Cannabinoids are widely used both for recreational and medical purposes. These compounds produce their pharmacological effects -locomotor and memory impairment, psychoactive and rewarding effects, anti-nociception, hypothermia and dependence- through the activation of at least two types of endocannabinoid receptors, namely CB1 (CB1R) and CB2 (CB2R).
CB1Rs are mainly expressed in the central nervous system and represent the most abundant G-protein coupled receptors in the brain. The endogenous cannabinoid system has a crucial modulatory role in the central nervous system, directly related to the control of motor activity, memory and cognition, emotion, sensory perception and autonomic and endocrine functions.
Moreover, it has been shown to play a central role in the tolerance, withdrawal effects and rewarding properties produced by other drugs of abuse like morphine, thus highlighting the relevance of the endogenous cannabinoid system in the effects of other abused drugs. However, the specific biochemical consequences of delta9-tetrahidrocannabinol administration (the main psychoactive component of cannabis) has been poorly documented in animal models.
The aim of this research project is to characterize the intracellular signalling pathways involved in the neuronal response to THC treatment in the mouse brain, paying special attention to processes such as the control of mitogen activated protein kinase (MAPK) pathway, known to be a target of the activation of the endocannabinoid system. The role of the MAPKs activation in processes such as tolerance and withdrawal to THC will be assessed by the inhibition of specific MAPK pathways in vivo.
In parallel, we will examine the changes in the CB1Rs signalling complexes by proteomic approaches in THC tolerant and withdraw n animals. This will further our understanding of the long term effects of THC exposure and the withdrawal response in relation to the CB1R activation.
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