Elsevier

Neuroscience

Volume 119, Issue 4, 16 July 2003, Pages 1045-1053
Neuroscience

Dopamine depletion abolishes apomorphine- and amphetamine-induced increases in extracellular serotonin levels in the striatum of conscious rats: a microdialysis study

https://doi.org/10.1016/S0306-4522(03)00219-7Get rights and content

Abstract

We investigated how serotonergic neurotransmission was affected by 6-hydroxydopamine (6-OHDA) lesioning of the adult rat brain dopamine (DA) system. In this animal model for Parkinson's disease (PD), the effect of destroying ascending DA pathways on extracellular levels of serotonin (5-HT) and 5-HT innervation in rat striatum were examined. Profound unilateral lesions of the nigrostriatal DA pathways were made by infusing 6-OHDA unilaterally into either the right medial forebrain bundle or the right substantia nigra. At 5 weeks after lesioning extracellular levels of DA and 5-HT were determined with microdialysis and high-pressure liquid chromatography under basal conditions and after systemic injections of apomorphine or amphetamine. DA nerve-terminal destruction and 5-HT innervation were determined with quantitative autoradiography. 6-OHDA lesioning reduced extracellular levels of DA below detection limits and led to statistically significant increases in extracellular 5-HT. Apomorphine, and amphetamine, respectively increased extracellular 5-HT to 8.2- and 2.2-fold above baseline levels in intact animals; these effects were absent in 6-OHDA-lesioned animals. Basal levels of [3H]paroxetine binding to 5-HT transporters in caudate-putamen increased by 41% in 6-OHDA-lesioned animals. These results suggest that 6-OHDA lesioning led to hyperinnervation of 5-HT nerve terminals and increases in basal extracellular 5-HT levels, but also to an unexplained loss of apomorphine and amphetamine-induced release of 5-HT. Addressing whether this impairment has significance in the onset of PD might lead to development of new strategies to manage parkinsonian symptoms.

Section snippets

Animals

Animal studies were performed in compliance with National Institutes of Health (NIH) guidelines, following review and approval by the institutional animal care and use committee (IACUC) at McLean Hospital. All efforts were made to minimize the number of animals used and their suffering. Sprague–Dawley rats initially weighing 200–225 g were purchased from Taconic Farms (Germantown, NY, USA), housed two per cage, kept on a 12-h light/dark cycle (on 07:00–19:00 h) with standard rat chow and water

Results

Baseline levels of DA and 5-HT in striatal dialysate from intact animals averaged 1.65±0.5 (N=16) and 0.15±0.04 (N=19) nM, respectively (Table 1). In 6-OHDA-lesioned animals baseline levels of DA in striatal dialysates were below detection levels and 5-HT averaged 0.59±0.2 (N=15) nM (Table 1). This was a significant increase (0.59 versus 0.20 nM, 31 df, t=−2.03, P=0.05) in baseline 5-HT levels in lesioned animals (Table 1).

Two-way ANOVA for 5-HT levels revealed a significant effect of lesion

Discussion

Apomorphine-induced striatal efflux of 5-HT was abolished in 6-OHDA-lesioned animals. d-Amphetamine also failed to increase 5-HT levels in 6-OHDA-lesioned animals. Our results are consistent with the hypothesis that DA has a stimulatory action on 5-HT neurotransmission in intact brain. Systemic apomorphine (0.5 mg/kg, s.c) was previously reported to increase 5-HT concentrations in dialysates from corpus striatum and hippocampus (Mendlin et al., 1998). Local administration of apomorphine (1–100

Acknowledgements

This work is supported by Udall Parkinson's Disease Research Center of Excellence grants P50 NS39793, NARSAD Young Investigator Award and Theodore and Vada Stanley Foundation. We also thank Dr. Lanya Hayden for her help in preparation of this manuscript and Dr. Ross Baldessarini for helpful comments.

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