Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D3R gene deletion or the D3R pharmacological blockade inhibits ethanol preference in mice. D3R-deficient mice (D3R−/−) and their wild-type (WT) littermates, treated or not with the D3R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D3R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D3R−/− and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D3R antagonists inhibited ethanol intake in WT but was ineffective in D3R−/− mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D3R−/−; in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D3R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D3R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D3R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.

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The aim of this study was to evaluate whether corneal reparative activity of hyaluronan is a concentration-dependent phenomenon. Corneal blocks from rabbit eyes were cultured for 20 hours with hyaluronan in different concentrations and molecular weight ranges. In another experiment, the corneal epithelium was denuded and hyaluronan was administered as eye drops. Distances of epithelial migration increased over exposed stroma proportionally to concentration, when hyaluronan was added with a molecular weight of 800-1,400 kD. Maximum effect was observed with 0.2% hyaluronan concentration. No difference was seen when corneal blocks were cultured with hyaluronan 0.2% in different molecular weight ranges (800-1,400, 1,400-2,000, and 2,000-2,600 kD). When hyaluronan (molecular weight, 800-1,400 kD) eye drops were administered after corneal epithelial denudation in rabbits, it was found to have faster wound reparation. This effect was concentration-dependent. The 2 highest concentrations (0.2% and 0.4%) were not different for the time needed to complete wound healing. In conclusion, hyaluronan-induced stimulation of corneal wound healing fulfills standards for being considered as a pharmacological effect.

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