Kappa-opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration

Abstract

Our study examined ethanol self-administration and accumbal dopamine concentration during kappa-opioid receptor (KOPr) blockade. Long-Evans rats were trained to respond for 20 min of access to 10% ethanol (with sucrose) over 7 days. Rats were injected s.c. with the long-acting KOPr antagonist, nor-binaltorphimine (NOR-BNI; 0 or 20 mg/kg) 15-20 h prior to testing. Microdialysis revealed a transient elevation in dopamine concentration within 5 min of ethanol access in controls. NOR-BNI-treated rats did not exhibit this response, but showed a latent increase in dopamine concentration at the end of the access period. The rise in dopamine levels correlated positively with dialysate ethanol concentration but not in controls. NOR-BNI did not alter dopamine levels in rats self-administering 10% sucrose. The transient dopamine response during ethanol acquisition in controls is consistent with previous results that were attributed to ethanol stimulus cues. The altered dopamine response to NOR-BNI during ethanol drinking suggests that KOPr blockade temporarily uncovered a pharmacological stimulation of dopamine release by ethanol. Despite these neurochemical changes, NOR-BNI did not alter operant responding or ethanol intake, suggesting that the KOPr is not involved in ethanol-reinforced behavior under the limited conditions we studied.

Fig. 1

Coronal brain sections indicating microdialysis probe placement within the nucleus accumbens. Lines denote the active dialysis regions. Numerals below the sections denote the position of the slice in relation to Bregma. Figure was adapted fromPaxinos and Watson (1998).

Fig. 2

Effect of NOR-BNI pretreatment (20 mg/kg) on U50488H-induced suppression of basal dopamine concentration in the nucleus accumbens. NOR-BNI pretreatment occurred 15–20 h prior to the experiment. Microdialysis perfusion of the accumbens with U50488H (0.4 μM) reduced basal dopamine levels in the control group. NOR-BNI pretreatment effectively blocked this effect. The U50 (0.4 μM) group showed a significant effect of time (p < 0.05), denoted by the asterisks, whereas the U50 (0.4 μM) group pretreated with NOR-BNI did not. Each point represents the mean ± sem (n = 4 for each group).

Fig. 3

Effect of NOR-BNI (20 mg/kg) or saline (CONTROL) pretreatment on extracellular accumbal dopamine concentration during operant self-administration of 10% ethanol (plus 10% sucrose). Wait refers to the time in which the rat was in the operant chamber prior to access of the drinking solution. Lever press (open arrow) is the time at which operant responding occurred. Drink refers to the 20-min ethanol access period free of operant responding. Post-drink refers to the 20-min period in which the rat remained in the chamber in the absence of the ethanol solution. Dopamine concentration increased significantly within 5 min of ethanol access for the CONTROL group and returned to basal levels thereafter. The NOR-BNI group displayed no change in dopamine concentration initially, followed by a transient elevation at the end of the drink period. Each point represents the mean ± sem (n = 8 for the saline control group; n = 7 for the NOR-BNI group). Asterisk denotes significance compared with the wait period by post hoc simple contrasts (p < 0.05).

Fig. 4

Dialysate ethanol concentrations (mM) from the nucleus accumbens following ethanol access for the NOR-BNI and saline CONTROL groups. Ethanol was analyzed from the same samples in which dopamine concentrations were measured. Both treatment groups showed very comparable ethanol pharmacokinetics. Peak dialysate ethanol levels were reached after the third sample of the drinking period. Each point is the mean ± sem.

Fig. 5

Ethanol/sucrose (panel A) and sucrose (panel B) consumption (spout licks) during each 5-min interval of the 20-min ethanol access period. CONTROL and NOR-BNI-treated animals showed very similar patterns of ingestion across all periods. The majority of ethanol/sucrose or sucrose consumption occurred within the first 5–10 min. Each plot is the mean ± sem.

Fig. 6

Effect of NOR-BNI (20 mg/kg) or saline (CONTROL) pretreatment on extracellular accumbal dopamine concentration during operant self-administration of 10% sucrose. Wait refers to the time in which the rat was in the operant chamber prior to access of the drinking solution. Lever press (open arrow) is the time at which operant responding occurred. Drink refers to the 20-min ethanol access period free of operant responding. Post-drink refers to the 20-min period in which the rat remained in the chamber in the absence of the ethanol solution. Dopamine concentrations during the drink and post-drink periods were not significantly different from basal levels in either group (p > 0.05). Each point represents the mean ± sem (n = 6 for each group).