Context-dependent attention and memory outcomes resulting from combined prenatal THC and nicotine exposure following chronic stress

Prenatal exposure to cannabis and nicotine frequently co-occurs in humans, yet studies on the long-term cognitive consequences remain limited. This early-life exposure may alter the way the brain responds to stress during adolescence. This study examined whether prenatal vaporized THC and nicotine (COMBO) co-exposure alters adolescent cognitive performance as a function of chronic stress, sex, diet, and developmental stage. Pregnant dams were exposed to either Air or COMBO inhalation daily from GD 2 until labor. At weaning, offspring were assigned to either a normal (ND) or high-fat diet (HFD), and at PND 35, half were exposed to unpredictable chronic mild stress (UCMS) during adolescence. Cognitive performance was assessed in early and late adolescence using the Novel Object Recognition (NOR) test and Morris Water Maze (MWM) to evaluate memory, and the Object-Based Attention (OBA) task to assess attention. Prenatal THC and nicotine co-exposure produced selective context-dependent cognitive effects rather than broad impairments across behavioral domains. In the NOR task, significant differences were primarily sex-dependent, while stress exposure was associated with reduced exploration behavior in COMBO offspring. OBA performance showed few significant main effects, although diet-, sex-, and stress-related differences emerged in specific measures. In the MWM task, latency decreased across testing days, with a treatment-related difference observed only within the UCMS cohort. Overall, these findings suggest that cognitive outcomes following combined prenatal THC and nicotine exposure are influenced by stress exposure, diet, and sex to a greater extent than by prenatal exposure alone.