Anxious disorders are among the most prevalent psychiatric conditions worldwide and they significantly handicap the lives of millions of people suffering from these conditions, without mentioning the heavy burden that they impose on the health systems. Unfortunately, the current treatments options available in the market are still sub-optimal in terms of therapeutic results and are associated with heavy side effects. Thereby, the research for treatments options against anxiety disorders is continuous and explores various possibilities. In that context, it is important to know and to understand the pathophysiology underlying these conditions. An important part of our knowledge comes from fear conditioning experiments. Indeed, fear and anxiety share the same pathophysiological circuits. The main structure that has been identified, at the basis of these feelings, is the amygdala, which is located deep in the temporal lobes. The amygdala is responsible for the categorization of emotional stimuli into a fearful emotion or not and it is responsible for the storage of fear memories and associations. Nevertheless, anxious disorders are composed of several clinical conditions sharing similarities but that are also separated by significant differences, thus fear conditioning experiments are not representative of all anxious disorders. The one with the biggest resemblance is Post-Traumatic Stress Disorder (PTSD).
Among the different treatment options that are being explored, one of the most promising lies in the modulation of glutamatergic signaling, more precisely in the modulation of glutamate receptors. Throughout the multiple that exists, the metabotropic glutamate receptor 7 (mGluR7) has been suggested as being an encouraging novel target for treatment. This metabotropic receptor is located on the presynaptic cell and its role is to negatively regulate the release of glutamate in the synapse, acting like an auto-inhibitor of glutamate release for the presynaptic cell. It is the most present mGlu receptor in the Central Nervous System (CNS) and it is most abundant in anatomic regions involved in emotional reactivity and cognitive functioning, such as hippocampus, amygdala, and the locus coeruleus thus suggesting a potential critical role in the modulations of pathways that are involved in fear and anxiety. Recent studies also underlined the potential role of glutamatergic neurotransmission in PTSD. Development in understanding the function of mGluR7 and its use as a potential target accelerated during the past years. The first part of this thesis elaborates in more details the above-mentioned circuitry underlying fear and anxiety, as well as it describes some of the main experiments exploring these conditions and recapitulates the information on mGluR7.
The pharmaceutical company Addex Therapeutics developed a negative allosteric modulator of mGluR7: ADX71743, which showed promising results in ex-vivo experiments on rats and human brain tissues from epileptic patients. Nonetheless, its poor pharmacokinetics parameters led to the development of a chemically improved version by the company: ADX94827-4. This compound is being tested in the laboratory of Professor Stoop (Centre des Neurosciences Psychiatriques du CHUV, site de Cery) by his team and this writing takes place in that context.
This thesis explores the neuromodulation of ADX94827-4 on glutamatergic neurotransmission through ex- vivo electrophysiological recordings of pyramidal cells of rats’ lateral amygdala. On that purpose, the cells were patched, and the spontaneous activity of these latter was recorded. In order to perform the experiments, the goal was also to acquire the knowledge underlying all the laboratory procedures that I was not familiar with. Unfortunately, the results that I obtained did not fulfill all my expectations and I could not properly verify the action of the compound on glutamate release. Nevertheless, those unexpected observations are in all likelihood the results of several manipulations errors that are discussed more
extensively in the text. Beyond these personal considerations, ADX94827-4 is a promising therapeutic drug and the new perspectives, that the modulation of metabotropic glutamate receptor number 7 offer, are thrilling for the future of psychiatric medicine