors. The effects of receptor knockout and and reducing receptor expression with an agonist won’t be exactly the same but they will usually be somewhat similar, although it depends on what receptors and what drugs you’re using, as this processes are highly complex. This data coincides with everything we know about delta 9 thc in developing organisms. It isn’t good for them. It alters development in negative ways. There are other studies that specifically study delta 9 thcs effects on development.

  5. Thus is not a real science magazine. The article is NOT about the discovery that THC inhibits canniboid receptors. The article clearly states mice were genetically engineered to have missing canniboid receptors and then they watched brain growth.
    Not at one time did they test if THC has the same effect on the growing brains dopamine system as genetically engineering mice brains does.

    I’m disappointed but not surprised my ap is throwing this kind of crap up on their news feed.

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