BRAIN CORTICOTROPIN-RELEASING FACTOR MEDIATES ANXIETY-LIKE BEHAVIOR INDUCED BY COCAINE WITHDRAWAL IN RATS

Anxiety is a key symptom of the cocaine withdrawal syndrome in human a ddicts, and it is considered to be one of the major factors in precipi tating relapse to chronic cocaine abuse. Corticotropin-releasing facto r (CRF) plays an important role in the pathophysiology of anxiety and depression, and it may also be involved in the acute behavioral and ne uroendocrine actions of cocaine. The role of endogenous CRF in cocaine withdrawal-induced anxiety was investigated in the present study. Ani mals were subjected to chronic cocaine (20 mg/kg, intraperitoneally, o nce a day for 14 days) administration. Rats tested 30 min after the la st cocaine injection did not show withdrawal anxiety on the elevated p lus maze or any alterations in brain CRF levels. Withdrawal (48 h) fro m chronic cocaine administration produced an intense anxiety-like beha vior characterized by decreased open arm exploration. Immunoreactive C RF (CRF-LI) levels were selectively altered in the hypothalamus, in th e amygdala and in the basal forebrain structures at the time of the be havioral anxiety, reflecting an increased activity of brain CRF system s. Daily intracerebroventricular (i.c.v.) pretreatment with an immunos erum raised against CRF completely prevented the development of anxiet y induced by cocaine withdrawal. These data suggest that extrahypothal amic-limbic CRF hypersecretion may be involved in the development of a nxiety related to cocaine withdrawal and that the CRF system may be a useful target for new pharmacotherapies for cocaine withdrawal and rel apse.