[Effects of methamphetamine on responsiveness to conditioned fear stress]

The present study examined the effect of repeated 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, 5 mg/kg s.c x2/every other day for a week). After a 5 day drug abstinent period, the rats were exposed to conditioned fear stress (CFS; exposure to an environment paired previously with footshock). 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 concentrations in the brain. Furthermore, repeated co-administration of MK-801 (non-competitive 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. While co-administration of SCH23390 (D1/5 antagonist) or raclopride (D2/3 antagonist) had no effect on the MA-induced increase in freezing, co-administration of nemonapride (D2/3/4 antagonist) prevented this increase. These results suggest that MA-induced enhancement of anxiety might be mediated by D4 receptors. The homovanilic acid (HVA) levels in the striatum were elevated by footshock in MA-treated rats but not in saline-treated rats. Furthermore, MA-treated rats showed increased metabolism of dopamine (DA) in the medial prefrontal cortex (mPFC), even when placed in the shock chamber without shocks. The HVA levels in the striatum in MA-treated rats were more elevated by CFS than these in saline-treated rats. These results suggest that the striatum DA system, as well as the mPFC DA system suggested previously, may be associated with emotional hypersensitivity to stress following repeated MA treatment.