Corticotropin-releasing factor-1 receptor antagonists decrease heroin self-administration in long- but not short-access rats

Abstract

Dysregulation of the stress-related corticotropin-releasing factor (CRF) system has been implicated in the development of drug dependence. The present study examined the effects of administering CRF type 1 (CRF(1)) receptor antagonists on heroin self-administration in animals allowed short (1 hour) or long (8-12 hours) access to intravenous heroin self-administration sessions. The nonpeptide CRF(1) antagonists MJL-1-109-2 (1 hour versus 8 hours access) or R121919 (1 hour versus 12 hours access) were systemically injected in both short- and long-access rats. MJL-1-109-2 (10 mg/kg) and R121919 (10 and 20 mg/kg) reduced heroin self-administration in long-access animals without altering heroin intake in short-access animals. Both MJL-1-109-2 and R121919 decreased first-hour intravenous heroin self-administration selectively in long-access rats, with R121919 decreasing cumulative heroin intake across the 12-hour session. The results demonstrate that blockade of the CRF-CRF(1) receptor system attenuates the increased heroin intake of rats with extended access to the drug.

Figure 1

Increased heroin intake in long-access (a: 8 hours; b: 12 hours) rats. Mean ±SEM heroin intake in μg/kg. (a) 8-hour rats (n = 7) increased their intake from Day 1 to Day 24 (to 4000 μg/kg). (b) 12-hour rats (n = 4) also increased intake to approximately 3800 μg/kg of heroin/day

Figure 2

Comparison of 1-hour heroin intake in long-access (12 hours) and short-access (1 hour). Mean ±SEM heroin intake in μg/kg in long-access (n = 7, closed circles) and short-access (n = 7, open circles) rats. Although the short-access rats started slightly higher in heroin responding, by Day 24 long-access rats surpassed short-access rats in heroin intake. Post hoc analysis of a significant time × access interaction indicated that escalated drug intake was only observed in long-access rats. A significant time × access interaction revealed that the long-access rats were different than the short-access rats (P < 0.001)

Figure 3

MJL-1-109-2 decreased first-hour heroin responses in long-access, but not short-access, rats. The CRF₁ antagonist MJL-1-109-2 at a dose of 10 mg/kg significantly (*P < 0.05) reduced heroin intake (mean ±SEM) in the first hour of 8-hour (long-access, n = 7, left panel) rats. No effect on heroin intake was observed in short-access rats (n = 8, right panel) at any of the doses tested. Symbols indicate an overall linear effect of dose (^$P < 0.05), significant differences from vehicle treatment (*P < 0.05) and significant differences between groups at the vehicle dose (^#P = 0.002)

Figure 4

Total heroin responses in rats after MJL-1-109-2 administration. (a) MJL-1-109-2 had no effect on total responses (8 hours) for heroin (mean ±SEM). (b) Responses (mean ±SEM) by hour in 8-hour access rats. In the first hour, MJL-1-109-2 had a significant effect (*P < 0.05, overall Dose effect compared with vehicle) on heroin intake, but at the other time points, no effect of MJL-1-109-2 on heroin intake was observed

Figure 5

R121919 decreased first-hour responding in long-access rats, but not in short-access rats. Mean ± SEM of heroin responses in 1 hour. (Left) Gray bars show long-access rats (n = 7). (Right) Black bars show short-access rats (n = 7). R121919 (20 mg/kg) significantly decreased heroin responding in long-access rats (*P < 0.05). Symbols indicate an overall linear effect of dose (^$P < 0.05) and significant differences from vehicle treatment (*P < 0.05)

Figure 6

R121919 reduced total heroin responses in long-access rats. (a) Mean ± SEM of heroin self-administration responses during R121919 treatment in long-access rats (n = 7). The 10 and 20 mg/kg doses were effective at reducing heroin self-administration in the long-access rats (P < 0.05). (b) Effect (mean ± SEM) of each dose of R121919 on heroin responding by hour of access. Heroin responses were the highest in the first hour for all doses. Heroin responding at the 20 mg/kg R121919 dose stayed relatively low across time, with some recovery after the third hour for the 10 mg/kg dose. ^#P < 0.05 for the first 3 hours of intake. *P < 0.05 for total intake and first-hour intake at the 20 mg/kg dose