Pharmacological and genetic modulation of Dopamine D3 receptor: Schizophrenia relevant phenotypes

Schizophrenia is a chronic and severe psychiatry disorder affecting 1% of the worldwide population, characterized by a heterogeneous genetic and neurobiological background that influence early brain development. The characteristic symptoms of the disease can be divided in three categories: positive, negative and cognitive, the latter expressed as a varied set of cognitive dysfunctions. The etiopathogenesis of schizophrenia is not fully understood, due to the complexity of the disease and to the large number of molecular targets involved. Yet, the current understanding of schizophrenia is represented by the “dopamine hypothesis” stating that the disease is caused by an imbalance in the dopaminergic transmission in both cortical and subcortical brain areas. The first line treatment for schizophrenic patients is represented by the first- and second- generation antipsychotic drugs, that act mainly as antagonist or partial agonist to dopamine D2-like receptors, that include D2R, D3R, and D4R. Among dopamine receptors, theD3R create interest because of its limited expression in limbic brain areas involved in cognition and emotional processes. To date, several preclinical studies show the involvement of D3R in the regulation of the activity of DA neurons in the mesolimbic, mesocortical and nigrostriatal dopaminergic pathways. Further, evidence show the role of D3R in physiological mechanisms underlying mPFC-dependent cognitive functions, suggesting that blocking D3R may impact cognitive impairment. Consequently, D3R could be considered as a new pharmacological target for schizophrenia. However, to date no available antipsychotic show a higher selectivity for the D3R over D2R. Based on data present in literature, the aims of this thesis are 1) to study the role of D3R as a therapeutic target for pro-cognitive treatment and 2) investigate the role of D3R as a genetic tool for patient stratification.