INDUCTION OF CHRONIC FOS-RELATED ANTIGENS IN RAT-BRAIN BY CHRONIC MORPHINE ADMINISTRATION

Previous studies have shown that repeated exposure to cocaine or to se veral other stimuli induces novel 35-37 kDa Fos-related antigens (chro nic Fras) in specific brain regions. Induction of these proteins is as sociated with prolonged increases in AP-1 DNA binding activity that pa rallel the long half-life of the chronic Fras in brain. In the current study, we characterized regulation of the chronic Fras in response to prolonged exposure to morphine. After 5 days of morphine treatment, w e observed increased levels of the chronic Fras and of AP-1 binding ac tivity in rat striatum and nucleus accumbens, effects that were not se en in most other brain regions that we studied. Concomitant administra tion of naltrexone, an opioid receptor antagonist, prevented the induc tion of these proteins. Two-dimensional gel analysis showed that the c hronic Fras induced by chronic morphine administration are identical t o those induced after chronic cocaine and other treatments. A time cou rse study indicated that chronic Fra induction was first apparent afte r 3 days of morphine treatment and peaked between 5 and 7 days of trea tment in both the striatum and nucleus accumbens. Withdrawal studies d emonstrated robust induction of several known acute Fras, including c- Fos, FosB, Fra-1, Fra-2, and Delta FosB, at 6 hr after naltrexone prec ipitation of withdrawal in the striatum, nucleus accumbens, and severa l other brain regions. Levels of these proteins returned to basal valu es by 72 hr. In contrast, no further induction of the chronic Fras was evident after 6 hr of withdrawal in the striatum and nucleus accumben s, but levels of the proteins increased beyond their already elevated chronic morphine values after longer periods (72 hr) of withdrawal, ev en though physical withdrawal symptoms had resolved at this time point . Chronic Fras were also induced after these prolonged withdrawal peri ods in several other brain regions, where the proteins were not induce d by chronic morphine alone, We discuss the possible roles played by t he chronic Fras in the adaptive responses of the brain to chronic opia te exposure and opiate withdrawal.