Stress-induced cross-sensitization to cocaine: effect of adrenalectomy and corticosterone after short- and long-term withdrawal.

We have recently shown that adrenalectomy (ADX) in rats blocks the appearance of cocaine-induced sensitization when this behavioral response is tested at early withdrawal times (1-2 days), but not after later withdrawal from cocaine (12 days). To determine if a similar phenomenon occurred with stress-induced sensitization, male Sprague-Dawley rats were given a sham ADX, ADX surgery, or ADX plus s.c. implanted corticosterone (CORT) pellets (CORT 12.5% pellets or CORT 50% pellets). A fifth group was given ADX surgery, but CORT 50% pellets were implanted after repeated stress treatment. One week after surgery, each group was divided into two additional groups, naive and stress. Naive animals remained unhandled, while stress rats were given a variety of daily stressors administered twice per day for 6 consecutive days. One day after the last stress, rats were given a saline injection followed by a cocaine injection (15 mg/kg, i.p.) the next day, and locomotor activity was monitored (early withdrawal). Two weeks after the last stress, the locomotor responses to an additional saline and cocaine injection were monitored (late withdrawal). At early withdrawal, no significant sensitization occurred for horizontal activity, but cross-sensitization was demonstrated for vertical activity. At late withdrawal, sham controls showed a stress-induced elevation in horizontal activity, with only a trend toward increased vertical activity. Animals given ADX surgery or ADX and CORT 12.5% pellets did not demonstrate sensitization to repeated stress, while CORT 50% pellets in ADX rats restored the sensitized horizontal response to cocaine challenge at late withdrawal. In contrast, stress-pretreated rats which were given CORT 50% pellets during the 2-week withdrawal period after the stress showed a marked decrease in horizontal activity in response to cocaine challenge at late withdrawal. The results provide evidence for a necessary role for adrenal hormones in long term, but not short-term, stress-induced cross-sensitization. Together with our previous study on the role of CORT in cocaine-induced sensitization, the results indicate that CORT is not the common factor mediating the long-term sensitization to cocaine and stress.