Modulation of alcohol consumption using an operant self-administration paradigm: effects of a new dopamine aminoacidic conjugate, Phenylalanine-β(3,4dihydroxyphenyl)-etilamide.

Abstract

Rewarding and reinforcing properties of alcohol have been shown to be mediated by activation of the mesolimbic dopaminergic system. Experimental evidences suggest that mesolimbic dopamine system is hypofunctional in addicted brain; further, reduced dopaminergic activity outlasts somatic signs of withdrawal and may drive craving and relapse. Boosting strategy on dopaminergic neurons could represent a valid therapy. Effects of pharmacological manipulation of brain Dopaminergic receptors by a new dopamine conjugate, Phenylalanine-β(3,4dihydroxyphenyl)-etilamide (DA-Phen), on operant behaviour and on both acute and prolonged withdrawal symptoms during ethanol abstinence have been evaluated. Male Wistar rats were tested in an operant conditioning task: they were subjected to Habituation (Ethanol 5%), Training (Ethanol 20%), and Extinction sessions. Then, three cycles of Deprivation/Relapse were performed. Rats were administered with DA-Phen (0.03mmol/kg i.p) during abstinence, or during relapse, 2h prior the operant task session. Locomotor activity and anxiety-like behaviour during withdrawal were also evaluated. Da-Phen, administered during abstinence phase, or during relapse, was able to reduce alcoholic intake pattern by 50% from the second day of operant conditioning task (p<0.001). DA-Phen induced significant differences in chronically alcohol-treated rats both on total distance travelled (p<0.001) and percentage of time on centre (p<0.05) in the Open Field, and percentage of open time (p<0.001), entries (p<0.05) and head dippings (p<0.001) in the Elevated plus Maze. Results suggest that DA-Phen can reduce ethanol intake by attenuating ethanol rewarding value and/or elevating endogenous dopaminergic activity, as well as the behavioural signs of withdrawal.