Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat

Corticotropin-releasing factor (CRF) and noradrenaline (NA) have been shown in independent studies to mediate stress-induced reinstatement of drug seeking. To date, however, a functional interaction between the systems in reinstatement has not been demonstrated. The objectives of this study were to determine whether CRF and NA systems can interact to influence reinstatement responding and, if so, in what direction the interaction occurs. Rats were trained to self-administer cocaine (0.23 mg/kg per infusion) for 8-10 days. Subsequently, responding for drug was extinguished, and tests for reinstatement were conducted following: (1) pretreatment with the CRF receptor antagonist, d-Phe CRF12-41 [1 mu g, intracerebroventricular (i.c.v.)], prior to i.c.v. injections of NA (10 mu g; Experiment 1); (2) pretreatment with the alpha(2) adrenoceptor agonist, clonidine (40 mu g/kg, i.p.), prior to i.c.v. injections of CRF (0.5 mu g; Experiment 2); (3) pretreatment with d-Phe (1, 5 mu g, i.c.v.), prior to systemic injections of the alpha(2) adrenoceptor antagonist, yohimbine (1.25 mg/kg; Experiment 3A); or (4) pretreatment with clonidine (40 mu g/kg, i.p.) prior to systemic injections of yohimbine (0.625 mg/kg, 1.25 mg/kg; Experiment 3B). NA reliably induced reinstatement, an effect that was blocked by pretreatment with d-Phe. In contrast, CRF-induced reinstatement was not attenuated by pretreatment with clonidine. Pretreatment with neither d-Phe nor clonidine was effective in blocking yohimbine-induced reinstatement. Together, the present findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA.