Partial reversal of stress-induced behavioral sensitization to amphetamine following metyrapone treatment

Several studies indicate that blockade of stress-induced corticosterone secretion prevents the development of stress-induced sensitization to the behavioral effects of stimulants. The present study examined whether chronic blockade of corticosterone synthesis with metyrapone could reverse stress-induced amphetamine sensitization in rats. Restraint stress in cylindrical chambers, 2 times 30 min/day for 5 days over an 8-day schedule, was used as the stressor. Following completion of the stress protocol, animals were cannulated with microdialysis guide cannulae over the nucleus accumbens, and then treated with either metyrapone (50 mg/kg, i.p.) or vehicle (1 ml/kg) for 7 days. On the seventh day, animals were implanted with microdialysis probes in the nucleus accumbens, and on the following day, all animals were tested for their locomotor, stereotypy, and nucleus accumbens dopamine and DOPAC release responses to an injection of saline followed 60 min later by d-amphetamine (1.5 mg/kg, i.p.). Neither stress or metyrapone treatment had an effect on the behavioral or dopamine release response to saline. However, amphetamine-stimulated locomotion and stereotypy were strongly enhanced, while amphetamine-stimulated dopamine release response was slightly enhanced (significant only by drug x time interaction), in stressed animals. Metyrapone treatment reduced the stress-induced increase in the locomotor, but not stereotypy, response to amphetamine. In contrast, the dopamine release response to amphetamine was enhanced in metyrapone-treated animals, in both stressed and non-stressed groups, while DOPAC levels were unaffected by treatment group. This augmentation was particularly evident in the stressed-metyrapone-treated animals. Furthermore, non-stressed animals showed an increased locomotor and stereotypy response to amphetamine after treatment with metyrapone. These findings indicate that metyrapone treatment can reverse, or inhibit the expression of, stress-induced sensitization to the behavioral effects of amphetamine. However, the ability of metyrapone treatment to enhance the behavioral (in non-stressed animals) and dopamine release (in non-stressed and stressed animals) responses to amphetamine indicate that chronic metyrapone treatment will produce stimulant sensitization when given alone.