The effects of chronic continuous versus intermittent levodopa treatments on striatal and extrastriatal D1 and D2 dopamine receptors and dopamine uptake sites in the 6-hydroxydopamine lesioned rat--an autoradiographic study.
The effects of chronic 'continuous' infusion and 'intermittent' modes of levodopa/carbidopa administration on apomorphine induced circling behaviour, DA uptake sites (labelled with [3H]mazindol) and D1 and D2 DA receptor binding (labelled with [3H]SCH 23390 and [3H]sulpiride, respectively) were investigated in rats with unilateral 6-OHDA lesions of the medial forebrain bundle. The circling behaviour in response to apomorphine was greatly enhanced following chronic 'intermittent' but not 'continuous' levodopa treatments. Following the 'intermittent' regime, the lower dose of apomorphine induced a period of intense circling with delayed onset and rapid offset, than in rats given either 'continuous' infusion of levodopa or saline. The 6-OHDA lesion itself induced gross depletion of [3H]mazindol binding in all striatal subregions, NAc and OT, but not frontal cortex. [3H]Sulpiride binding in the ventrolateral striatal quadrant was increased on the denervated side and this correlated with the peak contralateral turns in response to 0.5 mg/kg apomorphine challenge. This asymmetry in striatal [3H]sulpiride binding was reduced in both groups of rats receiving levodopa. [3H]sulpiride binding in the NAc and OT and [3H]SCH 23390 binding in the striatum, NAc, OT and SNr were unaffected by DA denervation or either regime of levodopa treatments. 'Continuous' infusion and not 'intermittent' injections of levodopa reduced [3H]mazindol binding in the striatal subregions and the frontal cortex on both the denervated and intact sides. The potentiation of the behavioural response to apomorphine by chronic 'intermittent' levodopa treatment does not correspond with the levodopa induced alterations in striatal or extrastriatal DA receptors. In the same group of animals the narrowing of the duration of response to the lower dose of apomorphine may mimic the fluctuations in response to levodopa, seen clinically in long-term levodopa treated parkinsonian patients.
Gnanalingham
K K
KK
Department of Cell and Structural Biology, University of Manchester, UK.
Robertson
R G
RG
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008454:Mazindol / Q000493:pharmacokinetics; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects; D013469:Sulpiride / Q000493:pharmacokinetics
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D013469:Sulpiride; D016627:Oxidopamine; D008454:Mazindol; D001058:Apomorphine; D004298:Dopamine