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


OBJECTIVE
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.


METHODS
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 CRF(12-41) [1 microg, intracerebroventricular (i.c.v.)], prior to i.c.v. injections of NA (10 microg; Experiment 1); (2) pretreatment with the alpha(2) adrenoceptor agonist, clonidine (40 microg/kg, i.p.), prior to i.c.v. injections of CRF (0.5 microg; Experiment 2); (3) pretreatment with D: -Phe (1, 5 microg, 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 microg/kg, i.p.) prior to systemic injections of yohimbine (0.625 mg/kg, 1.25 mg/kg; Experiment 3B).


RESULTS
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.


CONCLUSIONS
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.
Brown
Zenya J
ZJ
Centre for the Neurobiology of Stress, Department of Psychology, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada.
Tribe
Erin
E
D'souza
Nicole A
NA
Erb
Suzanne
S
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage; D000818:Animals; D016739:Behavior, Addictive; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003000:Clonidine / Q000008:administration & dosage; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000523:psychology; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism*; D005108:Extinction, Psychological; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D012646:Self Administration; D015016:Yohimbine / Q000008:administration & dosage
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000697:Central Nervous System Stimulants; D018341:Receptors, Adrenergic, alpha-2; D018019:Receptors, Corticotropin-Releasing Hormone; C113202:phenylalanyl corticotropin-releasing factor (12-41); D015016:Yohimbine; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine; D003000:Clonidine; D009638:Norepinephrine