Stress-induced relapse to cocaine seeking in the rat : contributions of central nervous system corticotropin-releasing factor and noradrenaline

The primary objective of the present thesis was to characterize the role of two neurobiological systems, corticotropin-releasing factor (CRF) and noradrenaline (NE), in stress- and cocaine-induced relapse to cocaine seeking, using an animal model of relapse. Rats were allowed to self-administer cocaine (0.5 or 1.0 mg/kg/infusion, i.v.) for 3 hours daily for 10-14 days and were then put on an extinction schedule during which lever pressing was no longer reinforced. Tests for reinstatement were given after intermittent electric footshock (10 or 15 min; 0.5-0.8 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). In a first series of experiments, footshock reinstated cocaine seeking in both intact animals and in animals given corticosterone replacement, but not in adrenalectomized animals. Intracerebroventricular injections of the CRF-receptor antagonist, D-Phe CRF 12-41 , blocked footshock-induced reinstatement in both intact animals and animals given corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF 12-41 . Additionally, systemic injections of the non-peptide CRF-receptor antagonist, CP-154,526, blocked the footshock-induced reinstatement of cocaine seeking. Collectively, these results demonstrate that CRF acting directly in the brain and independent of the hypothalarnic-pituitary-adrenal axis mediates the stress- but not cocaine-induced reinstatement of cocaine seeking. In an attempt to localize where in the brain CRF acts to initiate the behaviors involved in relapse, injections of D-Phe CRF 12-41 were made into the bed nucleus of the stria terminalis (BNST) and the amygdala (AMG), two sites that contain CRF receptors and that have been implicated in behavioral and physiological effects of stress. Injections into the BNST, but not the AMG, blocked the footshock-induced reinstatement of cocaine seeking and injections of CRF into the BNST, but not the AMG, were sufficient to induce reinstatement. These results suggest that the BNST is an import site of action for CRF in mediating the effects of footshock on relapse. In a second series of experiments, an important role for NE in stress-induced relapse was demonstrated. Systemic injections of three alpha-2 adrenergic receptor agonists (clonidine, lofexidine, and gunabenz), which act to block NE cell firing and release, blocked footshock-induced relapse but were without effect on relapse induced by priming injections of cocaine. Together with results of the first series of experiments, these data suggest that an interaction between CRF and NE systems, possibly within the extended AMG, underlies the footshock-induced reinstatement of cocaine seeking. Additionally, the findings argue in favor of a view that different neurobiological systems underlie footshock- and drug-induced relapse to drug seeking and that, therefore, different treatment interventions may be required under different circumstances