The motivational aspects of opiate dependence and protracted abstinence contribute to the chronic relapsing nature of the disorder and make treatment difficult. Animal models for protracted abstinence and conditioned withdrawal are well-established. Once dependent rats learn to associate a tone and smell with naloxone- induced opiate withdrawal, they show decreased responding in food lever-press paradigms when presented with the paired stimulus alone. After one month, motivational changes persist--the animal is challenged with the paired stimulus in the absence of both morphine and naloxone. Learned associations and motivational changes associated with withdrawal are hypothesized to involve the extended amygdala, but discrete subregions and molecular mechanisms fully elucidated. The following experiments described the cellular changes in the Galphao protein, PKC, and CREB modulated by conditioned withdrawal, protracted abstinence, and self-administration. Based on the results of the first set of experiments, the next series of studies will examine the behavioral effects of blocking subsequent stages of the mu-opiate receptor activation cascade with an intent to block conditioned withdrawal. The effects of intracerebral microinjections of antagonists of Galphao, PKC or CREB will elucidate regions f the extended amygdala involved in the learned association precipitated by opiate withdrawal. The studies will provide a neuropharmacological basis for conditioned withdrawal and will help elucidate the neuroadaptive mechanisms set in motion by opiate dependence.
