preproenkephalin and ropinirole

L-dopa induced dyskinesia is a complication of long-term L-dopa administration in patients with Parkinson's disease. This study uses the rodent model of dyskinesia to determine whether prior dopamine agonist treatment causes long-term changes that influence the development of L-dopa mediated behaviours. Rats with unilateral 6-OHDA lesions were injected with dopamine agonists (ropinirole, piribedil bromocriptine, all 1mg/kg) or saline (0.9%) daily for 21 days. Following a 1-week drug free interval L-dopa was administered for 15 days (10mg/kg with benserazide 15 mg/kg in saline s.c.). Rotational behaviour and abnormal involuntary movements (AIMs) were recorded at regular intervals. All dopamine agonists induced a contralateral rotational response on day 1, which increased in response to repeated administration but did not by themselves induce overt dyskinesias. On day 1 of L-dopa administration animals pre-treated with piribedil and ropinirole produced a more severe rotational response. In the saline pre-treated group, AIMs developed with repeated L-dopa administration, which was reflected in the increased expression of PPE-B mRNA. There was a trend for the same pattern in the dopamine agonist treated groups but this was non-significant. Therefore, while locomotor sensitivity is altered by the pre-treatment with dopamine agonists, there appears to be no increased risk of developing AIMs.

Topics: Animals; Antiparkinson Agents; Bromocriptine; Corpus Striatum; Dopamine Agonists; Dyskinesia, Drug-Induced; Enkephalins; Female; Indoles; Levodopa; Oxidopamine; Parkinsonian Disorders; Piribedil; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rotation; Time Factors

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), remains the most common treatment for Parkinson's disease. However, following long-term treatment, disabling side effects, particularly L-DOPA-induced dyskinesias, are encountered. Conversely, D2/D3 dopamine receptor agonists, such as ropinirole, exert an anti-parkinsonian effect while eliciting less dyskinesia when administered de novo in Parkinson's disease patients. Parkinson's disease and L-DOPA-induced dyskinesia are both associated with changes in mRNA and peptide levels of the opioid peptide precursors preproenkephalin-A (PPE-A) and preproenkephalin-B (PPE-B). Furthermore, a potential role of abnormal opioid peptide transmission in dyskinesia is suggested due to the ability of opioid receptor antagonists to reduce the L-DOPA-induced dyskinesia in animal models of Parkinson's disease. In this study, the behavioural response, striatal topography and levels of expression of the opioid peptide precursors PPE-A and PPE-B were assessed, following repeated vehicle, ropinirole, or L-DOPA administration in the 6-OHDA-lesioned rat model of Parkinson's disease. While repeated administration of L-DOPA significantly elevated PPE-B mRNA levels (313% cf. vehicle, 6-OHDA-lesioned rostral striatum; 189% cf. vehicle, 6-OHDA-lesioned caudal striatum) in the unilaterally 6-OHDA-lesioned rat model of Parkinson's disease, ropinirole did not. These data and previous studies suggest the involvement of enhanced opioid transmission in L-DOPA-induced dyskinesia and that part of the reason why D2/D3 dopamine receptor agonists have a reduced propensity to elicit dyskinesia may reside in their reduced ability to elevate opioid transmission.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Dyskinesia, Drug-Induced; Enkephalins; Gene Expression; In Situ Hybridization; Indoles; Levodopa; Male; Motor Activity; Opioid Peptides; Oxidopamine; Parkinsonian Disorders; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Synaptic Transmission

Chronic administration of L-DOPA to MPTP-treated common marmosets induces marked dyskinesia while repeated administration of equivalent antiparkisonian doses of ropinirole and bromocriptine produces only mild involuntary movements. The occurrence of dyskinesia has been associated with an altered balance between the direct and indirect striatal output pathways. Using in situ hybridisation histochemistry, we now compare the effects of these drug treatments on striatal preproenkephalin-A (PPE-A) and adenosine A(2a) receptor mRNA expression as markers of the indirect pathway and striatal preprotachykinin (PPT) mRNA and preproenkephalin-B (PPE-B, prodynorphin) mRNA expression as markers of the direct pathway.The equivalent marked losses of specific [3H]mazindol binding in the striatum of all drug treatment groups confirmed the identical nature of the nigral cell loss produced by MPTP treatment. MPTP-induced destruction of the nigro-striatal pathway markedly increased the level of PPE-A mRNA in the caudate nucleus and putamen and decreased the levels of PPT and PPE-B mRNA relative to normal animals. Repeated treatment with L-DOPA for 30 days produced marked dyskinesia but had no effect on the MPTP-induced increase in PPE-A mRNA in the caudate nucleus and putamen. In contrast, L-DOPA treatment normalised the MPTP-induced decrease in the level of PPT and PPE-B mRNA. Repeated treatment with ropinirole produced little or no dyskinesia but markedly reversed the MPTP-induced elevation in PPE-A mRNA in the caudate nucleus and putamen. However, it had no effect on the decrease in PPT or PPE-B mRNA. Similarly, bromocriptine treatment which induced only mild dyskinesia attenuated the MPTP-induced elevation in PPE-A mRNA in the caudate nucleus and putamen with no effect on reduced striatal PPT or PPE-B mRNA. Neither MPTP treatment nor treatment with L-DOPA, bromocriptine or ropinirole had any effect on adenosine A(2a) receptor mRNA in the striatum. These patterns of alteration in striatal PPE-A and PPT and PPE-B mRNA produced by L-DOPA, bromocriptine and ropinirole show differential involvement of markers of the direct and indirect striatal output pathways related to improvement of locomotor activity and mirror the relative abilities of the drugs to induce dyskinesia.

Topics: Animals; Antiparkinson Agents; Bromocriptine; Callithrix; Dopamine Uptake Inhibitors; Dyskinesia, Drug-Induced; Enkephalins; Female; Indoles; Levodopa; Male; Mazindol; Neostriatum; Neural Pathways; Neuropeptides; Parkinsonian Disorders; Protein Precursors; Receptors, Purinergic P1; RNA, Messenger; Tachykinins