Molecular mechanisms underlying cannabis abuse and schizophrenia: Focus on 5-HT2A receptors and Akt/mTOR signaling pathway

Abstract

Schizophrenia is a chronic and disabling mental illness that affects around 20 million people worldwide. The etiology of the disorder is multifactorial, and different genetic and environmental factors take part in its onset and course. However, the mechanisms underlying this interaction remain poorly understood. Cannabis abuse, especially during adolescence, has been associated with an increased risk of developing schizophrenia as well as with an earlier onset. The main aim of this Thesis consisted in evaluating the molecular mechanisms underlying this relationship, with a focus in two targets previously related with schizophrenia: serotonin 2A receptors (5-HT2AR) and Akt/mTOR signaling pathway. For this purpose, we evaluated (1) the G¿ protein subunits activation exerted by three cannabinoids, including THC in mouse brain cortex, (2) chronic THC effects on psychosis-like states, cortical 5-HT2AR functionality and Akt/mTOR signaling pathway status, (3) the implication of Akt/mTOR signaling pathway in these effects, (4) the Akt/mTOR signaling pathway status in postmortem prefrontal cortex (PFC) of subjects with schizophrenia, and (5) the 5-HT2AR protein expression and Akt functional status in platelets from subjects with a cannabis use disorder, with and without schizophrenia. Most significant results from this Thesis show that chronic THC leads to hyperactive 5-HT2AR functionality in the brain cortex associated with a hyperactive Akt/mTOR signaling and psychosis-like behavior. Disruption of this signaling pathway is also evident in postmortem PFC and platelets of subjects with schizophrenia, and cannabis abuse seems to exert different effects depending on the presence of schizophrenia pathology. Together, this Doctoral Thesis suggests that 5-HT2AR and Akt/mTOR pathway are elements of an interacting mechanism involving chronic cannabis pharmacological effects and schizophrenia pathogenesis.