Alterations in the turnover rate of dopamine D1 but not D2 receptors in the adult rat neostriatum after a neonatal dopamine denervation

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Abstract

Adult rats that were treated with intracerebral ventricular injection of 6-hydroxydopamine (6-OHDA) as neonates exhibit a profound loss of nigrostriatal dopamine innervation in addition to a variety of other neurochemical and anatomical changes, including alterations in the number of neostriatal D1 and D2 receptor binding sites. In the present study, the turnover of neostriatal dopamine D1 and D2 receptors was measured in rats previously treated with 6-OHDA or ascorbic acid vehicle as neonates at various time intervals after peripheral N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 10 mg/kg) administration. Dopamine receptors were labelled with [3H]SCH23390 (D1) and [3H]raclopride (D2), while the degree of dopamine denervation was assessed by the measurement of neostriatal dopamine, homovanillic acid and dihydroxyphenylacetic acid content. Two days after acute EEDQ treatment, the maximal binding capacity (Bmax) of [3H]SCH23390 and [3H]raclopride binding was significantly decreased to 58 and 32% of control values, respectively, without any significant alteration in their equilibrium dissociation constants (Kd). A time-dependent increase in the density of [3H]SCH23390 and [3H]raclopride binding was observed in both treatment groups following a single dose of EEDQ. The rate of recovery of D1 receptors was significantly slower in the 6-OHDA-lesioned animals as compared to controls with a half-life of 103 compared to 53 h, respectively. No differences were observed in the rate of recovery of D2 receptors in these two treatment groups. These data are consistent with the findings of decreased expression of D1 receptors in neonatal 6-OHDA-lesioned rats owing to decreased receptor synthesis, and further suggest that in this model the up-regulation of D2 receptors is a result of a post-transcriptional mechanism, such as an increased rate of post-synthetic maturation.

Section snippets

Neonatal 6-OHDA injections and tissue preparation.

Female Sprague–Dawley rats (Charles River; Montreal, Quebec) were purchased pregnant and individually housed under a fixed light/dark cycle with free access to food and water. All animal use procedures were in strict accordance with the Canadian Council on Animal Care Guide for the Care and Use of Experimental Animals, and all protocols were approved by the Comité de déontologie pour l'expérimentation animale of the Université de Montréal, and the Comité Institutionnel pour la Protection des

Dopamine denervation

As expected, the neonatal 6-OHDA administration resulted in profound reductions in the levels of neostriatal DA and its major metabolites DOPAC and HVA 3 months after lesion, as compared to sham-lesioned rats (Table 1). Interestingly, acute EEDQ treatment in adult rats (3 months old) that had received a sham-lesion also significantly reduced the concentration of striatal DA and DOPAC compared to animals that had received an injection of saline in place of EEDQ. In contrast, no significant

Discussion

The present study demonstrated significant decreases in the rate of repopulation kinetics of dopamine D1 receptors in the rostral neostriatum of adult rats subjected to severe nigrostriatal 6-OHDA denervation as neonates. This decreased rate of receptor synthesis and degradation was associated with an overall decrease in D1 receptor binding. In contrast, no significant differences were found in the repopulation kinetics of neostriatal D2 receptor between 6-OHDA and sham-lesioned animals,

Acknowledgements

This study was funded by a summer studentship from the Natural Sciences and Engineering Research Council of Canada (M. P.), and a Scholarship and Establishment Grant (K. M. D.) from the Fonds de la recherche en santé du Québec, as well as by grant MT-12966 (T. A. R.) from the Medical Research Council of Canada. The authors wish to acknowledge the excellent technical assistance of Louise Grondin and Patricia Bonnot.

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