DS0407 -

Sensory representation under psychotic-like states – ORUPS

Submission summary

After tobacco and alchool, cannabis is the most widely used psychotropic drug, with an estimated 125–227 million consumers worldwide. A link between cannabis intoxication and the development of psychosis has long been recognized and psychotic-like states have been documented in numerous case-reports and estimated to occur at least once in about 20%-50% of individuals who use cannabis. THC and synthetic cannabinoids have been shown to produce a full range of effects resembling positive and negative symptoms of psychosis, and other endophenotypes, such as cognitive and somatosensory gating alterations typically related with psychosis. Moreover, more than 40% of schizophrenic patients use cannabis regularly, with the general consequence of worsening positive symptoms. Due to the high prevalence of cannabis use, it is urgent to better understand cannabis-induced psychoses (CIP) in order to propose novel treatments. Whereas the cognitive and somatosensory gating endophenotypes or the negative symptoms of psychotic-like states can be studied in mice by evaluating specific behaviors, the positive symptoms (e.g. hallucinations and delusions) are difficult to assess in animals. A typical feature of psychotic positive symptoms is the presence of altered mental representations of external environment such as sensory hallucinations and delusions, which can be defined as impaired “reality testing”. For instance, delusions are defined as “erroneous beliefs that usually involve a misinterpretation of perception or experiences”, which implies an erroneous mental representation of stimuli. “Reality testing” is the process through which individuals verify the correspondence between the internal representations of stimuli and their real presence and meaning in the external world. Evidence exists that animals can construct complex internal representations of their world and these representations can be distorted in animal models of psychotic-like states presumably in a similar way as they do in humans. Similarly, alterations in behavioral flexibility, the process of adapting behavior to respond to changing circumstances in the most effective way, are considered amongst the most reliable cognitive deficits associated with psychotic states.
Recent efforts in the field have produced some convincing rodent behavioral paradigm to study “reality testing” and behavioral flexibility, based on olfactory cues which are particularly relevant for rodents. Impaired reality testing and altered behavioral flexibility constitute two key symptoms of psychotic states, involving aberrant integration of external information with internal representation and expectancy. These processes likely involve top-down control of sensory perception from higher brain circuits, which can determine the internal representation of the stimuli and provide information regarding their “real” meaning. In this sense, impaired formation of mental representations assessed through reality testing and behavioral flexibility can be seen as a mismatch between the real meaning of the “object perceived” (i.e. the stimulus, or percept) and its subjective internal representation (concept).
Using advanced genetic, electrophysiological, imaging and behavioral tools, this project aims at characterizing the role of top-down integration of sensory perception on psychotic-like states induced by acute and/or chronic cannabinoid intoxication. This project will provide key information to better understand the mechanisms underlying symptoms of psychoses and could lead to new therapeutic approaches. In particular, a recently discovered endogenous signaling-specific inhibitor of CB1 receptors (the neurosteroid pregnenolone or its stable derivatives) is proposed as a potential therapeutic tool to specifically counteract cannabis-induced psychotic states and to generally improve psychotic syndromes.

Project coordination

Giovanni MARSICANO (Institut National de la Santé et de la Recherche Médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INRA Institut National de la Recherche Agronomique
INSTITUT PASTEUR (BP)
INSERM Institut National de la Santé et de la Recherche Médicale

Help of the ANR 445,419 euros
Beginning and duration of the scientific project: January 2017 - 36 Months

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