ADOLESCENCE AS A CRITICAL WINDOW FOR SCHIZOPHRENIA-RELATED VULNERABILITY: SHORT- AND LONG-TERM OUTCOMES

Schizophrenia (SCHZ) is a chronic psychiatric disorder typically diagnosed in late adolescence/early adulthood. Its diagnosis is preceded by a prodromal phase, during which attenuated symptoms can be observed and when there is already a high prevalence of tobacco smoking among affected individuals. These findings place adolescence as a critical window to investigate interactions between nicotine exposure and SCHZ-related vulnerability. Here, we investigated the short- and long-term behavioral effects of adolescent co-exposure to nicotine and MK-801. On postnatal day (PND) 30, Swiss mice received osmotic minipumps delivering nicotine (24 mg/kg/day, subcutaneous) or vehicle. From PND31 until PND44, period of co-exposure, animals received daily injections of MK-801 (0.5 mg/kg, subcutaneous) or saline, forming four groups: Control, Nicotine, MK-801, and MK-801+Nicotine. Behavioral assessments were conducted during adolescence (PND49–55) or adulthood (PND64–70) using the open field (OF), passive avoidance (PA), social interaction (SI), and prepulse inhibition (PPI) tests. In the OF, no effects were observed during adolescence. In adulthood MK-801+Nicotine female mice increased locomotor activity compared to Control (F₃,₃₆ = 6.6, p < 0.001), indicating sex-specific exacerbation of SCHZ-like outcomes. In the PA, during adolescence, MK-801+Nicotine females exhibited increased latency in the second session compared to Control (F₃,₃₂ = 3.1, p < 0.05), reflecting enhanced fear-associated learning. This effect did not persist into adulthood. In contrast to OF and PA, SI and PPI were not affected by the co-exposure. Overall, adolescent nicotine exposure modulated MK-801 induced behavioral alterations in a sex- and time-dependent manner, with increased vulnerability in females.