How the body copes with fear

August 01, 2002

Using the model of fear conditioning in mice, researchers of the Max Planck Institute of Psychiatry together with colleagues from Naples were able to show that the cannabinoid receptor is important in erasing fear behavior. The researchers report in the current issue of the journal Nature 1st August 2002 that in mouse mutants lacking the cannabinoid receptor CB1, erasure of fear behavior evoked by an aversive acoustic sound was considerably lessened compared to normal control mice. The researchers hope that these findings will lead to new approaches for the treatments of phobias, posttraumatic stress disorders, and certain forms of chronic pain.

It is part of our evolutionary heritage that we are alert to potentially dangerous situations, such as confined spaces, wide open spaces, lofty heights, or situations where we are confronted by animals perceived to be repulsive or possibly dangerous for us, such as spiders or snakes. Although it is important to be aware of potential and real threats, it is equally important to react appropriately to them. In most human beings, the initial moment of alertness and the subsequent reactions are correctly balanced, and they are able to relax rather fast and to react well-planned if the expected "disaster" has not occurred. There are also people, however, (so called phobics) that are not able to adapt to such situations. They develop an uncontrollable over-reaction, which might eventually result in a panic attack. Similarly, some people are unable to cope emotionally with traumatic events, such as accidents or war experiences. Until recently, little was known about the mechanisms underlying the adequate adaptation to supposedly dangerous situations. Recent findings obtained by researchers of the Max Planck Institute of Psychiatry in Munich and by a research institute in Naples strongly suggest that the endogenous cannabinoid system of the brain plays an important role in these adaptation processes.

Extracts of Cannabis sativa, commonly known as marihuana or hashish, have been well known for their therapeutic and psychoactive effects for more than 5000 years. The substance Δ9-tetrahydrocannabinol (THC) was identified as the active component in Cannabis sativa. The cannabinoid receptor type 1 (CB1) constitutes an endogenous receptor for THC in the brain. This receptor is activated by endogenous fatty acids derivatives, the so-called endocannabinoids (Fig. 1). CB1 receptors exist abundantly in many brain regions including the amygdala, which is centrally involved in cognitive and emotional processes.

Researchers from the Max Planck Institute of Psychiatry (Beat Lutz with Giovanni Marsicano and Heike Hermann; Carsten Wotjak with Jianrong Tang, and Walter Zieglgänsberger with Shahnaz Azad and Gerhard Rammes) in collaboration with the Institute of Mammalian Genetics of the GSF in Neuherberg (Clementine Hofmann) and the Consiglio Nazionale delle Ricerche (CNR) in Naples (Vincenzo Di Marzo with Tiziana Bisogno and Maria Grazia Cascio) established a mouse lineage with genetically removed CB1 receptors (CB1 knock-outs). The role of endocannabinoids and CB1 for adapting to aversive or repellant situations was then studied in a fear-conditioning task. In this task, both CB1 knock-out and control mice had first to associate a tone signal with an aversive stimulus. Mice were next repeatedly exposed to the tone on following days. The behavioral reaction to the potentially aversive signal was analyzed. All animals showed a remarkable fear reaction during the first re-exposure to the tone. With repeated tone presentations, control mice quickly recovered from this fear reaction. CB1-deficient mice, in contrast, showed a weak reduction of fear (Fig. 2). Noteworthy, acquisition and consolidation of fear memory were completely normal in CB1 knock-out mice: the mice successfully learned to associate the tone with an aversive stimulus and they could hardly forget it.

The impaired ability of CB1-deficient mice to adapt to perceived dangerous situations was confirmed in an accompanying pharmacological experiment, in which the blockade of the CB1 receptor by a selective antagonist affected the fear reaction of normal mice only if the antagonist was applied before memory recall (i.e., re-exposure to the tone).

Using biochemical methods, the researchers were, furthermore, able to show that endocannabinoids were enriched in the amygdala of normal mice immediately after re-exposure to the tone. As retrograde messengers, endocannabinoids mediate the signal transfer from the post- to the presynapse of the nerve cells, i.e., in reverse direction to the common route of information flow. Binding to CB1 receptors at presynaptic terminals leads to a reduction of the release of distinct classical neurotransmitters. By means of an electrophysiological approach, the researchers could describe a novel kind of synaptic plasticity in the communication between the nerve cells that is controlled by the CB1 receptor and possibly involved in the adaptation to aversive stimuli.

Combined, the genetic, biochemical, electrophysiological, behavioral and pharmacological studies unveiled the central role of the endocannabinoid system in the erasure of aversive memories. Although the universality of these results for aversive situations other than fear conditioning has still to be shown, the newly described biological function of endocannabinoids might lead to the development of novel therapeutic strategies for the treatment of patients with inadequate reaction to potentially dangerous situations (for example phobics and patients with posttraumatic stress disorders, and certain forms of chronic pain).


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