Targeting dopamine d3 receptor: new insights into the pathophysiology of alcohol addiction and anxiety

The dopaminergic neurotransmission in the central nervous system (CNS) is mediated by two different classes of G protein-coupled receptors, the D1R-like receptors (D1R and D5R) and the D2R-like receptors (D2R, D3R and D4R) (Seeman et al., 1994). Since its discovery in the early 90 s, the dopamine D3 receptor (D3R) has aroused great interest in the scientific community. Indeed, its limited distribution in the limbic brain areas involved in the control of cognitive and emotional functions has made this receptor a promising target for the treatment of several neuropsychiatric disorders such as drug addiction, depression and schizophrenia (Leggio et al., 2016). Several data suggest that D3R, likely acting as autoreceptor, modulates the activity of dopaminergic neurons throughout the mesolimbic, mesocortical and nigrostriatal dopaminergic pathways (Gobert et al., 1995; Tepper et al., 1997; Diaz et al., 2000). Yet, D3R-deficient mice (D3R-/-) ehibit extracellular levels of dopamine (DA) twice as high as their wild-type (WT) littermates suggesting that D3R could play a inhibitory role in the control of basal extracellular DA levels (Koeltzow et al., 1998; Joseph et al., 2002). The central hypothesis of my PhD research project has been that D3R exerting a pivotal role in the control of the mesolimbic dopamine pathway, is involved in the pathophysiological mechanisms subserving neuropsychiatric disorders linked to dysfunctionality of this dopaminergic pathway. In particular, the present thesis aimed to: 1) investigate the role of D3R in the mesolimbic DA control of ethanol reward; 2) assess the involvement of a GABAA/D3R interaction in the mesolimbic DA modulation of anxiety-like behavior by using both genetic and pharmacological approaches.