Effect of repeated methamphetamine pretreatment on freezing behavior induced by conditioned fear stress

The present study examined the effect of methamphetamine (MA) pretreatment on conditioned fear stress in male Wistar-King rats. Rats received MA or the vehicle according to the repeated escalating dose schedule (1.25, 2.5, 3.75, and 5 mg/kg s.c. x 2/every other day for a week). After a 5-day drug abstinent period, the rats were exposed to conditioned fear stress (exposure to an environment paired previously with foot shock). Repeated but not single MA pretreatment significantly increased conditioned freezing behavior, suggesting that rats previously exposed to chronic MA are hypersensitive to subsequent stress than control rats. Repeated MA treatment did not decrease basal dopamine or serotonin concentrations in the brain. Furthermore, coadministration of MK-801 (noncompetitive NMDA antagonist), amfonelic acid (dopamine reuptake inhibitor), or fluoxetine (serotonin reuptake inhibitor) with MA did not alter the enhanced freezing behavior. Taken together, it seems that MA-induced hypersensitivity to stress is not due to the neurotoxic effect of MA. Coadministration of nemonapride (D2/3/4 antagonist) with MA prevented the MA-induced increase in freezing. These results suggest that D2/3/4 receptors play an important role for MA-induced enhancement of fear or anxiety.