Studio dell’Effetto dell’Inibitore Selettivo della Dopamina β-Idrossilasi, Nepicastat, su Modelli Animali di “Alcohol Addiction” e “Chocolate Addiction”

Background: Nepicastat is a selective dopamine β-hydroxylase (DBH) inhibitor that has been found to suppress the reinstatement of cocaine-seeking behaviour triggered in rats by cocaine priming, environmental cues previously paired with cocaine availability, and stress. The present studies were designed to extend to different alcohol-like behaviours the investigation into the “anti-addictive” properties of nepicastat. Moreover, we investigated whether nepicastat was capable of modifying the reinforcing and motivational properties of a chocolate solution and preventing the reinstatement of chocolate seeking in rats. Methods: Sardinian alcohol-preferring (sP) rats, selectively bred for excessive alcohol consumption, were exposed to different procedures of alcohol-motivated behaviours while Wistar rats were exposed to a series of procedures of use in evaluating the reinforcing and motivational properties of the chocolate solution. Results: Effect on alcohol: Acute treatment with nepicastat (0, 25, 50, and 100 mg/kg, i.p.) completely suppressed the “alcohol deprivation effect” (i.e., the temporary increase in alcohol intake occurring after a period of abstinence; model of alcohol relapse episodes) in sP rats exposed to the 2-bottle choice regimen, and dose dependently and selectively reduced oral alcohol self-administration in sP rats trained to lever-respond for alcohol (15% v/v) on a fixed ratio (FR) 4 schedule of reinforcement. Finally, combination of nepicastat (0, 50, and 100 mg/kg, i.p.) and alcohol (2 g/kg, intragastrically) did not alter spontaneous locomotor activity in sP rats. Effect on chocolate solution: Acute treatment with nepicastat (0, 25, 50, and 100 mg/kg, i.p.) produced a dose-related inhibition of operant self-administration of the chocolate solution in rats under FR10 and progressive ratio schedules of reinforcement (indexes of the reinforcing and motivational properties of the chocolate solution, respectively). The effect of nepicastat on the reinstatement of chocolate seeking was studied in rats in which lever-responding had been extinguished by removing the chocolate solution for approximately 8 consecutive daily sessions. Nepicastat dose-dependently suppressed the reinstatement of lever-responding triggered by a ‘priming’ of the chocolate solution together with cues previously associated with availability of the reward. In a separate group of food-restricted rats trained to lever-respond for regular food pellets, nepicastat reduced FR10 lever-responding with the same potency as for the chocolate solution. Spontaneous locomotor activity was not modified by nepicastat doses that reduced self2 administration of the chocolate solution and regular food pellets and suppressed reinstatement of chocolate seeking. Notably, data on the suppressing effect of nepicastat on chocolate-related behaviors were reproduced by treatment with disulfiram (0, 25, 50 and 100 mg/kg, i.p.), another DBH inhibitor. The different time-course of the suppressing effect of disulfiram on chocolate-related behaviors may suggest a dual mechanism of action, including the involvement of a substrate other than DBH. Conclusions: (a) These data extend to alcohol- and food-related behaviours the capacity of nepicastat to suppress different behaviours motivated by natural stimuli and drugs of abuse; (b) DBH is a promising target for pharmacotherapies targeting cocaine and alcohol dependence as well as eating disorders; (c) These data provide additional proof that food and drugs of abuse share the same neural pathways in producing their rewarding, reinforcing, and stimulating properties.