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 s ite which mediates both fear-like and avoidance behaviors, and intra-a mygdala administration of a CRF antagonist blocks the increase in anxi ogenic-like behavior characteristic of ethanol withdrawal. In order to evaluate the role of brain CRF in negative motivational states associ ated with other classes of abused drugs, the present studies examined the effects of suppression of amygdala CRF systems on the characterist ic aversive state of precipitated withdrawal in morphine-dependent sub jects. In a place conditioning paradigm, administration of a CRF antag onist, alpha-helical CRF (9-41) [250 ng], bilaterally into the central nucleus of amygdala, reversed the withdrawal-induced conditioned plac e aversion produced by injection of the opiate antagonist, methylnalox onium [500 ng], into the same site. In a conditioned operant suppressi on paradigm, impairment of CRF neurons by immuno-targeted toxins admin istered into the central nucleus of amygdala, one month prior to testi ng, attenuated the decrease in response rate produced by exposure to d istinctive sensory cues associated previously with systemic administra tion of naloxone [25 mu g/kg s.c.] in morphine-dependent subjects. The se results indicate that suppression of intra-amygdala CRF systems wea kens the aversive stimulus properties of conditioned opiate withdrawal , and suggest a general role for CRF in coordinating behavioral respon ses to negative motivational effects of drug withdrawal.