Agrelax reduces conditioned place preference of ethanol and compulsive behavior in rats during its withdrawal
INNOVATIVE PHARMACOLOGY
Abstract
Introduction. Among the orexigenic peptides that mediate the emotional effects of psychoactive substances, the peptide hormone ghrelin attracts attention. It was shown that the ghrelin receptor antagonist agrelax, synthesized at the Institute of Experimental Medicine, reduced the manifestations of compulsive overeating and impulsivity in a model of gambling addiction. Aim. To study the effect of agrelax on the conditioned place preference of ethanol and compulsive behavior against the background of its withdrawal in male rats.Materials and methods.A conditioned place preference of ethanol was developed in male rats in a two-chamber setup, over a period of eight days, for two hours per day. In the first hour, the rats were placed in the first chamber and administered saline solution. Then, ethanol (0.5 g/kg) was administered intraperitoneally and the rats were placed in the second compartment of the setup for 1 hour. On the 9th day, the doors between the compartments were opened, and the rat test groups were administered either agrelax (10μg in 20μL) intranasally, naloxone (1mg/kg) intraperitoneally, or simple saline, and the animal was placed in the setup for 10 min. Then, place preference extinction was carried out for seven days, which consisted of daily testing without the introduction of alcohol and other drugs. On the 11th day of the experiment, compulsive behavior was recorded by burying marbles in the marble test after the introduction of each of the substances. On the 18th day of the experiment, ethanol was administered and the resumption of the conditioned place preference reaction was recorded. Some animals were administered agrelax or naloxone 5 minutes before the introduction of ethanol to determine the effect on the resumption of the conditioned place preference reaction.Results.After the introduction of saline on the 8th day of the experiment, the animals spent 71% of the time in the chamber associated with the introduction of ethanol. In rats given agrelax or naloxone, a decrease in staying in the chamber associated with ethanol was observed, respectively, to 45% (p <0.05) and 39% (p <0.01). Naloxone caused a blockade of the renewal of preference for the ethanol chamber, which was manifested by a 26% decrease in the time spent in the preferred chamber associated with the introduction of ethanol. The ghrelin receptor antagonist agrelax (10μg in 20μl, intranasally) did not cause a decrease in the reproduction of the conditioned reaction of preference for the ethanol chamber. On the 10th day of the experiment, after the introduction of saline, the animals buried 17.2±2.3 marbles in the marble test. Agrelax and naloxone reduced the number of buried marbles against the background of ethanol withdrawal to 13±3.5 (p <0.05) and 11±2.4 (p <0.05), respectively.Conclusion.Agrelax reduces the manifestation of the conditioned reaction of ethanol place preference and compulsive behavior in rats against the background of its withdrawal, which is comparable to the effect of naloxone. At the same time, unlike naloxone, agrelax did not cause a decrease in the resumption of ethanol place preference. Thus, we demonstrate the important role of the ghrelin system in the mechanisms of the reinforcing effect of alcohol, which invites further investigation into the use of new ghrelin antagonists in the correction of pathological craving.
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