The effect of MK-801 on stress-ethanol cross-sensitization is dissociable from its effects on nNOS activity

Locomotor behavioral sensitization represents an animal model for understanding neuroadaptive processes related to repeated drug exposure. Repeated stress can elicit a cross-sensitization to the stimulant response of ethanol, which involves neuronal nitric oxide synthase (nNOS). Activation of N-methyl d-aspartate (NMDA) glutamate receptors triggers nNOS and the synthesis of nitric oxide (NO). In this study, we investigated the effects of blocking NMDA receptors using the NMDA receptor antagonist MK-801 on the cross-sensitization between restraint stress and ethanol. We also evaluated the nNOS activity in the prefrontal cortex (PFC) and hippocampus. Mice were pretreated with saline or MK-801 30 min before an injection of saline or stress exposure for 14 days. On the following day, they were challenged with either saline or 1.8 g/kg ethanol. Swiss male mice pretreated with 0.25 mg/kg MK-801 exhibited a sensitized response to ethanol. Moreover, MK-801 potentiated the cross-sensitization between stress and ethanol. However, MK-801 prevented the enhanced nNOS activity in stress-exposed groups (challenged with saline or ethanol) in the PFC; the antagonist also prevented the ethanol-induced increase in nNOS activity and reduced this enzyme activity in mice exposed to stress in the hippocampus. These data indicate that systemic treatment with the NMDA antagonist potentiated, rather than blocked, ethanol-induced behavioral sensitization and that this effect is dissociable from the capacity of NMDA antagonists to reduce ethanol/stress-induced NOS stimulation in the PFC and hippocampus.