The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats

Abstract

Craving for chocolate is a common phenomenon, which may evolve to an addictive-like behaviour and contribute to obesity. Nepicastat is a selective dopamine b-hydroxylase (DBH) inhibitor that suppresses cocaine-primed reinstatement of cocaine seeking in rats. We verified whether nepicastat was able to modify the reinforcing and motivational properties of a chocolate solution and to prevent the reinstatement of chocolate seeking in rats. Nepicastat (25, 50 and 100 mg/kg, intraperitoneal) produced a dose-related inhibition of operant self-administration of the chocolate solution in rats under fixed-ratio 10 (FR10) and progressive-ratio schedules of reinforcement, measures 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 d. Nepicastat dose-dependently suppressed the reinstatement of lever-responding triggered by a 'priming' of the chocolate solution together with cues previously associated with the 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 self-administration of the chocolate solution and regular food pellets and suppressed the reinstatement of chocolate seeking. The results indicate that nepicastat reduces motivation to food consumption sustained by appetite or palatability. Moreover, the results suggest that DBH inhibitors may be a new class of pharmacological agents potentially useful in the prevention of relapse to food seeking in human dieters.

Selective inhibition of dopamine‐beta‐hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex

“…Dopamine-beta-hydroxylase (DBH), the enzyme that converts dopamine (DA) to noradrenaline (NA), is a promising target for pharmacotherapies targeting cocaine (George et al 2000;Petrakis et al 2000;Carroll et al 2004;Kosten et al, 2013), alcohol dependence (Johansson 1992;Colombo et al 2014), and eating disorders (Zaru et al 2013;Farci et al 2015).…”

The Dopamine β‐Hydroxylase Inhibitor, Nepicastat, Reduces Different Alcohol‐Related Behaviors in Rats

“…The results of Experiments 1 to 3 extend to 3 different alcohol‐related behaviors the capacity of nepicastat to suppress several rat behaviors motivated by natural stimuli and cocaine. Recent studies have indeed reported that treatment with nepicastat reduced (i) self‐administration of chocolate and reinstatement of chocolate‐seeking behavior (Zaru et al., ) and (ii) reinstatement of cocaine‐seeking behavior (Schroeder et al., , ) in rats. As neural circuitries of food and drug taking and seeking largely overlap (see Volkow et al., ), it is not fully surprising that drugs may affect similarly some food‐ and drug‐motivated behaviors (see Volkow and Wise, ).…”

“…Alternatively, it may be considered that nepicastat affected the regulation of appetite and food intake. The relatively few studies conducted to date on this issue have produced controversial results, with nepicastat treatment (i) reducing operant self‐administration of regular food pellets in food‐deprived Wistar rats (Zaru et al., ), (ii) having no effect on operant self‐administration of regular food pellets in food‐deprived Sprague‐Dawley rats (Schroeder et al., , ), (iii) reducing operant self‐administration of a chocolate‐flavored beverage in unrestricted Wistar rats (Zaru et al., ), (iv) having no effect on operant self‐administration of sucrose pellets in unrestricted Sprague‐Dawley rats (Schroeder et al., ), and (v) having no effect on regular food intake in the sP rats exposed to the “alcohol deprivation effect” test (Experiment 2 of the present study). The several methodological differences existing among these experiments (e.g., rat line/strain, procedure of food feeding or self‐administration, food availability, and palatability) may account for these discrepancies.…”

“…(injection volume: 2 ml/kg), once daily (3 hours before lights off), and for 10 consecutive days, at the doses of 0, 25, 50, and 100 mg/kg. This dose range was known to be behaviorally active without exerting sedative or motor‐incapacitating effects in adult, male rats (e.g., Zaru et al., ). One rat from the 100 mg/kg nepicastat‐treated group died for unknown reasons on the last day of the treatment phase and was excluded from data analysis.…”

“…Based on this premise, nepicastat appears to be a relatively unique tool to pharmacologically manipulate 2 neurotransmitter systems (noradrenaline and dopamine) and 2 brain areas (medial prefrontal cortex and nucleus accumbens) known to play a pivotal role in the neural substrates mediating the reinforcing and rewarding properties of natural stimuli and drugs of abuse (see Koob and Le Moal, ). Accordingly, recent studies have reported that nepicastat (i) suppressed self‐administration of chocolate and reinstatement of chocolate‐seeking behavior (Zaru et al., ), (ii) potentiated the discriminative stimulus effects of cocaine (Manvich et al., ), and (iii) suppressed cocaine‐ and stress‐primed reinstatement of cocaine‐seeking behavior (Schroeder et al., , ) in rats. Based on the latter results, nepicastat has been proposed as a promising pharmacotherapy for cocaine‐associated disorders (Gaval‐Cruz and Weinshenker, ; Weinshenker and Schroeder, ).…”