CRF1 receptor antagonists attenuate escalated cocaine self-administration in rats
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Previous work suggests a role for stress-related corticotropin-releasing factor (CRF) systems in cocaine dependence. However, the involvement of activation of CRF1 receptors in rats self-administering cocaine with extended access is unknown.
The current study examined whether CRF1 receptor antagonist administration alters cocaine self-administration in animals given extended access.
Materials and 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 CRF1 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.).
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).
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.
KeywordsCocaine Self-administration Escalation Rats Corticotropin-releasing factor Addiction Antalarmin MPZP
We gratefully acknowledge the technical assistance of Yanabel Grant and Robert Lintz and the chemical expertise of Kim Janda and Pete Wirsching for MPZP synthesizing. Additionally, we thank Mike Arends for editorial assistance. This is publication number 18741 from The Scripps Research Institute. The experimental protocol was in compliance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (The National Academies Press, 1996). Additionally, there is no relationship with the organization supporting this research and no conflict of interest.
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