👤 Kacper Witek

Preclinical evidence suggests that maternal fructose (FRU) exposure during pregnancy and lactation can shape offspring emotional development. It remains unclear whether isocaloric perinatal FRU exposure selectively alters distinct components of cocaine reinforcement, motivation, and reinstatement of cocaine-seeking behavior, and whether such effects are associated with mesostriatal receptor adaptations. Male and female Wistar rat offspring from dams fed a standard diet or an isocaloric FRU diet acquired intravenous cocaine self-administration (COC SA) under a stable fixed-ratio schedule of reinforcement across increasing doses (0.25-1.0 mg/kg/infusion), followed by a progressive-ratio (PR) test, extinction, and cue- and cocaine-induced reinstatement. Based on these behavioral findings, synaptosomal melanocortin-4 receptor (MC4R) and dopamine D1/D2 receptors (DRD1/DRD2) were assessed in the nucleus accumbens (NAc) and dorsal striatum (dSTR) of male offspring, in both cocaine-naïve and cocaine-experienced animals. Maternal FRU exposure produced sex-, dose-, and phase-dependent shifts in the session-dependent patterns of cocaine responding, without increasing cumulative cocaine intake. Notably, FRU-exposed males exhibited a lower PR breakpoint, indicating reduced effort-based motivation for cocaine. Extinction learning was preserved in both sexes, although maternal FRU exposure influenced the rate of response decline across sessions. Cue- and cocaine-induced reinstatements were not significantly altered by maternal diet. In cocaine-naïve males, maternal FRU exposure was associated with reduced DRD1 and increased MC4R in both regions, with no change in DRD2. Following COC SA and reinstatement, FRU-exposed males exhibited reduced DRD2 and a lower DRD2/DRD1 ratio in both regions, accompanied by a selective reduction of MC4R in dSTR. Together, these findings indicate that maternal isocaloric FRU exposure selectively shapes the motivational organization of COC SA, most evident under high-effort conditions, without altering reinstatement behavior, and is accompanied by experience-dependent remodeling of mesostriatal dopaminergic and melanocortin receptor profiles in male offspring. Show less

Maternal consumption of monosaccharides during pregnancy and lactation can program long-term metabolic and neurobehavioral outcomes in offspring. The melanocortin-4 receptor (MC4R) is a key regulator of metabolism and behavior. However, the impact of maternal monosaccharide diets on MC4R signaling within mesocorticolimbic regions remains unclear. In this study, we investigated the effects of maternal glucose (GLU) and fructose (FRU) diets on metabolic, molecular, and neurochemical outcomes in offspring. Adolescent and young adult male and female Wistar rat offspring, following maternal GLU and FRU exposure during pregnancy and lactation, underwent sucrose preference testing, intraperitoneal glucose tolerance tests, and serum lipid profiling. In addition, the gene expression of The maternal GLU diet reduced total calorie intake during lactation, while the FRU diet increased the dams’ caloric intake from sugar during both pregnancy and lactation. In the offspring, a maternal FRU diet increased sucrose consumption in young adult males and dysregulated glucose homeostasis in both adolescent and young adult males. Maternal monosaccharide diets also influenced serum lipid profiles and increased the body weights of their offspring. At the molecular level, region-, sex-, and age-specific changes in gene expression were observed, particularly the upregulation of These findings suggest that maternal monosaccharide diets induce persistent alterations in the metabolic profiles of offspring and MC4R signaling, potentially contributing to the development of programmed metabolic and behavioral outcomes. Not applicable. The online version contains supplementary material available at 10.1007/s43440-025-00785-8. Show less