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Cannabinoids - important for memory?

Cannabis intoxication is certainly not the original purpose of the cannabinoid receptors in the human brain. Nowadays, there are known body substances which dock to the receptor molecules of nerve cells in a similar way to cannabis. A group of researchers led by pharmacologist Prof. Dr. med. Bela Szabo at the University of Freiburg is investigating the role of this molecular system in the human brain. Their research reveals a neuronal feedback mechanism that might be important for the brain, amongst other things.

Twenty years ago, pharmacologists knew very little about the effect of the plant Cannabis sativa. As the plant’s main psychotropic substance, D9 tetrahydrocannabinol (THC), is fat soluble, the researchers assumed that it would be stored in the nerve cell membrane, alter the electrophysiological properties of the lipid bilayer and affect the communication between neurones. However this is not so. In the 1990s, a membrane receptor was discovered which detects the presence of this intoxicating substance and translates it into the cell’s interior: the CB1 cannabinoid receptor, a molecule that invokes a chemical cascade and can lead to molecular alterations in the cells’ interior, which will eventually affect electrical activity. This receptor is present in almost all areas of the brain, and in an astonishingly high density. In addition, it is found in most types of nerve cells. “So, the question is: what is the exact function of CB1 receptors,” said Professor Szabo from the Institute of Experimental and Clinical Pharmacology and Toxicology at the University of Freiburg. “Or let me put it bluntly – I am sure they don’t exist just so we can smoke cannabis.”

An attenuation system?

Since then, a relative of the CB1 receptor, the CB2 receptor, has been discovered which is found mainly on immune system cells. Over the last 15 years, the researchers have also identified some cannabinoids (endocannabinoids) in the human body, for example anandamide or 2-arachidonoylglycerol (2-AG). These substances must play a key role in the human body, otherwise they would not exist. Szabo and his colleagues investigated how the electrical behaviour of nerve cells changed in different brain slices upon the activation or inhibition of the CB1 receptor. They used synthetic substances that stimulated the CB1 receptor to the same extent as THC, anandamine or 2-AG (agonists) or substances that inhibit the receptors (antagonists). The researchers have carried out these electrophysiological experiments on tissue from various different brain regions of mice, for example areas that are important for the control of movement.
Schematic of an electrophysiological experiment used to test the role of the cannabionid system.
Top: Schematic of an electrophysiological experiment used to test the role of the cannabionid system. The schematic shows two specific types of serially connected neurones in a brain slice of the caudate putamen region in mice. One electrode stimulates the cell at the top (PV-FSN, paralbumin-positive fast spiking interneurone), another one measures the cannaboid-regulated activity of a postsynaptic cell (MSN, medium spiny neurone). Bottom: That’s how the difficult experiment looks in reality. The left and right pictures show the same tissue region. Under the fluorescence microscope (left picture), the PV-FSN cell can be clearly seen because it is labelled with EGFP. Under the light microscope (right picture), only the two electrodes can be seen. (Figure: Prof. Dr. med Bela Szabo)
Results show that endocannabionids and their receptors play an important role at the contact sites between two nerve cells (synapses). If a nerve cell repeatedly sends electrical impulses to a postsynaptic nerve cell, then from a certain point in time this will produce endocannabinoids. The endocannabinoids come from the cell’s interior and diffuse back – across the synaptic cleft – to the axon terminal of the presynaptic nerve cell where they dock to the CB1 receptors. This leads to a chemical cascade which prevents calcium from entering the axon terminal with the result that a much smaller amount of transmitters enters the synaptic cleft. This in turn leads to the inhibition of the synaptic transmission between axon terminal and postsynaptic nerve cell.
The graphic shows the electrical response of a cell stimulated by a pre-synaptic cell. Normally, the activity is high (black dots); following the addition of the cannabinoid receptor agonist WIN55212-2 (WIN), it is strongly inhibited.
The graphic shows the electrical response of a cell stimulated by a presynaptic cell. Normally, the activity is high (black dots); following the addition of the cannabinoid receptor agonist WIN55212-2 (WIN), it is strongly inhibited. (Figure: Prof. Dr. med. Bela Szabo)

Neuronal plasticity

The CB1 receptor and the endocannabinoids are part of what is known as a retrograde signalling system. A negative feedback loop, which also involves endocannabinoids, registers when the stimulatory synaptic activity is too high and needs to be lowered. “This is most likely the most common type of retrograde signal transmission in the brain,” assumes Szabo. The endocannabinoid-based principle is important for the permanent modification of the strength of synaptic contacts; it is used to mediate synaptic plasticity. For example, a specific initial activity of synapses can lead to the long-term depression (LTD) of synapses (this can last for several hours), a phenomenon that is regarded as an important neuronal basis of memory. In many areas of the brain, endocannabinoids are important prerequisites for the occurrence of LTD.

Szabo and his colleagues have also investigated the role of cannabinoid receptors in other areas of the nervous system, for example in the peripheral nervous system where the cannabinoids can have an effect on blood pressure. At present, the Freiburg researchers are investigating the mechanisms that control the endocannabinoid production in the nerve cells. The field of cannabinoid biology and pharmacology is not only interesting from the perspective of basic researchers, the pharmaceutical industry might also benefit from this research. For example, there is evidence that cannabinoid agonists have a pain relieving effect. Another example is stroke patients who might benefit from cannabinoid receptors that are able to maintain a low activity of nerve cells in risk areas and thus prevent the neurones from suffering long-term damage. The CB2 receptor also attracts the scientists’ attention. As it is found on the cell membrane of immune system cells, its activation might lead to the inhibition of certain inflammatory reactions. However, it is difficult to use these approaches for therapeutic applications. “The problem is the ubiquitous localisation of the cannabinoid receptors,” said Szabo. “It is a challenge to find substances that are able to activate or inhibit specific cannabinoid receptors in specific areas, thereby creating fewer side effects.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/cannabinoids-important-for-memory