CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats

Abstract

Rationale: 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.

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 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).

Conclusion: 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.

Fig. 1

Chemical structures of antalarmin and MPZP

Fig. 2

Self-administration of cocaine by rats under a fixed-ratio schedule during the escalation period. Data from entire sessions (a) and from the first hour of sessions (b). The data represent mean (+SEM) cocaine intake adjusted for body weight (milligram per kilogram). Open symbols are the data for rats in 1-h sessions (ShA, n=16). Filled symbols are the data for rats in 6-h sessions (LgA, n=16). *p<0.05, **p<0.01, ***p<0.001 compared with session 1

Fig. 3

Antalarmin effects on cocaine intake in ShA and LgA rats under a fixed-ratio schedule. Antalarmin was intraperitoneally injected 80 min before a test session. Test sessions lasted 1 h and were separated by one or two treatment-free escalation sessions. Data are expressed as mean (+SEM) cocaine intake (milligram per kilogram). *p<0.05 compared with the vehicle

Fig. 4

MPZP effects on cocaine intake in ShA and LgA rats under a fixed-ratio schedule. MPZP was subcutaneously injected 45 min before a test session. Test sessions lasted 1 h and were separated by one or two treatment-free escalation sessions. Data are expressed as mean (+SEM) cocaine intake (milligram per kilogram). *p<0.05, **p <0.01 compared with the vehicle