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Almaamari, Alameri, Almansouri, and Bahi: Inhibition of urokinase plasminogen activator activity alters ethanol consumption and conditioned place preference in mice

Introduction: Urokinase plasminogen activator (uPA) is a serine protease implicated in addiction to drugs of abuse. Using its specific inhibitor B428, the role of uPA in the rewarding properties of psychostimulants, including cocaine and amphetamine, have been characterized but none have examined the role of uPA in ethanol use disorders.

Objectives: In the current study, observations on the role of uPA in ethanol consumption and ethanol-induced conditioned place preference have been extended. The general aim of the present series of experiments was to investigate the effects of the administration of B428 on voluntary alcohol intake and ethanol conditioned reward.

Materials and methods: A two-bottle choice, unlimited-access paradigm was used to compare ethanol intake between vehicle and 3, 10 and 30 mg/kg B428 administered to mice. For this purpose, the mice were presented with an ethanol solution (2.5–20%) and water, at each concentration for 4 days, and their consumption was measured daily. Consumption of saccharin and quinine solutions was also measured.

Results: Systemic administration of B428 dose-dependently decreased ethanol intake and preference. In addition, B428 mice did not differ from vehicle mice in their intake of graded solutions of tastants, suggesting that the uPA inhibition did not alter taste function. Furthermore, ethanol metabolism was not affected following B428 injection. More importantly, 1.5 g/kg ethanol-induced conditioned place preference acquisition was blocked following B428 administration.

Conclusions: Taken together, our results are the first to implicate uPA inhibition in the regulation of ethanol consumption and preference, and suggest that uPA may be considered as a possible therapeutic drug target for alcoholism and abstinence.




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