Separable roles of the nucleus accumbens core and shell in context- and cue-induced alcohol-seeking

Abstract

Conditioned responding to drug-predictive discrete cues can be strongly modulated by drug-associated contexts. We tested the hypothesis that differential recruitment of the nucleus accumbens (NAc) core and shell mediates responding to drug cues in a drug vs non-drug context. Rats were trained to discriminate between two 10-s auditory stimuli: one stimulus (CS+) was paired with ethanol (10% v/v; 0.2 ml; oral) whereas the other (CS-) was not. Training occurred in operant conditioning chambers distinguished by contextual stimuli, and resulted in increased entries into the ethanol delivery port during the CS+ when compared with the CS-. In experiment 1, port entries were then extinguished in a second context by withholding ethanol, after which context-induced renewal of ethanol-seeking was tested by presenting both stimuli without ethanol in the previous training context. This manipulation stimulated strong responding to the CS+ in rats pretreated with saline in the core (n=9) or shell (n=10), which was attenuated by pharmacologically inactivating (muscimol/baclofen; 0.1/1.0 mM; 0.3 microl/side) either subregion pretest. In experiment 2, after discrimination, training rats were habituated to a different context in which ethanol and both stimuli were withheld. Cue-induced ethanol-seeking was then elicited by presenting the CS+ and CS- without ethanol in the different context. Saline-pretreated rats responded more to the CS+ than the CS- (core n=8; shell n=9), and inactivating the core but not shell attenuated this effect. These data highlight an important role for the core in cue-induced ethanol-seeking, and suggest that the shell is required to mediate the influence of contexts on conditioned ethanol-seeking.

Figure 1

Inactivating the NAc core reduces context-induced renewal of conditioned responding to an EtOH-predictive CS+. (a) Mean (±SEM) normalized port entries during the CS+ (filled symbols) and CS− (open symbols) during 19 Pavlovian discrimination training (PDT) sessions with 10% EtOH in context A and eight extinction (EXT) sessions in context B in which EtOH was withheld. (b) Mean (±SEM) normalized port entries to the CS+ (filled bars) and CS– (open bars) during EXT in context B and at test in context A after saline or M/B infusion. The EXT baseline represents data averaged for the last two sessions of two extinction epochs. Test data are averaged over a single test session. Filled triangles in this and subsequent figures represent difference scores, obtained by subtracting CS+ responding after M/B from CS+ responding after saline for individual rats. The horizontal line represents the mean difference score. ^p<0.01 CS+ saline vs CS+ EXT. ^*p<0.01 CS+ saline vs CS+ M/B.

Figure 2

Inactivating the NAc shell reduces context-induced renewal of conditioned responding to an EtOH-predictive CS+. (a) Mean (±SEM) normalized port entries during the CS+ (filled symbols) and CS− (open symbols) during 19 PDT sessions with EtOH in context A and eight EXT sessions in context B in which ethanol was withheld. (b) Mean (±SEM) normalized port entries during the CS+ (filled bars) and CS– (open bars) during EXT in context B and at test in context A after saline or M/B infusion. The EXT baseline represents data averaged for the last two sessions of two extinction epochs. Test data are averaged over a single test session. ^p<0.01 CS+ saline vs CS+ EXT. ^*p<0.01 CS+ saline vs CS+ M/B.

Figure 3

Inactivating the NAc core but not shell attenuates responding to the CS+ when it is paired with ethanol. Bars in (a) and (b) depict mean (±SEM) normalized port entries to the CS+ (filled) and CS– (open) after pre-session saline or M/B infusion during PDT in context A in which the CS+ is paired with ethanol. Data are averaged over a single test session. ^*p<0.05 CS+ saline vs CS+ M/B.

Figure 4

Inactivating the NAc core reduces conditioned responding to an EtOH-predictive cue presented in a context not associated with EtOH. (a) Mean (±SEM) normalized port entries during the CS+ (filled symbols) and CS− (open symbols) during 19 Pavlovian discrimination training sessions with ethanol in context A. (b) Mean (±SEM) normalized port entries to the CS+ (filled bars) and CS– (open bars) after saline or M/B pretreatment at test when the non-extinguished CS+ and CS− were presented without EtOH in context B. Data are averaged over a single test session. ^*p<0.05 CS+ saline vs CS+ M/B.

Figure 5

Inactivating the NAc shell does not affect conditioned responding to an EtOH-predictive cue presented in a context not associated with EtOH. (a) Mean (±SEM) normalized port entries during the CS+ (filled symbols) and CS− (open symbols) during 19 Pavlovian discrimination training sessions with ethanol in context A. (b) Mean (±SEM) normalized port entries to the CS+ (filled bars) and CS– (open bars) after saline or M/B infusion at test when the non-extinguished CS+ and CS− were presented without EtOH in context B. Data are averaged over a single test session.

Figure 6

Histological verification of injector tip placements in the NAc core and shell for rats in (a) Experiment 1a and 1b and (b) Experiment 2, according to the rat brain atlas of Paxinos and Watson (1997).