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Volume 17, Number 7, Issue of April 1, 1997 pp. 2605-2614
Copyright ©1997 Society for Neuroscience

Corticotropin-Releasing Factor, But Not Corticosterone, Is Involved in Stress-Induced Relapse to Heroin-Seeking in Rats

Received Dec. 2, 1996; accepted Jan. 21, 1997.

Yavin Shaham², Douglas Funk¹, Suzanne Erb¹, Theodore J. Brown³, Claire-Dominique Walker⁴, and Jane Stewart¹

¹ Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, Québec, Canada H3G 1M8, ² Biobehavioral Research Department, Addiction Research Foundation, Toronto, Ontario, Canada M5S 2S1, ³ Department of Zoology, University of Toronto, Toronto, Ontario, Canada M6A 2EI, and ⁴ Department of Psychiatry, McGill University, Douglas Hospital Research Center, Montréal, Québec, Canada H4H 1R3

We showed previously that brief footshock stress and priming injections of heroin reinstate heroin-seeking after prolonged drug-free periods. Here, we examined whether the adrenal hormone, corticosterone, and brain corticotropin-releasing factor (CRF) were involved in such reinstatement. We tested the effects of adrenalectomy, chronic exposure to the corticosterone synthesis inhibitor metyrapone (100 mg/kg, s.c., twice daily), acute exposure to metyrapone, acute intracerebroventricular injections of CRF (0.3 and 1.0 µg), and intracerebroventricular injections of the CRF antagonist -helical CRF (3 and 10 µg). Rats were trained to self-administer heroin (100 µg/kg/infusion, i.v.) for 12-14 d. Extinction sessions were given for 4-8 d (saline substituted for heroin). Tests for reinstatement were given after priming injections of saline and of heroin (0.25 mg/kg, s.c.), and after intermittent footshock (15 or 30 min, 0.5 mA). Adrenalectomy (performed after training) did not affect reinstatement by heroin but appeared to potentiate the reinstatement by footshock. Chronic exposure to metyrapone (from the beginning of extinction) or an acute injection of metyrapone (3 hr before testing) did not alter the reinstatement of heroin-seeking induced by footshock or heroin. Acute exposure to metyrapone alone potently reinstated heroin-seeking. In addition, acute exposure to CRF reinstated heroin-seeking, and the CRF antagonist -helical CRF attenuated stress-induced relapse. The effect of the CRF antagonist on reinstatement by heroin was less consistent. These results suggest that CRF, a major brain peptide involved in stress, contributes to relapse to heroin-seeking induced by stressors.

Key words: adrenalectomy; corticosterone; CRF; metyrapone; opioid self-administration; reinstatement; relapse; stress

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