The brain’s own cannabis: the endocannabinoid system

Did you know that the brain contains its own set of chemicals that act like chemicals found in cannabis? You may have heard of endorphins (not to be confused with the Australian electronic musician), opiate-like chemicals made by our bodies that help us control pain and feel good after exercise. Well, the body also makes its own cannabis-like chemicals, called endocannabinoids, that help us with everyday functions such as memory and appetite.

Endocannabinoids act as gates between neurons. After detecting what is happening in its immediate environment, a neuron can send out endocannabinoid molecules to bind to endocannabinoid receptors on a neighbouring neuron, telling the neighbour to stop sending out its message. Telling individual neurons to ‘quiet down’ helps clean up the signals that one part of the brain sends to another – essential when you want to concentrate on reading a book, remember the directions to a friend’s house, or know that you are hungry.

Dr Leonora Long

The genes I studied included CB1, the receptor for the endocannabinoid neurotransmitters, DAGLalpha and NAPE-PLD, synthetic enzymes that make the endocannabinoid neurotransmitters, and MGL, ABHD6 and FAAH, inactivating enzymes that break down the neurotransmitters.

The brain doesn’t get all of its functions in perfect working order overnight. It has to develop, going through turbulent stages like toddlerhood and adolescence on its way to adulthood. My latest research has explored how the endocannabinoid system develops, in order to better understand how the brain approaches the important task of regulating neuronal communication as it matures.

Using brain samples donated after death from people 39 days old to 45 years old, I looked for genes that are part of the endocannabinoid system in a part of the brain called the dorsolateral prefrontal cortex. This part of the brain helps to regulate working memory and decision-making and is also related to some illnesses such as schizophrenia.

I was interested, but not surprised, to find that endocannabinoid elements undergo dynamic change throughout postnatal life. For example, the main brain endocannabinoid receptor, the CB1 receptor, starts off at very high levels in the brains of neonates and stays high throughout toddlerhood, but by teenagerhood it is starting to decline. On the other hand, NAPE-PLD (the gene for the enzyme that makes anandamide, one of the endocannabinoid neurotransmitters) starts off low just after birth but keeps on increasing to peak in adults. Overall, it seems like the most change in these elements is happening in adolescence.

Why is this important? Well, we know that cannabis use is most commonly started during the teenage years. Teenagerhood is also the most important time for the development of adult behaviours like decision-making and for the fine-tuning of processes like working memory. So, if there is a lot of change going on in the brain at this time, particularly in the endocannabinoid system and its function as a ‘balancer’ for neuronal communication, then perturbing this natural change by cannabis exposure could have devastating consequences for some individuals.

It is now clear that cannabis use can increase the risk of developing schizophrenia by as much as double. This increased risk is particularly important if cannabis use commences during teenage years. Furthermore, it has been known for some years that genetic makeup can make the effects of cannabis worse – in a long-term study in New Zealand, people with a genetic variant who also smoked cannabis as adolescents were far more likely to be diagnosed with psychotic illness as adults than those without the genetic variant.

So what else do we need to know? We need to see whether the normal changes that happen in the endocannabinoid system have gone offline during development in the brains of people with schizophrenia. We have some evidence that this is the case – people with a paranoid subtype of schizophrenia seem to have higher levels of CB1 receptor protein binding. But we don’t know how this happens, and in particular we still don’t know the mechanisms underlying how cannabis use can affect normal development. Our ongoing research is using animal models of genes related to schizophrenia to look at exactly these questions.

Dr Leonora Long is a Research Officer with the Shannon-Weickert group at NeuRA.

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