Keeping the brain's activity under control

Max Planck Researcher team identifies an important self-defence mechanism in the brain on the basis of cannabinoid receptors

October 22, 2003

The cells of our brain intensively exchange information among each other using electrical and chemical signals. This is a prerequisite for the brain to work properly. However, if the intensity of this information exchange exceeds a certain threshold, "stormy activities" can occur, as for example during epileptic seizures in humans. Together with colleagues from the University of Mainz and teams from Heidelberg, Naples and Madrid, researchers from the Max Planck Institute of Psychiatry in Munich showed that the brain's cannabinoid receptors together with the body's own cannabinoids constitute a system which protects the neurons from such hazardous excessive activities. The researchers reported in the current issue of the journal Science (October 3, 2002) that genetically modified mice lacking the cannabinoid receptor are highly susceptible to seizures and to concomitant cell death, i.e. the threshold for seizures is lower than in intact wild-type control mice. Additionally, a drug-induced increase in the body's cannabinoids protects the brain from seizures, thus from resulting neuronal cell death.

Both delta-9-tetrahydrocannabinol, the psychoactive component of Cannabis sativa, and the body's own cannabinoid, anandamide bind to the same cannabinoid receptor, which is abundantly present in the brain. Binding of delta-9-tetrahydrocannabinol and anandamide to this receptor leads to a decreased excitability of the respective neuron.

The psychoactive and therapeutic effects of extracts from the plant Cannabis sativa have been known for more than 5000 years. The active component of Cannabis was identified as delta-9-tetrahydrocannabinol (THC). In the brain, THC binds to proteins, called cannabinoid receptors, which act like an antenna and mediate the effects of THC (Fig. 1). The existence of such an antenna has suggested that the brain produces cannabinoids on its own. In fact, such substances have been identified: They are fatty acid derivatives which can be released from neurons when needed. By binding to the cannabinoid receptor, both THC and endogenous cannabinoids change the neuron's reactivity to stimuli thus leading to a lowered transmission of electrical and chemical signals. THC and the body's cannabinoids are able to dampen the neuronal excitability.

Using genetic, biochemical and electrophysiological methods, researcher teams led by Beat Lutz and Walter Zieglgänsberger from the Max Planck Institute of Psychiatry in Munich and by Christian Behl from the Johannes Gutenberg University of Mainz together with colleagues from Heidelberg (G. Schütz), Naples (V. DiMarzo) and Madrid (M.L. Lopez-Rodrigues) investigated a mouse model with no cannabinoid receptor in those neurons that stimulate the information exchange between particular forebrain neurons. The reaction to an experimentally induced strong activation of the neurons was tested in these mice. The absence of cannabinoid receptors in the mouse mutants caused an increased sensitivity to neuronal hyperactivity and induced much stronger seizures as compared to intact wild-type control mice (Fig. 2). Thus, these results put forward the notion that the cannabinoid receptor together with the body's cannabinoids are important at the moment when neuronal "stormy activities" occur.

Mice that lack the cannabinoid receptor (black bar) are more seizure-prone than intact wild-type control mice (white bar). Induced by a specific drug, the enhancement of the body's cannabinoid concentration shifts the seizure threshold upwards and provides protection against seizures (grey bar).

In fact, as shown by biochemical investigations, endogenous cannabinoids were formed abundantly during these excessive neuronal activities. Electrophysiological experiments further revealed that the neurons lacking cannabinoid receptors showed an enhanced sensitivity towards activating neurotransmitters (such as glutamate). This is further indication that cannabinoids can dampen neuronal systems. In the cannabinoid receptor-deficient mice, several genes could not be switched on whose protein products are known to protect neurons from cell death induced by seizure.

As several neurodegenerative and neurological diseases in humans are also characterised by excessive neuronal activity, novel therapeutical approaches for the treatment of such diseases could possibly be derived from the knowledge of the protective function of the body's cannabinoid. Ideally, cannabinoid receptors should only be activated where and when an excessive neuronal activity occurs. This could be achieved using specific drugs that block the degradation of the body's cannabinoids. This enhances the action of these cannabinoids, leading to lowered seizure sensitivity (Fig. 2).

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