Currently, it is widely thought that the psychotic effects of cannabis abuse mainly rely on their action on neurons. However, the brain is a complex tissue formed by the intercommunication of at least 4 different cell types, amongst which astrocytes represent one of the most active at supporting neuronal function. Here, we plan to address whether astrocytes play a major role in the neurological effects of cannabis by re-programming the normal metabolic interaction with neurons. To address this issue, we plan to implement a unique genetically-modified mice model that lacks one of the most relevant cannabinoid receptors, CB1, specifically in astrocytes. By comparing the effects of cannabis chronic administration to these genetically-modified mice, both in cells isolated from these animals and in the in vivo animals themselves, against those to the wild type ones, we will deduct whether CB1 in astrocytes actively play a role in the neurochemical (metabolic and redox) status of neurons. Furthermore, using the appropriate CB1 agonists, we will assess if the mitochondrial- located CB1 is responsible for the observed effects. Provided we demonstrate this role, this project will serve to implement an in vivo strategy using this mice model to assess using imaging techniques, brain functioning in vivo, as well as behavior. In addition, we expect to understand if the high production of reactive oxygen species (ROS, responsible for the so-called oxidative stress when abundant) that we have detected in astrocytes, play a major role at coordinating both the metabolic and the redox status of neighbor neurons. We believe that elucidating these issue will greatly impact on our current knowledge on (i) the physiological regulation of brain energy metabolism, and (ii) the molecular mechanism of action of cannabis abuse. We therefore think that this project deals with the aims of the agency in this call, i.e. (i what molecular processes regulate brain energy utilization? (ii) How do these regulatory processes impact the functions of neurons, or glia, or their interactions? (iii) How do these energy regulatory processes synergize with or oppose molecular events that occur in response to exposure to substances of abuse? (iv) How do drugs of abuse affect brain energy substrate preference over time? Are alternative substrates of energy metabolism utilized due to substance use? (v) What molecular mechanisms regulate these processes? (vi) What transcription factors or epigenetic regulatory processes influence regulation of brain energy utilization? (vi) Do substances of abuse impact these same processes? (viii) What is the impact of substances of abuse on molecular regulation of mitochondrial function or on nuclear/mitochondrial communication? (ix) What are the molecular regulatory mechanisms by which abused substances induce oxidative stress in the mitochondria and deplete ATP in neurons and glia? and (x) How is redox homeostasis in the brain altered by chronic exposure to drugs of abuse?
This project will investigate the interplay between molecular regulation of brain energy utilization resulting from chronic exposure to abused substances. We will focus on cannabinoids under chronic exposure. In view that the PI has limited experience in substance abuse research, he collaborates with researchers that have substance abuse expertise. The application has a primary focus on molecular mechanisms regulating brain energy utilization and, accordingly, a primary deliverable of this project is a genetically-modifie mice that will be useful to explore the important and yet ignored role of astrocytes in regulating energy metabolism and chronic abused substances.
