Assessment of the Effects of the Ghrelin Antagonists [D-Lys3]-GHPR-6 and YIL 781 on Impulsive and Compulsive Behavior in Rats Experienced with Maternal Deprivation in Early Ontogenesis

Brain development and function are shaped by neural networks, regulatory factors, and environmental influences, with early postnatal stress-such as maternal deprivation-inducing lasting neurobiological changes linked to impulsivity and compulsivity. Ghrelin receptors, central to the reward system, are implicated in these behaviors. This study investigated the effects of ghrelin receptor antagonists [D-Lys3]-GHRP-6 and YIL 781 on impulsivity and compulsivity in rats exposed to early maternal deprivation. Rats received intranasal antagonists for 7 days (20 mcg/dose). Impulsivity was assessed via a modified Iowa Gambling Task, and compulsivity via the marble burying test. Statistical analysis used ANOVA and Tukey’s post hoc test, alongside theoretical receptor affinity assessments. Maternal deprivation increased impulsivity, with deprived rats favoring high-risk, high-reward choices (p = 0.0002). [D-Lys3]-GHRP-6 reversed this effect, reducing risky choices (p = 0.0003), while YIL 781 also decreased impulsivity (p = 0.003) and uniquely reduced compulsive digging (p = 0.002). Molecular docking suggested YIL 781 has higher ghrelin receptor affinity but lower selectivity; however, simulations indicated minimal off-target binding to serotonin or dopamine receptors. These findings highlight the potential of ghrelin antagonists in modulating impulsive and compulsive behaviors, offering avenues for pharmacological interventions in related disorders.