Cannabinoid receptors in animal models of cognitive impairment.

Abstract

The endocannabinoid system (eCB) plays a crucial role in various physiological processes including fear responses, learning and memory. This system comprises cannabinoid receptors, endogenous ligands and enzymes, and its many roles make it an interesting target for therapeutic interventions. This Doctoral Thesis delves into the modulation of fear expression, memory processes and neuroinflammation by CB1 receptors, highlighting their therapeutic potential. This work encompasses diverse models, such as fear expression and extinction paradigms based on the passive avoidance test, models of cognitive impairment derived from cholinergic dysfunction, mouse models of familial Alzheimer's disease, a mouse model of a neurodevelopmental disorder, Williams-Beuren syndrome, and mice lacking a specific kinase, PKC, greatly involved in cognition. The investigation reveals alterations in CB1 receptors across different brain areas in these models and evaluates the effect of subchronic cannabinoid treatments in some of them.Furthermore, underscoring the importance of developing more specific drugs targeting the eCB system, newly synthesized molecules are screened for affinity for cannabinoid receptors. Finally, the thesis studies the impact of lipids, especially polyunsaturated fatty acids, on CB1 receptor ligand binding. These findings have the potential to change the current understanding of pharmacology, paving the way for the development of more effective and targeted therapeutic interventions.