PARTIAL REVERSAL OF STRESS-INDUCED BEHAVIORAL SENSITIZATION TO AMPHETAMINE FOLLOWING METYRAPONE TREATMENT

Several studies indicate that blockade of stress-induced corticosteron e secretion prevents the development of stress-induced sensitization t o the behavioral effects of stimulants. The present study examined whe ther chronic blockade of corticosterone synthesis with metyrapone coul d 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 cann ulae over the nucleus accumbens, and then treated with either metyrapo ne (50 mg/kg, i.p.) or vehicle (1 ml/kg) for 7 days. On the seventh da y, animals were implanted with microdialysis probes in the nucleus acc umbens, and on the following day, all animals were tested for their lo comotor, stereotypy, and nucleus accumbens dopamine and DOPAC release responses to an injection of saline followed 60 min later by D-ampheta mine (1.5 mg/kg, i.p.). Neither stress or metyrapone treatment had an effect on the behavioral or dopamine release response to saline. Howev er, amphetamine-stimulated locomotion and stereotypy were strongly enh anced, while amphetamine-stimulated dopamine release response was slig htly enhanced (significant only by drug X time interaction), in stress ed animals. Metyrapone treatment reduced the stress-induced increase i n the locomotor, but not stereotypy, response to amphetamine. In contr ast, the dopamine release response to amphetamine was enhanced in mety rapone-treated animals, in both stressed and non-stressed groups, whil e DOPAC levels were unaffected by treatment group. This augmentation w as particularly evident in the stressed-metyrapone-treated animals. Fu rthermore, non-stressed animals showed an increased locomotor and ster eotypy response to amphetamine after treatment with metyrapone. These findings indicate that metyrapone treatment can reverse, or inhibit th e expression of, stress-induced sensitization to the behavioral effect s of amphetamine. However, the ability of metyrapone treatment to enha nce the behavioral (in non-stressed animals) and dopamine release (in non-stressed and stressed animals) responses to amphetamine indicate t hat chronic metyrapone treatment will produce stimulant sensitization when given alone. (C) 1998 Elsevier Science B.V.