Opposite change of in vivo dopamine release in the rat nucleus accumbens and striatum that follows electrical stimulation of dorsal raphe nucleus: role of 5-HT3 receptors

Abstract

In the present study we investigate, using in vivo microdialysis, the involvement of central 5-HT3 receptors in the effect of dorsal raphe nucleus (DRN) electrical stimulation on dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindole-3-acetic acid (5-HIAA) extracellular levels monitored in the nucleus accumbens and the striatum of halothane-anesthetized rats. DRN stimulation (300 microA, 1 msec at 3, 5, 10, and 20 Hz for 15 min) induced a frequency-dependent increase of accumbal DA release and a concomitant reduction of DA release in the ipsilateral striatum at 20 Hz. In both structures DOPAC and 5-HIAA dialysate contents were enhanced in a frequency-dependent manner. Central serotonin (5-HT) depletion, induced by intra-raphe injections of 5, 7-dihydroxytryptamine neurotoxin, abolished the effect of 20 Hz DRN stimulation on DA, DOPAC, and 5-HIAA extracellular levels in both regions. The 5-HT synthesis inhibitor para-chlorophenylalanine (3 x 400 mg/kg, i.p., for 3 d), although preventing the effect on DA release, failed to modify significantly the effect of 20 Hz DRN stimulation on DOPAC and 5-HIAA outflow in both structures. Ondansetron (0.1 and 1 mg/kg) and (S)-zacopride (0.1 mg/kg), two 5-HT3 antagonists, significantly impaired the increase of accumbal DA release induced by 20 Hz DRN stimulation but did not affect either the decrease of striatal DA release or the increase in DOPAC outflow in both structures. These results indicate that an enhancement of central 5-HT transmission induced by DRN stimulation differentially affects striatal and accumbal DA release and that endogenous 5-HT, via its action on 5-HT3 receptors, exerts a facilitatory control restricted to the mesoaccumbal DA pathway.

Fig. 1.

Photomicrographs from cresyl violet-stained coronal brain sections through the nucleus accumbens (NAC) (A), the striatum (B), and the dorsal raphe nucleus (DRN) (C), showing the tracks left by the microdialysis probes and the electrode. Two microdialysis probes were implanted simultaneously within the right NAC (2-mm-membrane long) and the right striatum (3-mm-membrane long) by stereotaxic surgery. Thereafter, a bipolar concentric electrode was lowered stereotaxically into the DRN (see Materials and Methods).Arrows indicate the tracks left by the microdialysis membrane and the tip of the electrode corresponding to the stimulation site within the DRN.

Fig. 2.

Time course of the effect of dorsal raphe nucleus (DRN) electrical stimulation at 3, 5, 10, and 20 Hz on DA, DOPAC, and 5-HIAA extracellular levels in the rat nucleus accumbens (NAC) and striatum. Each data pointrepresents the mean percentage ± SEM of baseline values calculated from three samples before DRN stimulation, performed for a 15 min period as indicated by the horizontal bar. Each experiment was performed on five or six animals per group. *p < 0.05 and **p < 0.01 as compared with the sham-stimulated group (unfilled circles) for each time point (Dunnett’s test).

Fig. 3.

Time course of the effect of 20 Hz dorsal raphe nucleus (DRN) electrical stimulation on DA and DOPAC extracellular levels in the nucleus accumbens (NAC) and the striatum in sham-operated (unfilled circles) and 5,7-dihydroxytryptamine-lesioned (5,7-DHT, filled squares) rats. Each data point represents the mean percentage ± SEM of baseline values calculated from three samples before DRN stimulation, performed for a 15 min period as indicated by the horizontal bar. Each experiment was performed on five animals per group 18–21 d after intra-DRN injection of vehicle or 5,7-DHT. 5,7-DHT treatment reduced the overall effect of DRN stimulation on DA and DOPAC extracellular levels in both the NAC and the striatum (see Results). *p < 0.05 and **p < 0.01 as compared with the sham-operated group for each time point (Student’s t test).

Fig. 4.

Time course of the effect of 20 Hz dorsal raphe nucleus (DRN) electrical stimulation on DA and DOPAC extracellular levels in the nucleus accumbens (NAC) and the striatum in saline-treated (unfilled circles) andpara-chlorophenylalanine-treated (pCPA, filled squares) rats. Eachdata point represents the mean percentage ± SEM of baseline values calculated from three samples before DRN electrical stimulation, performed for a 15 min period as indicated by thehorizontal bar. Each experiment was performed on five or six animals per group 24 hr after the last injection of saline or pCPA. In both the NAC and the striatum, pCPA treatment reduced the overall effect of DRN stimulation on DA, but not on DOPAC, extracellular levels (see Results). *p < 0.05 and **p < 0.01 as compared with the saline group for each time point (Student’s t test).

Fig. 5.

Time course of the effect of 20 Hz dorsal raphe nucleus (DRN) electrical stimulation on DA extracellular levels in the nucleus accumbens (NAC) and the striatum in saline- and ondansetron-treated rats. Each column represents the mean percentage ± SEM of the results from four to six animals per group of the three dialysate fractions collected during and after DRN stimulation, performed during the first dialysate fraction (15 min). Ondansetron, subcutaneously injected at 0.1 or 1 mg/kg 30 min before DRN stimulation, significantly reduced the overall effect of DRN stimulation on DA release only in the NAC (p< 0.05 and p < 0.01, respectively, two-way ANOVA; see Results). ***p < 0.001 versus the sham stim + saline group; ^#p < 0.05, ^##p < 0.01, and^###p < 0.001 versus the 20 Hz stim + saline group; °p < 0.05 versus the sham stim + ondansetron 0.1 group;⁺p < 0.05 and⁺⁺p < 0.01 versus the sham stim + ondansetron 1 group (Tukey’s test for each time point).

Fig. 6.

Time course of the effect of 20 Hz dorsal raphe nucleus (DRN) electrical stimulation on DA and DOPAC extracellular levels in the nucleus accumbens (NAC) and the striatum in saline- and (S)-zacopride-treated rats. Eachcolumn represents the mean percentage ± SEM of the results from four to six animals per group of the three dialysate fractions collected during and after DRN stimulation, performed during the first dialysate fraction (15 min). (S)-zacopride, subcutaneously injected at 0.1 mg/kg 30 min before DRN stimulation, significantly reduced the overall effect of DRN stimulation on DA release only in the NAC (p < 0.01, two-way ANOVA; see Results). ***p < 0.001 versus the sham stim + saline group; ^##p < 0.01 and^###p < 0.001 versus the 20 Hz stim + saline group; ⁺p < 0.05 versus the sham stim + (S)-zacopride 0.1group (Tukey’s test for each time point).