Context-induced relapse of conditioned behavioral responding to ethanol cues in rats

Abstract

Background: The environmental context in which drug-conditioned cues are encountered could modulate the capacity of such cues to trigger relapse in abstinent addicts. We explored this hypothesis using a behavioral animal model.

Methods: Rats were trained to discriminate between two auditory stimuli; the first (CS+) was paired with 10% ethanol and the second (CS-) was presented without ethanol. Training occurred in operant conditioning chambers equipped with distinct contextual stimuli, and entries into the ethanol delivery port during the stimuli were measured. Behavior was then extinguished by presenting both stimuli without ethanol in a second, different context. Context-dependent renewal of port entries was tested by presenting the CS+ and CS- without ethanol in the original training context.

Results: At test, port entries during the CS+ increased compared with extinction levels, while responding during the CS- remained unchanged (n = 11). This effect was attenuated after multiple extinction sessions in three distinct contexts (n = 18), compared with an equivalent number of extinction sessions in a single unique context (n = 16). Context-dependent renewal of port entries was also observed to a CS+ paired with 14% sucrose (n = 7) but not to a CS+ paired with 2% sucrose (n = 8).

Conclusions: Environmental contexts can trigger the relapse of behavioral responding to ethanol- and sucrose-predictive cues in rats. For ethanol, this effect can be reduced by extinguishing responses to the ethanol cue in multiple distinct contexts, a manipulation that could increase the efficacy of cue-reactivity treatments for addiction.

Figure 1

Discrimination training and extinction with a 10% ethanol reinforcer. Data represent Mean (± S.E.M.) port-entries during the CS+ (filled circles) and CS− (open circles) in daily discrimination training sessions with ethanol (Context A, sessions 1-18) and extinction sessions without ethanol (Context B, sessions 19-26). (A) Port-entries during each 10-sec stimulus (B) Port-entries during the 10-sec interval before each stimulus (pre-CS) (C) Normalized port-entries during each CS, obtained by subtracting pre-CS responding from responding during the corresponding 10-sec CS. *p<0.05, CS+ vs. corresponding CS-.

Figure 2

Renewal of conditioned responding for ethanol. Mean (± S.E.M.) normalized port-entries made during the CS+ (filled bars) and CS- (open bars) in discrimination training sessions with ethanol in Context A, extinction sessions in Context B, and renewal testing in Context A. Data are averaged over the last 2 sessions for discrimination training and extinction, and are from the single session renewal test. *p<0.05, **p<0.001, CS+ vs. corresponding CS-; #p<0.05, CS+ training vs. CS+ extinction; ˆp<0.05, CS+ extinction vs. CS+ test.

Figure 3

Extinction in multiple contexts attenuates renewal of conditioned responding for ethanol. (A) Mean (± S.E.M.) normalized port-entries made during the CS+ (filled) and CS-(open) in discrimination training (DT) sessions with ethanol (Bars; averaged across the last 2 sessions) and extinction sessions without ethanol (symbols) when extinction occurred in a single context (left panel) or multiple contexts (right panel). *p<0.05, **p<0.0001, CS+ vs. corresponding CS-. (B) Mean (± S.E.M.) normalized port-entries for extinction (averaged across the last 2 sessions) and 1 renewal test session in the original training context without ethanol. *p<0.01, CS+ vs. corresponding CS-; ˆp<0.01, CS+ extinction vs. CS+ test; #p<0.01, CS+ single context vs. CS+ multiple contexts at test.

Figure 4

Renewal of conditioned responding for 14.2%, but not 2%, sucrose. (A & C) Mean (± S.E.M.) normalized port entries across session made during the CS+ (filled circles) and CS-(open circles) for rats trained with either 14.2% sucrose (A; 14S) or 2% sucrose (C; 2S). Discrimination training was conducted with sucrose in Context A (sessions 1-18) and extinction sessions without sucrose in Context B (sessions 19-27). *p<0.05, CS+ vs. corresponding CS- (B & D) Mean (± S.E.M) normalized port-entry data across the last 2 days of discrimination training, the last 2 days of extinction, and from the single session renewal test (CS+ filled bars; CS- open bars; Mean ) for rats trained with 14S (B) or 2S (D) *p<0.05, **p<0.01 CS+ vs. corresponding CS-; #p<0.001, CS+ training vs. CS+ extinction; ˆp< 0.01, CS+ extinction vs. CS+ test.