Pathophysiological correlates of adolescent cannabis use – CANNADO

Cannabis is the most commonly used illicit drug in the world. The widespread use of cannabis derivatives in adolescent and young adults is linked with an increased risk for mental illness and a major public health concern. A meta-analysis revealed that cannabis users developed psychosis about 2.7 years younger than those who did not use, suggesting of the existence of an association between adolescent cannabis use (ACU) and an earlier onset of illness.
Adolescence is a period of profound morphological and neurodevelopmental maturation, notably in the prefrontal cortex (PFC) a brain structure involved in higher cognitive functions, emotions and social behavior. PFC dysfunctions participate to the etiology of schizophrenia, a late onset neuropsychiatric disorder characterized by a breakdown of thought processes, poor emotional responsiveness and significant social or occupational dysfunction. The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of about 0.3–0.7%. In addition to producing clinically significant distress, schizophrenia is almost uniformly accompanied by some degree of social and/or occupational impairments degrading the quality of life and well being and therefore contribute to the societal burden associated with loss of work and health care costs.
The main psychoactive ingredient of cannabis-based preparations is THC. In the CNS, THC hijacks the cannabinoid type 1 receptor (CB1R). CB1R is a core component of the endogenous cannabinoid system (ECS), which participates to many fundamental neuronal and synaptic processes. Recent discoveries in the laboratory fuel the concept of a common central role of ECS dysfunctions in neuropsychiatric diseases of environmental or genetic origins.
The cellular underpinnings of the physiopathological mechanisms linking adolescent cannabis use (ACU) to schizophrenia remain to be fully elucidated. How ACU modifies synaptic connectivity in the circuits involved in emotional behavior and high cognitive functions are just beginning to be understood. In this context we want to elucidate the interactions between ACU and the vulnerability to develop schizophrenia. Our working hypothesis is that the repeated hijacking of the ECS and other synaptic plasticity by THC during ACU has protracted effects on specific PFC circuits and/or PFC-mediated behavior and that identifying these alterations can help identifying new therapeutic strategies.
Based on a daring “bed to bench” association between a Psychiatry department and three Basic Research groups and new unpublished data, we propose to identify the molecular, synaptic and circuit substrates linking adolescent cannabis use to the vulnerability to develop schizophrenia symptoms and to:
1/ Discover and compare the neurobiological substrates of the functional/behavioral alterations induced by ACU in schizophrenia patients with those induced in a rat model of ACU.
2/ Describe and understand the behavioral, synaptic and circuitry alterations of PFC functions in ACU exposed rats.
Practically the Psychiatry group will first perform the clinical evaluation followed by combined Magnetic Resonance Imaging and Diffusion Tensor Imaging of schizophrenia patients with a documented history of cannabis use during adolescence. The human anatomical, functional and behavioral data will then be transposed to rats. In rats exposed during critical and well-defined periods during adolescence to cannabis, the Neurophysiology groups will then combine their expertise in state-of-the art electrophysiological, optogenetic and behavioral ex vivo and in vivo methods. They will describe PFC dependent behaviors, reconstruct the tri-dimensional architecture of PFC neurons, portray their synaptic plasticity profiles and establish afferent and efferent PFC circuit connectivity to shed new light on the long-lasting consequences of ACU.