The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats

Abstract

We have shown previously that footshock stress and priming injections of cocaine reinstate cocaine seeking in rats after prolonged drug-free periods (Erb et al., 1996). Here we examined the role of brain corticotropin-releasing factor (CRF) and the adrenal hormone corticosterone in stress- and cocaine-induced reinstatement of cocaine seeking in rats. The ability of footshock stress and priming injections of cocaine to induce relapse to cocaine seeking was studied after intracerebroventricular infusions of the CRF receptor antagonist D-Phe CRF12-41, after adrenalectomy, and after adrenalectomy with corticosterone replacement. Rats were allowed to self-administer cocaine (1.0 mg/kg/infusion, i.v) for 3 hr daily for 10-14 d and were then placed on an extinction schedule during which saline was substituted for cocaine. Tests for reinstatement were given after intermittent footshock (10 min; 0.5 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). Footshock reinstated cocaine seeking in both intact animals and animals with corticosterone replacement but not in adrenalectomized animals. The CRF receptor antagonist D-Phe CRF12-41 blocked footshock-induced reinstatement at all doses tested in both intact animals and animals with corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF12-41. These data suggest that brain CRF plays a critical role in stress-induced, but only a modulatory role in cocaine-induced, reinstatement of cocaine seeking. Furthermore, the data show that although reinstatement of cocaine seeking by footshock stress requires minimal, basal, levels of corticosterone, stress-induced increases in corticosterone do not play a role in this effect.

Fig. 1.

Top, The effect of the CRF receptor antagonist d-Phe CRF_12–41(d-Phe) on the mean ± SEM total number of responses (saline infusions + time-out responses) on the active lever in 3 hr tests for reinstatement afterSaline (physiological saline, 1.0 ml/kg, i.p.; 5 min before the start of the session), Footshock(intermittent footshock, 10 min; 0.5 mA; 0.5 sec on; mean off period of 40 sec; immediately before the start of the session), andCocaine (20 mg/kg, i.p.; 5 min before the start of the session). Groups of intact animals were tested in each reinstatement test condition under one dose ofd-Phe given intracerebroventricularly (0 μg, n = 10; 0.1 μg, n = 9; 0.3 μg, n = 11; and 1.0 μg, n = 10). The asteriskindicates a difference from the 0 μg dose ofd-Phe in the same test condition; Mann–Whitney (p < 0.05).Bottom, The effect ofd-Phe on the mean number of responses (saline infusions + time-out responses) on the active lever in each hour of each of the 3 hr tests for reinstatement. Theasterisk indicates a difference from all doses ofd-Phe in theFootshock test condition in hour 1; Mann–Whitney (p < 0.05).

Fig. 2.

Top, The effect of adrenalectomy (ADX; n = 11) and corticosterone replacement (CORT/PW; n = 9) and sham surgery (SHAM;n = 10) on the mean ± SEM total number of responses (saline infusions + time-out responses) on the active lever in 3 hr tests for reinstatement after Saline(physiological saline, 1.0 ml/kg, i.p.; 5 min before the start of the session), Footshock (intermittent footshock, 10 min; 0.5 mA; 0.5 sec on; mean off period of 40 sec; immediately before the start of the session), and Cocaine (20 mg/kg, i.p.; 5 min before the start of the session). Animals in each group (SHAM, ADX, and CORT/PW) were tested under all three test conditions. Theasterisk indicates a difference from SHAM and CORT/PW in the Footshock test condition; Mann–Whitney (p < 0.05). Bottom, The effect of adrenalectomy (ADX; n = 11) and corticosterone replacement (CORT/PW; n = 9) and sham surgery (SHAM; n = 10) on the mean number of responses (saline infusions + time-out responses) on the active lever in each hour of the 3 hr tests for reinstatement. Theasterisk indicates a difference from SHAM and CORT/PW in the Footshock test condition; Mann–Whitney (p < 0.05).

Fig. 3.

Effect ofd-Phe in adrenalectomized animals with corticosterone replacement (CORT/P; n= 5) on the mean ± SEM total number of responses on the active lever (saline infusions + time-out responses) in 2 hr tests for reinstatement after No Footshock andFootshock (intermittent footshock, 10 min; 0.5 mA; 0.5 sec on; mean off period of 40 sec; immediately before the start of the session). All animals were tested after pretreatment with vehicle and with d-Phe given intracerebroventricularly 40 min before the test in both the No Footshock and Footshock test conditions. The number of responses in Footshock tests was greater than that in the No Footshock tests with both vehicle andd-Phe (Wilcoxon,p < 0.05). The asterisk indicates a difference from vehicle in the Footshock test condition (Wilcoxon, p < 0.05).