title: The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol.
abstract: Using an animal model of drug relapse, we found that intermittent footshock stress reinstates alcohol seeking, an effect attenuated by the 5-HT reuptake blocker fluoxetine and by corticotropin-releasing factor (CRF) receptor antagonists. Here we studied the role of the 5-HT cell body region of the median raphe nucleus (MRN) and CRF receptors in this site in reinstatement of alcohol seeking. Rats were given alcohol in a two-bottle choice procedure (water vs alcohol) for 25 d and were then trained for 1 hr/d to press a lever for alcohol (12% w/v) for 23-30 d. Subsequently, lever pressing for alcohol was extinguished by terminating drug delivery for 5-9 d. Tests for reinstatement of alcohol seeking were then performed under extinction conditions. Intra-MRN infusions of 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] (a 5-HT1A agonist that decreases 5-HT cell firing and release) reinstated alcohol seeking. Reinstatement of alcohol seeking also was observed after intra-MRN infusions of low doses of CRF (3-10 ng), which mimicked the effect of ventricular infusions of higher doses of the peptide (300-1000 ng). Finally, intra-MRN infusions of the CRF receptor antagonist d-Phe CRF (50 ng) blocked the effect of intermittent footshock (10 min) on reinstatement. These data suggest that an interaction between CRF and 5-HT neurons within the MRN is involved in footshock stress-induced reinstatement of alcohol seeking.
authors.affiliation: Department of Neuroscience, Center for Addiction and Mental Health, Toronto, Ontario, Canada M5S 2S1. anh_le@camh.net
authors.forename: A D
authors.initials: AD
authors.lastname: Lê
authors.forename: S
authors.initials: S
authors.lastname: Harding
authors.forename: W
authors.initials: W
authors.lastname: Juzytsch
authors.forename: P J
authors.initials: PJ
authors.lastname: Fletcher
authors.forename: Y
authors.initials: Y
authors.lastname: Shaham
mesh_terms: D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004597:Electroshock; D000431:Ethanol / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012008:Recurrence; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013312:Stress, Physiological / Q000378:metabolism
chemical_list: D003346:Corticotropin-Releasing Hormone; D000431:Ethanol; D005473:Fluoxetine; D018019:Receptors, Corticotropin-Releasing Hormone; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors