Effects of Ghrelin Receptor Antagonists [D-Lys3]-GHRP-6 and YIL 781 on Impulsivity and Compulsivity in Rats Exposed to Early Maternal Deprivation

Early maternal deprivation (MD) in rats increases impulsivity and compulsivity, resembling features of behavioral addictions. We examined the effects of intranasal ghrelin receptor (GHSR-1a) antagonists [D-Lys 3 ]-GHRP-6 and YIL 781 in adult male Wistar rats exposed to MD (3 h daily, postnatal days 2–12). Impulsive-like behavior was assessed using a three-arm probabilistic reinforcement task (adapted Iowa Gambling Task), and compulsivity via the marble-burying test. MD rats showed strong preference for high-magnitude/low-probability rewards and increased marble burying compared to controls. Chronic [D-Lys 3 ]-GHRP-6 treatment significantly reduced risky choices ([Formula: see text][Formula: see text]vs. saline), while YIL 781 further decreased risky preferences ([Formula: see text]) and markedly lowered compulsive burying ([Formula: see text]). Molecular docking and 500-ns molecular dynamics simulations indicated YIL 781 has higher affinity and greater complex stability with GHSR-1a ([Formula: see text] (docking) [Formula: see text][Formula: see text]kcal/mol; [Formula: see text][Formula: see text]kcal/mol) than [D-Lys 3 ]-GHRP-6, with comparatively weaker binding to serotonin (5HT1a/2a/3a) and dopamine (D2/D3) receptors. These results suggest GHSR-1a blockade attenuates MD-induced maladaptive decision-making and repetitive behaviors, with YIL 781 exhibiting broader efficacy, likely due to stronger target engagement.