Extended heroin access increases heroin choices over a potent nondrug alternative

Abstract

Epidemiological research shows that the proportion of drug users who become addicted to heroin is higher than to cocaine. Here we tested whether this difference could be due to a difference in the addiction liability between the two drugs. Addiction liability was assessed under a discrete-trials choice procedure by measuring the proportion of rats that prefer the drug over a potent alternative reward (ie, water sweetened with saccharin). Previous research on choice between self-administration of i.v. cocaine or sweet water showed that the proportion of cocaine-preferring rats remains relatively low and invariable (ie, 15%), even after extended drug access and regardless of past drug consumption (ie, total drug use before choice testing). By contrast, the present study shows that under similar choice conditions, the proportion of heroin-preferring rats considerably increases with extended heroin access (6-9 h per day for several weeks) and with past heroin consumption, from 11 to 51% at the highest past drug consumption level. At this level, the proportion of drug-preferring rats was about three times higher with heroin than with cocaine (51% vs 15%). This increase in the rate of heroin preference after extended heroin access persisted even after recovery from acute heroin withdrawal. Overall, these findings show that choice procedures are uniquely sensitive to different drugs and suggest that heroin is more addictive than cocaine. This higher addiction liability may contribute to explain why more drug users become addicted to heroin than to cocaine in epidemiological studies.

Figure 1

Choice between heroin and water sweetened with saccharin in naive rats (n=12). (a) Mean preference scores (±SEM) as a function of testing sessions. The horizontal dashed line at 0 represents the indifference level. Values above 0 indicate a preference for water sweetened with saccharin, while values below 0 indicate a preference for intravenous heroin. *Different from the indifference level (P<0.05, t-test). (b) Mean sampling (±SEM) of lever S (black bar) and lever H (white bar) (maximum possible per session=2). (c) Bars represent mean (±SEM) latencies of saccharin (black bar) and heroin (white bar) sampling (ie, time to complete the FR requirement after trial onset). *Different from saccharin (P<0.05, Tukey's HSD test). Data in (b) and (c) were obtained by averaging individual performances over the last three stable sessions.

Figure 2

Choice between heroin and water sweetened with saccharin in operant-trained rats (n=18). (a) Mean total responses (±SEM) for saccharin (black bar) or heroin (white bar). (b) Mean numbers of earned heroin or saccharin rewards (maximum possible per session=30). *Different from saccharin (P<0.05, Wilcoxon's test). (c) Mean preference scores (±SEM) as a function of testing sessions. For other information, see legend of Figure 1a. *Different from the indifference level (P<0.05, t-test). (d) Mean numbers (±SEM) of cage crossings as a function of heroin doses. Cage crossings were measured during 10 min after the first heroin sampling. *Different from the lowest dose of heroin (P<0.05, Tukey's HSD test, n=12). (e) Mean heroin choices as a function of heroin doses. *Different from the indifference level (P<0.05, t-test). All data, except in (c), were obtained by averaging individual performances over the last three sessions.

Figure 3

Choice between heroin and saccharin after extended heroin access. (a) Responding for and (b) intake of saccharin (ml) across sessions after differential access to heroin in ShA rats (closed circles, n=20) and LgA-6 h rats (open circles, n=20). *Different from ShA rats (P<0.05, Tukey's HSD test). Saccharin sessions alternated with sessions of heroin self-administration. (c) Mean (±SEM) preference scores in both ShA and LgA-6h rats across repeated choice sessions. Choice sessions alternated with sessions of heroin self-administration. For other information, see legend of Figure 1a. *Different from the indifference level (P<0.05, t-test). ^#Different from ShA rats (P<0.05, Tukey's HSD test). (d) Distribution of individual preferences in ShA and LgA-6h rats. Individual preferences were computed by averaging preference scores over the last three choice sessions. There were 5 and 12 heroin-preferring rats in the ShA and LgA groups, respectively (P<0.05, two-proportion z-test).

Figure 4

Effects of a more extended heroin access on saccharin responding and on choice between heroin and saccharin. (a) Mean (±SEM) responses on lever S in LgA-9 h rats (n=10) during saccharin sessions. Saccharin sessions alternated with sessions of heroin self-administration. *Different from the first session (P<0.05, Tukey's HSD test). (Inset in (a)) Mean responses (±SEM of the last three sessions) on lever S by ShA, LgA-6 h and LgA-9h rats. *Different from ShA rats (P<0.05, Tukey's HSD test). ^#Different from LgA-6h rats (P<0.05, Tukey's HSD test). (b) Percentage of completed trials (±SEM) during the choice procedure between heroin and saccharin in ShA (closed circles), LgA-6h (open circles) and LgA-9h rats (open squares). *Different from ShA and LgA-6h rats (P<0.05, Tukey's HSD test). (Inset in (b)) Mean (±SEM) number of earned heroin rewards. *Different from ShA rats (P<0.05, Tukey's HSD test). ^#Different from LgA-6h rats (P<0.05, Tukey's HSD test). (c) Saccharin intake in abstinent LgA-9h until recovery from HW. *Different from the first session (P<0.05, Tukey's HSD test). (d) Mean responses (±SEM) for saccharin during HW (last three sessions) and after recovery (REC, last three sessions). After recovery, rats were re-exposed to one single 9-h session of heroin self-administration and tested for saccharin responding 15 h later (sHW). *Different from HW (P<0.05, Tukey's HSD test). ^#Different from REC (P<0.01, Tukey's HSD test).

Figure 5

Lack of effects of heroin withdrawal on choice between heroin and saccharin. (a) Mean (±SEM) preference scores of LgA-9h rats (n=10) after recovery from HW. For other information, see legend of Figure 1a. (b) Distribution of individual preferences (averaged over the last three sessions, open circles) in LgA-9h rats. Four out of 10 LgA-9h rats preferred heroin over saccharin. (c) Mean (±SEM) saccharin (black bar) and heroin sampling (white bar) during post-recovery baseline (BL) and after HW. (d) Mean (±SEM) percentage of completed choice trials during post-recovery baseline (BL) and after HW. (e) Mean (±SEM) preference scores of rats during post-recovery baseline (BL) and after HW. *Different from BL (P<0.05, Tukey's HSD test). Data in (c–e) were obtained by averaging individual performances over the last three sessions of each condition.

Figure 6

Effects of past heroin consumption on heroin choices. (a) Mean preference scores (±SEM) over the last three sessions (n=191) as a function of past heroin use. The number of rats per level of past heroin consumption is indicated below each bar. #Different from the lowest level of past heroin consumption (P<0.05, Tukey's HSD test). *Different from the indifference level (P<0.05, t-test). (b) Frequency of heroin-preferring individuals (ie, heroin choices >50% of completed trials over the last three sessions) as a function of past heroin use. The horizontal dashed line at 15% represents the frequency of cocaine-preferring individuals at the highest level of past cocaine use. ^#Different from the lowest level of past heroin consumption (P<0.05, Tukey's HSD test). (c) Mean preference scores (±SEM) of LgA-6 h rats (n=5) between heroin (closed circles) or cocaine (open circles) and saccharin. *Different from the indifference level (P<0.05, t-test). (d) Individual preferences (as averaged over the last three sessions) as a function of the available drug option.