Science Interviews


Tue, 4th Nov 2014

Missed connections

Zsolt Lenkei, CNRS

Listen Now    Download as mp3 from the show eLife Episode 15: Flu, Cannabis and HIV

Cannabis-detecting receptors are in both adult and embryonic brains. But what isCannabinoid receptor their purpose? Zsolt Lenkei has an intriguing theory, and this could tell us why cannabis users can be at an increased risk of developing schizophrenia. 

Zsolt - These receptors are sensitive to neurotransmitters and they are also sensitive to cannabis and we were mapping the localization of these proteins and we were very surprised that we found a lot of these receptors in very young developing neurons. And this was surprising because these receptors are mostly known as the regulator of synaptic transmission between neuronal cells.

Chris - Why were you surprised that there should be so much of the activity of these receptors in a developing brain because after all, itís producing lots and lots of nerve cells and itís producing lots and lots of connections between nerve cells as those cells develop the brain.

Zsolt - We weíre surprised because the expression of this receptor, came very early. When neurons just started to be defined as neuronal cells, the did not have any axons or dendrites. The expression of these receptors was very high during the growth of these neurites during the axons that grow to contact either brain regions. And very surprisingly when these regions were reached and synapses started to form, these receptors just started to disappear from neurons.

Chris - Do you think that that might be because when youíve got a developing brain and you want cells to grow a bit, if you let them connect too soon they may make lots of aberrant local connections and not grow to their target before they start connecting to it. Could it be that thatís also part of the issue.

Zsolt - Absolutely. Correct connections are very highly regulated in the brain. In order to have the right number of connections, cannabinoid receptors are working as a brake. We started to think that maybe in developing neurons, they can also have a role at braking growth.

Chris - So how can one find out whether or not these endocannobinoid receptors are stopping nerve cells connecting to each other albeit prematurely?

Zsolt - So in the beginning, we were growing neurons in dishes and we treated these neurons with pharmacological ligands, molecules that would either stimulate or block the activation of this receptor and we have found that molecules that activate the receptor will lead to neurons that grow shorter axons and less dendrites. While blocking this receptor led to neurons that had longer or more developed neurites. Then we wanted to have a closer look at the mechanism of these negative regulator effect so we set up endomicroscopy. So we have young neurons from the embryonic rat brain in a dish. We transformed genetically these neurons so fluorescent molecules be label microtubules and also that cytoskeleton. We put these neurons under a microscope where we filmed 20 or 30 neurons typically one or two hours and we were very surprised because as soon as we put molecules that stimulate the activation of the receptor growth cones of the growing axons responded with a very strong contraction.

Chris - So on the surfaces of these growth cones which are the structures that the developing nerve are putting out to grow and find a target ultimately to connect to it. There are receptors for these endocannabinoids. If you stimulate those receptors this makes the growth cone collapse and retract. Do you understand whatís going on in the cell to force that retraction?

Zsolt - Simply by looking at the contracting growth cone we have seen that F-actin which is an important cytoskeletal polymer, is redistributed exactly at the places where the contraction takes place.

Chris - So putting all this together, what weíve got is nerve cells from very early on in development are expressing a receptor for the brainís own cannabis-like chemicals. This receptor is connected to systems that can rearrange the cells skeleton and this leads to the forcible retraction of these growth cones. Just extrapolating this we know that thereís an association between cannabis use and psychosis. Do you think that there could be a connection here? Excuse the pun.

Zsolt - The brain is very sensitive to cannabis in the adolescent period. In the adolescent brain, there is a final large-scale remodelling of connections mostly in regions which are important for cognitive functions. And interestingly in brain areas which are remodelling in the late adolescent period, you find a lot of cannabis receptors. So overstimulation by heavy cannabis use may lead to large-scale remodelling. These individuals will have less connections and psychosis is known as connectivity disease so these molecular mechanisms that we described can explain why psychosis will develop in these individuals.



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The brain's own cannabinoids, also called endocannabinoids, are important lipid signaling molecules which mediate synaptic function. The brain respond to intracellular THC delivery by activation of CB1 receptors mediating retrograde endocannabinoid signaling and releasing endocannabinoids to neurons via astrocytes. Neuron-astrocytes communication is an important method of endocannabinoid mobilization. tkadm30, Wed, 9th Dec 2015

I would like to know why my brain does not react to cannabis. I have tried edibles and they have no effect. lately I tried some caramels amounting to 30mg of TCH -THC? or whatever - the stuff that make syou high- and had no effect whatever.Why? annie123, Thu, 10th Dec 2015

Maybe you were taken for a ride and sold elephant dung - quite literally shit - or some such; drug dealers don't tend to subscribe to codes of ethical trading or the consumer marketing act, I've heard... chris, Thu, 10th Dec 2015

Males and females regulates cannabinoid-induced energy homeostasis differently:

- pmid 19427130

Females regulates brain energy homeostasis through estrogen-mediated attenuation of CB1 receptor:

- pmid 19758570
- pmid 22538462

This might help identifying sex differences in endocannabinoid mediated neurotransmission through proopiomelanocortin (POMC) synapses. tkadm30, Thu, 10th Dec 2015

I don't know what the pm etc means.
No I was not sold rubbish. I bought it at one of the several medicinal marihuana shops  here in  BC (Canada) where medical marihuana is allowed when sanctioned by a doctor. And no it had not had the active ingredient taken out. I did look online to see if others had this problem and apparently they do, but don't know why.
perhaps when our sunny days Prime Minister has legalized it for recreational use as well I may get to try a wider variety of things such as the patch to see if anything else works, because i don't want to smoke it. But I still would like to know why it had no effect. annie123, Fri, 11th Dec 2015

As a female your body produces estrogen. Estrogen prevent the effects Cannabis is doing to the brain. tkadm30, Fri, 11th Dec 2015

Then why do females get high at all?
Anyway, my body doesn't produce estrogen. I have to take it artificially and when I stopped taking it to see what would happen it didn't make any difference. annie123, Fri, 11th Dec 2015

Sex differences in endocannabinoid signaling and distribution of CB1 receptors in the brain may provide
females with higher sensitivity to THC due to estrogen levels. Your lack of estrogen may explain your indifference to cannabis. tkadm30, Mon, 14th Dec 2015

I just love how THC emancipate my mind from toxic chemicals we breathe and eat. The power of THC to neutralize oppression from the outer world is priceless. Our brains react to cannabis like eating chocolate; It's a powerful antidepressant and antiinflammatory medicine with obvious neuroprotective function.

We should protect organic cannabis cultivation to ensure its perennity and the understanding of its pharmacology;

The knowledge of cannabis science is missing from education, and its effects on the brain are still poorly understood and stonewalled by modern psychiatry. If psychiatry is not a religion then it must properly educate psychiatrists about the use of cannabis as a psychiatric treatment.
tkadm30, Sat, 23rd Jul 2016

THC stops your mind from worrying about toxic chemicals (or any number of potentially worrying things, like the pedestrian who is about to step off the kerb in front of your car....).

However, it does not stop your liver from worrying about toxic chemicals we breathe and eat, which will still kill you just as effectively whether or not you have THC in your system.

Nor does it does not stop your lungs from worrying about toxic chemicals we breathe, which are probably more prevalent from air that has just passed through a marijuana joint. evan_au, Sun, 24th Jul 2016

Agreed. However the toxicity of THC is fairly low compared to others combustion-derived nanoparticles
and fluoride.

tkadm30, Mon, 25th Jul 2016

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