Prenatal Exposure to the CB1 Receptor Agonist WIN 55,212-2 Causes Learning Disruption Associated with Impaired Cortical NMDA Receptor Function and Emotional Reactivity Changes in Rat Offspring

Abstract

The aim of this study was to investigate whether prenatal exposure to the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN) at a daily dose devoid of overt signs of toxicity and/or gross malformations (0.5 mg/kg, gestation days 5-20), influences cortical glutamatergic neurotransmission, learning and emotional reactivity in rat offspring. Basal and K+-evoked extracellular glutamate levels were significantly lower in cortical cell cultures obtained from pups exposed to WIN during gestation with respect to those measured in cultures obtained from neonates born from vehicle-treated dams. The addition of NMDA to cortical cell cultures from neonates born from vehicle-treated dams concentration-dependently increased glutamate levels, and this was absent in cell cultures obtained from WIN-exposed pups. WIN-exposed rats also revealed a poorer performance in homing (10-12 days of age) and active avoidance tests (80 days of age) as well as a decrease in the rate of separation-induced ultrasonic emission (10 days of age). Finally, prenatal exposure to WIN induced a reduction in the number of cortical neuronal population. These findings (i) provide evidence for a deficit in cortical glutamatergic neurotransmission and behaviour in the rat neonate following prenatal exposure to WIN; and (ii) suggest that the reduction in cortical glutamatergic neurotransmission, NMDA receptor activity and alterations in neuronal development might underlie, at least in part, the learning deficit and decreased emotional reactivity observed in the offspring.