Alcohol self-administration: further examination of the role of dopamine receptors in the nucleus accumbens

Abstract

One of the functions of the mesolimbic dopamine (DA) system is to regulate the process of reinforcement, a process that is thought to influence drug self-administration. This study tested the effects of centrally administered DA receptor ligands on ethanol self-administration behavior. Long-Evans rats were trained to lever press on a fixed-ratio 4 schedule of ethanol (10% v/v) reinforcement. DA agonists and antagonists were then bilaterally microinjected (0.5 microliter/side) into the nucleus accumbens (N Acc) 10-min before sessions to test for effects on the onset, maintenance, and termination of ethanol self-administration. Infusions of the D1-like agonist SKF 38393 (0.03 to 3.0 micrograms) produced no effect on ethanol self-administration. The D1-like antagonist SCH 23390 (0.5 to 2.0 micrograms) reduced total responding by decreasing the time course of self-administration without altering response rate. The D2-like agonist quinpirole produced a biphasic effect on self-administration. Quinpirole (1.0 microgram) increased total responses and response rate, whereas higher doses (4.0 to 10.0 micrograms) decreased total responding as a result of early termination. The D2-like antagonist raclopride (0.1 to 1.0 microgram) reduced total responding by decreasing time course and response rate. Co-administration of either SKF 38393 or SCH 23390 with quinpirole prevented the behavioral effects observed with the low doses of quinpirole. Thus, in the N Acc either increased activation of D1-like receptors or their blockade can affect the expression of the behavioral effects of the D2-like agonist. This suggests that some intermediate level of D1 activation is required to observe the D2 effect. The decreases in total responding produced by raclopride were enhanced by co-administration of SKF 38393, but not altered by SCH 23390, thus suggesting that D1-like and D2-like receptors in the N Acc interact in the regulation of ethanol self-administration in a manner similar to their interactive regulation of other behaviors.

Fig. 1.

Mean number of ethanol-reinforced responses (top), time course of responding (middle), and response rate (bottom) for n = 10 animals plotted as a function of quinpirole dosage. Because the behavioral baseline shifted during the course of the experiment, data from control (C) sessions (no-injection and sham injection) from each corresponding weekly drug injection are shown on the left of the x-axis break. The left control point is for the lowest drug dose, the center control point for the middle drug dose, and the right control point for the highest drug dose. Error bars are ±SEM. * Significantly different from the appropriate no injection. † Significantly different from the appropriate sham control (p < 0.05, Student-Newman-Keuls test).

Fig. 2.

Mean number of ethanol-reinforced responses (top) and time course of responding (bottom) for n = 9 animals plotted as a function of SCH 23390 dosage. Because the behavioral baseline shifted during the course of the experiment, data from control (C) sessions (no-injection and sham injection) from each corresponding weekly drug injection are shown on the left of the x-axis break. The left control point is for the lowest drug dose, the center control point for the middle drug dose, and the right control point for the highest drug dose. Error bars are ±SEM. * Significantly different from no injection, † Significantly different from sham control (p < 0.05, Student-Newman-Keuls test).

Fig. 3.

Mean number of ethanol-reinforced responses (top), time course of responding (middle), and response rate (bottom) for n = 9 animals plotted as a function of quinpirole dosage when co-administered with SKF 38393. Because the behavioral baseline shifted during the course of the experiment, data from control (C) sessions (no-injection and sham injection) from each corresponding weekly drug injection are shown on the left of the x-axis break. The left control point is for the lowest drug dose, the center control point for the middle drug dose, and the right control point for the highest drug dose. Error bars are ±SEM. * Significantly different from no injection. † Significantly different from sham control (p < 0.05, Student-Newman-Keuls test).

Fig. 4.

Mean number of ethanol-reinforced responses (top), time course of responding (middle), and response rate (bottom) for n = 9 animals plotted as a function of quinpirole doseage when co-administered with SCH 23390. Because the behavioral baseline shifted during the course of the experiment, data from control (C) sessions (no-injection and sham injection) from each corresponding weekly drug injection are shown on the left of the x-axis break. The left control point is for the lowest drug dose, the center control point for the middle drug dose, and the right control point for the highest drug dose. Error bars are ±SEM. * Significantly different from no injection. † Significantly different from sham control (p < 0.05, Student-Newman-Keuls test).

Fig. 5.

Mean number of ethanol-reinforced responses (top), time course of responding (middle), and response rat (bottom) for n = 8 animals plotted as a function of raclopride (Rac) dosage, and when co-administered with SKF 38393 and SCH 23390. Error bars are ±SEM. * Significantly different from sham injection control. † Significantly different from raclopride alone (p < 0.05, Student-Newman-Keuls test). Nl, no injection control; SH, sham injection control.