The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol

Abstract

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.

Fig. 1.

Cannula placements. A, The placements of the tip of the injectors in the DRN and MRN in experiments 1 and 2 (Paxinos and Watson, 1998). B, A pictograph of cannula placement and injector tip in the DRN.C, A pictograph of cannula placement and injector tip in the MRN.

Fig. 2.

8-OH-DPAT. Reinstatement of alcohol seeking by MRN, but not DRN, infusions of the 5-HT_1A agonist 8-OH-DPAT. Data are mean ± SEM responses on the previously active lever and responses on the inactive lever on the 60 min after infusions of 8-OH-DPAT into the DRN (n = 15) (A) and MRN (n = 16) (B). *p < 0.05, different from vehicle.

Fig. 3.

CRF and d-Phe CRF. Reinstatement of alcohol seeking by intraventricular and intra-MRN infusions of CRF and blockade of footshock stress-induced reinstatement by intra-MRN infusions of the CRF receptor antagonist d-Phe CRF.A, Mean ± SEM responses on the previously active lever and on the inactive lever on the 60 min after ventricular infusions of vehicle and CRF (n = 15 per dose). *p < 0.05, different from vehicle.B, Mean responses on the active and inactive levers on the 60 min after MRN infusions of vehicle and CRF (n = 17). *p < 0.05, different from vehicle. C, Mean responses on active and inactive lever after exposure to 10 min of intermittent footshock or no shock in rats pretreated with vehicle and d-Phe CRF (50 ng) into the MRN (n = 10). *p < 0.05, different from the other experimental conditions.