A switch in the neuromodulatory effects of dopamine in the oval bed nucleus of the stria terminalis associated with cocaine self-administration in rats

Abstract

Chronic exposure to drugs of abuse alters brain reward circuits and produces functional changes in the dopamine (DA) system. However, it is not known whether these changes are directly related to drug-driven behaviors or whether they simply are adaptive responses to long-term drug exposure. Here, we combined the rat model of cocaine self-administration with brain slice electrophysiology to identify drug-use related alterations in the neuromodulatory effects of DA in the oval bed nucleus of the stria terminalis (ovBST), a robust DA terminal field. Long-Evans rats self-administered cocaine intravenously (0.75 mg/kg/injection) for an average of 15 d, on reward-lean or -rich schedules of reinforcement. Brain slice recordings conducted 20 h after the last self-administration session revealed a reversal of the neuromodulatory effect of DA on GABA(A)-IPSCs. Specifically, the effect of DA switched from a D2-mediated decrease in drug-naive rats to a D1-receptor-mediated increase in GABA(A)-IPSC in cocaine self-administering rats. Furthermore, the switch in DA modulation of GABA(A)-IPSC remained after a 30 d withdrawal period. In contrast, this switch was not observed after the acquisition phase of cocaine self-administration, when rats received cocaine passively, or in rats maintaining sucrose self-administration. Therefore, our study reveals a reversal in the effects of DA on inhibitory transmission, from reduction to enhancement, in the ovBST of cocaine self-administering rats. This change was unique to voluntary intake of cocaine and maintained after a withdrawal period, suggesting a mechanism underlying the maintenance of cocaine self-administration and perhaps craving during drug-free periods.

Figure 1.

Brain slice recordings of evoked whole-cell postsynaptic currents in the rat ovBST. A, Schematic illustration of the experimental procedures for ovBST (shaded area in the inset) GABA_A-IPSC and AMPA-EPSC measurements. B, Representative traces showing evoked whole-cell GABA_A-IPSC (B1) and AMPA-EPSC (B2) in brain slices from three representative experimental groups. Two electrical stimuli were applied at 50 ms interval to calculate PPRs (S2/S1). C1, Bar graph summarizing PPR_{50 ms} of evoked GABA_A-IPSC and AMPA-EPSC. C2, Bar graph summarizing the incidence of ovBST neurons displaying PPF (bottom part of bars) or PPD (top part of bars).

Figure 2.

Effects of DA on GABA_A-IPSC. A, Representative traces showing the effects of bath-applied DA on the amplitude of evoked GABA_A-IPSC in brain slices from control (A1), sucrose (A2), and cocainePR (A3) rats. B, Bar graphs summarizing the effect of DA on the amplitude (B1) and PPR (B2) of evoked GABA_A-IPSC. *Significantly different from 0 (amplitude) or 1 (PPR); two-tailed Student's t tests, p < 0.001. ^†Significantly different from control, sucrose, acquisition, and yoked; one-way ANOVA, p < 0.01. Numbers indicate the number of neurons (above) and rats (below), respectively. C, Dot plots summarizing CV analyses of the effects of DA (0.1–30 μm) on evoked GABA_A-IPSC in brain slices from control (C1), sucrose (C2), and cocainePR (C3) rats. Dot plots show r [(1/CV_drug²)/(1/CV_baseline²)] as a function of π (Peak amplitude_drug/Peak amplitude_baseline).

Figure 3.

D2R-mediated effects of DA on GABA_A-IPSC. A, Representative traces showing the effects of the D2R agonist quinpirole (1 μm) on evoked GABA_A-IPSC in brain slices from control (A1) and cocainePR (A2) rats. B, Bar graph summarizing the effect of quinpirole on amplitude (B1) and PPR (B2) of GABA_A-IPSC. C, Bar chart summarizing the effect of DA (1 μm) on the amplitude of evoked GABA_A-IPSC in the presence of the D2R antagonist sulpiride (10 μm). *Significantly different from 0 (amplitude) or 1 (PPR); two-tailed Student's t tests, p < 0.001. ^†Significantly different from control, sucrose, acquisition, and yoked; one-way ANOVA, p < 0.05. Numbers indicate the number of neurons (above) and rats (below), respectively.

Figure 4.

D1R-mediated effects of DA on GABA_A-IPSC. A, Bar graph summarizing the effects of the D1R agonist SKF-81297 on the amplitude of GABA_A-IPSC. B, Dot plot (representative experiment) showing the effect of DA on the amplitude of GABA_A-IPSC as a function of time in the absence (open circles) or presence (closed circles) of the D1R antagonist SCH-23390 (10 μm). Black bar indicates bath application of DA. C, Bar chart summarizing the effect of DA (1 μm) on the amplitude of evoked GABA_A-IPSC in the presence of the D1R antagonist SCH-23390 (10 μm). *Significantly different from 0 (amplitude) or 1 (PPR); two-tailed Student's t tests, p < 0.001. ^†Significantly different from all other groups; one-way ANOVA, p < 0.05. Numbers indicate the number of neurons (above) and rats (below), respectively.

Figure 5.

Effect of DA on AMPA-EPSC. A, Representative traces showing the effect of DA on evoked AMPA-EPSC in the ovBST of control (A1) and cocainePR (A2) rats. B, Bar graphs summarizing the effect of DA on the change in amplitude (B1) and PPR (B2) of evoked AMPA-EPSC. *Significantly different from 0 (amplitude) or 1 (PPR); two-tailed Student's t tests, p < 0.005. C, Dot plot showing CV analyses of the effect of DA (1–30 μm) on evoked AMPA-EPSC. D, Representative traces showing the effect of NA on evoked AMPA-EPSC in the ovBST of control (D1) and cocainePR (D2) rats. E, Bar graphs summarizing the effects of NA on the change in amplitude (E1) and paired-pulse ratios (E2) of evoked AMPA-EPSC. *Significantly different from 0 (amplitude) or 1 (PPR); two-tailed Student's t tests, p < 0.001. F, Dot plot showing CV analyses of the effect of NA (0.1–10 μm) on evoked AMPA-EPSC in both control and cocainePR groups.