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Final Report Summary - SCHIZO-MTCB1 (Cannabinoid receptors CB1 in schizophrenia: role of brain mitochondrial activity and astroglial signalling)

The main aim of this project was to investigate if mitochondrial CB1 receptor (mtCB1) signalling in the brain participate in the development and/or symptomatology of psychotic-like states induced by cannabinoid drugs, and whether astroglial cells might play a particular role in these processes. During this two-years project we have almost fulfilled all the objectives previously proposed:

First, we have generated some tools to try to discriminate mtCB1 receptor from other cellular locations. Thus, we have used a specific inhibitor that block one of the downstream signalling proteins depending on mtCB1 receptor (the soluble adenyl cyclase). On the other hand, we have generated a mutant CB1 protein (DN22CB1) that is not able to be present in the mitochondrial membranes. All these tools have been described in a recent publication by the host lab in Nature (Hebert-Chatelain et al., 2016). Using these tools by local injections in the brain or the generation of cell-specific viral approaches we are able to interfere the mtCB1 signalling in specific brain regions or cell-types to better understand the possible implication of mtCB1 in the effects induced by THC.

Second, we have set up a complete battery of behavioural tests in order to study the psychotic-like effects induced by cannabinoids. Thus, we have started to choose the optimal doses of the main psychoactive component of the plant Cannabis sativa, THC, that produce several psychotic-like effects: working memory (cognitive symptoms), prepulse inhibition (sensorymotor symptoms), social interaction (negative symptoms), locomotion and reality testing tasks (positive symptoms). Indeed, a strong effort was dedicated to set up this new model in mice to study reality testing that can be an interesting and useful tool to study the positive-like psychotic symptoms. All these results have been recently published in the Molecular Psychiatry Journal (Busquets-Garcia et al. 2017). Moreover, we have been able to demonstrate a potential new therapeutic strategy to tackle all the psychotic-like states induced by THC using pregnenolone. Some years ago, it was shown that pregnenolone treatment inhibited THC-induced molecular and behavioral effects. This suggested that pregnenolone might act as an endogenous signalling-specific negative allosteric modulator of CB1Rs. Interestingly, pregnenolone is synthetized in the mitochondria from cholesterol by cytochrome P450scc. Importantly, pregnenolone administration blocked all the psychotic-like effects induced by THC. These results also suggests that pregnenolone can be used as a new therapeutic tool to prevent psychoses induced by cannabinoid drugs. All these results have been published in the Molecular Psychiatry Journal (Busquets-Garcia et al. 2017). In fact, in the same line, I have been collaborating with Aelis Farma which is a pharmaceutical company trying to develop pregnenolone derivatives compounds in order to block THC induced effects and psychotic-lie symptoms.

Third, we have also obtained strong preliminary data pointing to the possible involvement of mitochondria and astrocytes in the psychotic –like effects induced by cannabinoids. Thus, we have preliminary results that pointed to the mtCB1 receptor localized in the astrocytes as the responsible for some of the psychotic-like effects induced by THC (e.g. social interaction impairment). Moreover, it seems that mitochondrial reactive oxygen species (mtROS) can play an important role in these effects induced by cannabinoids. However, more work will be needed to further confirm these interesting results.

Finally, we started to set up cannabinoid-dependent mouse models of psychotic-like states to try to investigate the role of astrocytic or mitochondrial CB1 receptor. First, we wanted to set up the optimal conditions with THC treatments during critical periods (e.g. adolescence and in the prenatal period) in order to combine these pharmacological strategies with the maternal deprivation or other models of schizophrenia. Adolescent THC administration during adolescence impacts different behaviours that can be considered psychotic-like phenotypes (e.g. social interaction, impairment or deficits in working memory).

Thus, during these two years project we have substantially advanced on the understanding of the possible role of mtCB1 receptor in the development of psychotic-like states induced by cannabinoid drugs. Moreover, (i) we have provided new pharmacological and viral tools to interfere a specific mitochondrial protein (mtCB1), (ii) we have set up a possible new behavioural approach to study positive psychotic-like effects in mice, (iii) we have demonstrated a new possible therapeutic approach against cannabis-induced psychoses and, finally, (iv) we have obtained valuable data implicating astrocytes in some of the psychotic-like states induced by THC.

Related information

Reported by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)
France
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