The role of dopamine D3 receptor in alcohol addiction and schizophrenia

Dopamine (DA) modulates several essential functions of the central nervous system (CNS), including reward and cognition. The dopaminergic neurotransmission in the CNS is mediated by two different classes of G protein- coupled receptors (GPCR), the D1R-like receptors (D1R and D5R) and D2R- like receptors (D2R, D3R and D4R, Seeman et al., 1994). Among dopamine receptors, the dopamine D3 receptor (D3R) has captured the scientific interest because of its restricted distribution in the brain, seemingly related to functions of dopamine associated with the limbic brain. So, the dopamine D3R shows a limited distribution in the limbic brain areas involved in the control of cognitive and emotional functions, and it seems to represent a target for the treatment of several neuropsychiatric disorders such as drug addiction and schizophrenia (Leggio et al., 2016). D3R, acting as autoreceptor, regulates the activity of DAergic neurons throughout the mesolimbic, mesocortical and nigrostriatal DAergic pathways (Gobert et al., 1995; Tepper et al., 1997; Diaz et al., 2000). D3 deficient mice (D3R-/-) exhibit extracellular levels of dopamine twice as high as their wild-type (WT) littermates suggesting that D3R could play an inhibitory role in the control of basal extracellular DA levels (Koeltzow et al., 1998; Joseph et al., 2002). Moreover, Leggio and colleagues (2014) demonstrated that D3R-/- mice display significant lower levels of alcohol intake compared to their WT littermates, in several ethanol-drinking paradigms. Furthermore, D3R-/- mice show a 15-fold higher expression of gamma-aminobutyric acid receptor A (GABAA) alpha6 subunit in striatum compared to their WT littermates (Leggio et al., 2015). Based on previous data present in literature, the main hypothesis of my research project has been that the D3R, showing a main role in the control of the mesolimbic DAergic pathway, is involved in neuropsychiatric disorders linked to alteration of DAergic pathways. So, the aims of this thesis were: 1) to investigate the role of the cross-talk between GABAA/D3R in the mesolimbic DA control of ethanol consumption; 2) to assess the involvement of D3R in the pathophysiology of schizophrenia