title: CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats.
abstract: BACKGROUND
  Previous work suggests a role for stress-related corticotropin-releasing factor (CRF) systems in cocaine dependence. However, the involvement of activation of CRF(1) receptors in rats self-administering cocaine with extended access is unknown.
  
  
  OBJECTIVE
  The current study examined whether CRF(1) receptor antagonist administration alters cocaine self-administration in animals given extended access.
  
  
  METHODS
  Wistar rats (n = 32) acquired cocaine self-administration (0.66 mg/kg per infusion) in 1 h sessions for up to 11 days. Rats then were assigned to receive either daily short (1 h, ShA) or long (6 h, LgA) access to cocaine self-administration (n = 7-9 per group). Following escalation of intake, animals received one of two selective CRF(1) antagonists: antalarmin (6.3-25 mg/kg, i.p.) or N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5a]pyrimidin-7-amine (MPZP; 3.6-27.5 mg/kg, s.c.).
  
  
  RESULTS
  By day 11 of the escalation period, LgA rats increased their cocaine intake, reaching an intake level of 15.1 mg/kg, compared to 11.1 mg/kg in ShA rats, during the first hour of sessions. Antalarmin reduced cocaine self-administration at the highest dose selectively in the LgA group but not the ShA group. MPZP reduced cocaine intake both in LgA and ShA rats. However, MPZP did so at a lower dose in LgA rats than in ShA rats. Within the LgA group, MPZP decreased cocaine intake in the first 10 min (loading phase) as well as in the latter session intake (maintenance phase).
  
  
  CONCLUSIONS
  The data suggest that hypersensitivity of the CRF system occurs with extended access to cocaine self-administration and that this altered CRF system may contribute to the increased motivation to self-administer cocaine that develops during psychostimulant dependence.
authors.affiliation: The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Specio
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.forename: Laura E
authors.initials: LE
authors.lastname: O'Dell
authors.forename: Benjamin
authors.initials: B
authors.lastname: Boutrel
authors.forename: Eric P
authors.initials: EP
authors.lastname: Zorrilla
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
mesh_terms: D000818:Animals; D016739:Behavior, Addictive; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012646:Self Administration; D013997:Time Factors; D000099052:CRF Receptor, Type 1
chemical_list: D018765:Dopamine Uptake Inhibitors; C528552:N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5-a)pyrimidin-7-amine; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D000099052:CRF Receptor, Type 1; D003042:Cocaine