5-HT2C receptor antagonists enhance the behavioural response to dopamine D1 receptor agonists in the 6-hydroxydopamine-lesioned rat

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Abstract

Non-dopaminergic therapies are of potential interest in the treatment of Parkinson's disease given the complications associated with current dopamine-replacement therapies. In this study we demonstrate that SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrol[2,3-f]indole) (20 mg/kg) enhanced the actions of the dopamine D1 receptor agonist, SKF 82958 ((+)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) (1 mg/kg), in eliciting locomotion in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. This action was only seen following prior priming with l-DOPA (l-3,4-dihydroxyphenylalanine). SB 206553 had no effect on rotational behaviour when given alone. 5-HT2C receptor antagonists may have potential as a means of reducing reliance on dopamine replacement in the treatment of Parkinson's disease.

Introduction

Dopamine replacement, with the precursor l-3,4-dihydroxyphenylalanine (l-DOPA), is the predominant treatment of Parkinson's disease. Unfortunately, long-term treatment results in the emergence of side effects. The severity of these side effects are related to the duration and cumulative dose of dopamine replacement (Nutt, 1990). Thus, a potentially useful strategy for the treatment of Parkinson's disease would be to define approaches that reduce the dose of dopamine replacement, or replace it entirely, yet still maintain full anti-parkinsonian efficacy (Brotchie, 1997).

Parkinsonian symptoms occur as a result of excessive inhibition of thalamo-cortical circuits secondary to overactivity of the substantia nigra pars reticulata and medial globus pallidus Albin et al., 1989, Alexander et al., 1990, Brotchie et al., 1991. These structures together form the output regions of the basal ganglia. 5-HT2C receptors are found in high concentrations within the substantia nigra pars reticulata Pazos et al., 1987, Mengod et al., 1990 and are excitatory (Rick et al., 1995). Thus, stimulation of 5-HT2C receptors may contribute to overactivity of the SNR in parkinsonism. We have previously demonstrated that the selective 5-HT2C receptor antagonist, SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrol[2,3-f]indole) (Forbes et al., 1995) induces a contraversive rotational response when infused into the substantia nigra pars reticulata on the dopamine-depleted side of the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (Fox et al., 1998). Such behaviour represents a reduction in activity of basal ganglia outputs and can be taken as representing a potential anti-parkinsonian action. No rotational response was seen following infusion into the dopamine-intact side, suggesting that activation of 5-HT2C receptors in the substantia nigra pars reticulata occurs in the parkinsonian but not the normal basal ganglia. In keeping with this idea that abnormalities of 5-HT2C transmission within the substantia nigra pars reticulata may occur in parkinsonism are our preliminary findings that 5-HT2C receptor binding is increased in patients with Parkinson's disease (Fox and Brotchie, 1996b). In addition, systemic administration of selective 5-HT2C receptor antagonists, normethylclozapine, SB 200646A (N-(1-methyl-5-indolyl)-N′-(3-pyridyl)urea hydrochloride) or SB 206553, enhances the action of the dopamine D2 receptor agonist, quinpirole in the 6-hydroxydopamine-lesioned rat Fox and Brotchie, 1996a, Fox et al., 1998.

Current directly acting dopamine receptor agonists used in the treatment of Parkinson's disease predominantly act at dopamine D2 receptors, e.g. ropinirole, cabergoline, pramipexole (Watts, 1997). However, there is growing evidence that dopamine D1 receptor agonists may also be useful in the treatment of Parkinson's disease Blanchet et al., 1993, Brefel et al., 1997. Indeed, the greater efficacy of l-DOPA over selective dopamine D2 receptor agonists may be a result of a synergistic effect of dopamine D1 and D2 receptor-mediated action (Walters et al., 1987).

In this study, we investigate the ability of the selective 5-HT2C receptor antagonist, SB 206553 to enhance the anti-parkinsonian action of the dopamine D1 receptor agonist, SKF 82958 ((+)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) (O'Boyle et al., 1989).

Section snippets

6-Hydroxydopamine lesioning

Male Sprague–Dawley rats (260–280 g, Manchester University, BSU) were anaesthetised with sodium pentobarbitone (60 mg/kg i.p.), 30 min following pre-medication with pargyline (5 mg/kg) and desiprimine (25 mg/kg). 12.5 μg of 6-hydroxydopamine·HCl (in 2.5 μl, 0.02% ascorbic acid) was then infused into the right medial forebrain bundle, using routine stereotaxic procedures (co-ordinates, +2 mm right, −2.8 mm posterior, 9 mm vertical to skull from bregma, according to Paxinos and Watson, 1996).

6-Hydroxydopamine lesion efficacy

All animals included in the statistical analysis showed greater than 200 rotations per hour contraversive to the 6-hydroxydopamine lesion, following treatment with l-DOPA-methyl ester (50 mg/kg) and benserazide (25 mg/kg). Mean rotations contraversive to the lesioned side were 371.0±16.7 per hour. The mean rotational response was not significantly different between any treatment group, P>0.05, ANOVA, F(3,19)=0.2349, unprimed groups and P>0.05, ANOVA, F(3,16)=0.9051 primed groups.

Behavioural effects of SB 206553 alone and in combination with SKF 82958

In the

Methodological considerations

All animals included in the statistical analysis had a behavioural response of greater than 200 rotations contraversive to the lesioned side per hour following challenge with l-DOPA methyl ester (100 mg/kg). This has previously been shown to indicate greater than 90% loss of striatal dopaminergic terminals, as measured by tyrosine hydroxylase immunoreactivity and [3H] mazindol binding Papa et al., 1994, Thomas et al., 1994, Duty and Brotchie, 1997. There was no significant difference in the

Acknowledgements

This work was funded by the Parkinson's Disease Society (UK) and the Medical Research Council (UK). The authors wish to thank Dr. T. Blackburn, SmithKline Beecham Pharmaceuticals for the generous gift of SB 206553.

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