Suppression of corticotropin-releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal.

The central nucleus of the amygdala is a CRF-containing limbic brain site which mediates both fear-like and avoidance behaviors, and intra-amygdala administration of a CRF antagonist blocks the increase in anxiogenic-like behavior characteristic of ethanol withdrawal. In order to evaluate the role of brain CRF in negative motivational states associated with other classes of abused drugs, the present studies examined the effects of suppression of amygdala CRF systems on the characteristic aversive state of precipitated withdrawal in morphine-dependent subjects. In a place conditioning paradigm, administration of a CRF antagonist, alpha-belical CRF (9-41) [250ng], bilaterally into the central nucleus of amygdala, reversed the withdrawal-induced conditioned place aversion produced by injection of the opiate antagonist, methylnaloxonium [500ng], into the same site. In a conditioned operant suppression paradigm, impairment of CRF neurons by immuno-targeted toxins administered into the central nucleus of amygdala, one month prior to testing, attenuated the decrease in response rate produced by exposure to distinctive sensory cues associated previously with systemic administration of naloxone [25µg/kg s.c.] in morphine-dependent subjects. These results indicate that suppression of intra-amygdala CRF systems weakens the aversive stimulus properties of conditioned opiate withdrawal, and suggest a general role for CRF in coordinating behavioral responses to negative motivational effects of drug withdrawal.