IGF2 modulates behavioral and hippocampal changes induced by chronic cocaine exposure during adolescence in mice

Adolescence is a period of heightened neuroplasticity and vulnerability to environmental insults, including drug exposure. In this study, we investigated the short- and long-term behavioral effects, as well as the long-term hippocampal effects, of chronic cocaine administration during adolescence, along with the potential neuroprotective role of insulin-like growth factor 2 (IGF2) in male C57BL/6J mice. Over 21 days, mice received daily intraperitoneal injections of saline, cocaine, IGF2, or a combination of cocaine and IGF2. Behavioral assessments were conducted immediately after treatment and following a 30-day abstinence period, using a battery of tests including marble burying, nest building, elevated plus maze, open field, novel place and object recognition, and forced swim. Cocaine-treated mice exhibited persistent compulsive-like behaviors and altered risk perception, effects that were attenuated by IGF2 co-administration. At the cellular level (after 40 days of abstinence), chronic cocaine reduced the density of parvalbumin-positive interneurons in the CA1 and CA3 hippocampal regions, an effect not mitigated by IGF2 co-administration. IGF2 treatment also increased expression of the presynaptic marker synaptotagmin, without altering postsynaptic proteins (PSD-95) or neurotrophic factors (BDNF, pro-BDNF). However, IGF2 downregulated IGF2R expression and impaired performance in hippocampus-dependent spatial memory, suggesting that receptor downregulation may underlie cognitive side effects. No significant differences were observed in markers of oxidative stress, neurogenesis, or basal corticosterone levels. These findings indicate that IGF2 partially counteracts behavioral and cellular alterations induced by adolescent cocaine exposure but may also impact specific cognitive domains. Overall, this study supports further investigation of IGF2 as a therapeutic strategy to mitigate long-term neurobehavioral consequences of adolescent drug use.