The Role of Corticotropin-Releasing Factor in the Median Raphe Nucleus in Relapse to Alcohol

Using an animal model of drug relapse, we found that intermittent footshock stress reinstates alcohol seeking, an effect attenuated by the 5-HT reuptake blocker fluoxetine and by corticotropin-releasing factor (CRF) receptor antagonists. Here we studied the role of the 5-HT cell body region of the median raphe nucleus (MRN) and CRF receptors in this site in reinstatement of alcohol seeking. Rats were given alcohol in a two-bottle choice procedure (water vs alcohol) for 25 d and were then trained for 1 hr/d to press a lever for alcohol (12% w/v) for 23-30 d. Subsequently, lever pressing for alcohol was extinguished by terminating drug delivery for 5-9 d. Tests for reinstatement of alcohol seeking were then performed under extinction conditions. Intra-MRN infusions of 8-OH-DPAT 8-hydroxy-2-(di-n-propylamino)tetralin (a 5-HT1A agonist that decreases 5-HT cell firing and release) reinstated alcohol seeking. Reinstatement of alcohol seeking also was observed after intra-MRN infusions of low doses of CRF (3-10 ng), which mimicked the effect of ventricular infusions of higher doses of the peptide (300-1000 ng). Finally, intra-MRN infusions of the CRF receptor antagonist d-Phe CRF (50 ng) blocked the effect of intermittent footshock (10 min) on reinstatement. These data suggest that an interaction between CRF and 5-HT neurons within the MRN is involved in footshock stress-induced reinstatement of alcohol seeking.