Impaired locomotion and associative learning induced by chronic exposure to the antiepileptic drug carbamazepine in a widely used molluscan model.

Carbamazepine (CBZ) is a widely used antiepileptic drug and a persistent aquatic contaminant due to its high global consumption and poor removal by wastewater treatment plants. Although numerous studies have documented its adverse effects on aquatic organisms, knowledge about its impact on learning and the underlying neuronal mechanisms in invertebrates remains limited. Here, we investigated the behavioral and cellular effects of chronic exposure to an environmentally relevant concentration of CBZ (1 μg L-1) in the great pond snail (Lymnaea stagnalis), a well-established model in neuroscience and ecotoxicology. Adult snails were exposed for 21 days, followed by assessments of feeding and locomotion activity, as well as food-reward classical conditioning. According to our results, the exposure did not affect feeding behavior but caused a significant reduction in locomotor activity and a pronounced impairment of associative learning and long-term memory. Locomotor deficits recovered after a 21-day cleaning period, whereas learning impairment persisted, identifying cognition as a particularly vulnerable and long-lasting target of CBZ exposure. Electrophysiological recordings on the Cerebral Giant Cell (CGC), a key serotonergic interneuron involved in food-reward classical conditioning, revealed that CBZ selectively blocked the persistent, but not the transient, component of voltage-gated sodium currents, providing a mechanistic link between CBZ exposure and long-lasting cognitive deficits. These findings demonstrate that CBZ interferes with evolutionarily conserved neuronal targets in invertebrates, yet induces species- and circuit-specific outcomes. From an ecotoxicological perspective, our results pinpoint cognition as a sensitive and persistent endpoint of CBZ pollution and highlight that CBZ may severely compromise individual fitness, with potential consequences for survival and adaptation in natural ecosystems.