Lunch in Campea Thursday at 12:00
Abstract
Converging pharmacological, genetic and human post-mortem data have demonstrated the central role of D3R in the pathophysiology and treatment of schizophrenia, drug addiction, Parkinson’s disease and depressive disorders. Addiction still represents the main research field and potential application for D3R ligands. However, more recently, several studies have underscored novel roles of D3R in diseases that were not previously taken into account. This talk discusses data about the D3R targeting as clinical application for several neuropsychiatric disorders. In particular, it focuses on recent findings about the role of D3R in both alcohol addiction and anxiety.
We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-/- and their WT littermates treated or not with the D3R antagonists SB277011A and U99194A, were tested in the two-bottle choice and in the drinking in the dark. Ethanol intake was negligible in D3R-/- and robust in WT. D3R antagonists inhibited ethanol intake in WT but were ineffective in D3R-/-. In this context, an increased D3R expression associated with activation of RACK1/BDNF pathway in WT mice seems to operate as a reinforcing mechanism in voluntary ethanol intake. From a translational point of view, buspirone, an approved drug for anxiety endowed with D3R antagonist activity, resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and may represent a therapeutic target for weaning.
About the role of D3R in anxiety disorders, we reported that D3R-/- exhibit low anxiety levels and that acutely administrated diazepam is more effective in D3R-/- than WT tested in the elevated plus maze. Recently, we tested the hypothesis that genetic deletion or pharmacological blockade of D3R affect GABAA subunit expression, which in turn modulates anxiety-like behavior as well as responsiveness and tolerance to diazepam. D3R-/- mice exhibited a fast tolerance to diazepam (3 day); conversely, WT exhibited tolerance to diazepam after a 14–21 day-treatment. GABAA α6 subunit mRNA expression in striatum was about 15-fold higher in D3R-/- than in WT. Diazepam treatment did not modify α6 expression in D3R-/-, but progressively increased α6 expression in WT, to the level of untreated D3R-/-. The selective D3R antagonist SB277011A (7 days) induced in WT a fast tolerance to diazepam accompanied by a robust increase in α6 subunit expression. Thus, the modulation of GABAA receptor by DA transmission may be involved in the mechanisms of anxiety and, if occurring in humans, may have therapeutic relevance following repeated use of drugs targeting D3R.
