Dottorato in FARMACOLOGIA E TOSSICOLOGIA

Titolo della tesi: Novel approaches and pharmacological strategies for the study of mGlu5 metabotropic glutamate receptors in CNS disorders

mGlu5 metabotropic receptors are G-protein coupled receptors (GPCR) which are implicated in mechanisms of activity-dependent synaptic plasticity, underlying learning and memory. Abnormalities in the expression or function of mGlu5 receptors are associated with many CNS disorders, thus they are candidate drug targets for neuropsychiatric disorders. mGlu5 receptors signalling proceeds through the multiple signalling pathways, resulting in mobilization of intracellular calcium. Besides mGlu5 receptors are coupled to calcium-independent transduction pathways such as phosphorylation of ERK 1/2, AMPc, mTOR/PI3K which can interact and modulate the activity of other GPCRs and ion channels. In this work we offered different strategies for the development of positive allosteric modulators of mGlu5 receptors allowing treatment of CNS disorders. In particular, we studied the effects of VU0360172 and VU0409551 investigating the biased agonism modulation of mGlu5 receptors in several systems. In addition we proposed an innovative method for the assessment of mGlu5 receptor signaling in vivo. Moreover we showed alterations in mGlu5 receptors-dependent LTD in the hippocampus of WAG/Rij rats a validated animal model of absence epilepsy.