Involvement of protracted withdrawl in morphine relapse

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DESCRIPTION (provided by applicant): Many drug abusers succeed in becoming drug-free for days to months, but most of these individuals experience persistent cravings and relapse long after acute, physical withdrawal, during a period termed protracted withdrawal. Such results indicate that previous exposure and dependence on a drug causes long-term changes that affect subsequent drug preference and seeking. Recently, our lab found that rats made dependent on morphine via pellet implantation and then withdrawn for 5 weeks showed an enhanced preference for morphine as compared to placebo pellet-implanted animals when tested in a conditioned place preference paradigm. Our lab also found that the ventral noradrenergic bundle, which carries information from medullary noradrenergic neurons to the bed nucleus of the stria terminalis (BNST), is crucial for the aversiveness of acute opiate withdrawal. This finding is important because the aversiveness of acute withdrawal is a primary factor motivating addicts to seek drugs, and this pathway may continue to play a role even after long periods of abstinence. The studies proposed here will investigate possible mechanisms of enhanced preference and potentially relapse, including sensitization and anxiety following dependence and withdrawal. Noradrenergic signaling will be investigated for its possible contributions to enhanced preference and reinstatement. Results from these experiments will reveal mechanisms underlying the long-lasting changes in the brain caused by dependence that increase drug seeking during protracted withdrawal.