title: Signal transduction pathway activity compensates dopamine D₂/D₃ receptor density changes in Parkinson's disease: a preliminary comparative human brain receptor autoradiography study with [³H]raclopride and [³⁵S]GTPγS.
abstract: The degeneration of dopaminergic nigrostriatal pathway in Parkinson's disease (PD) results in alterations of the dopamine receptor system. In the present study we have investigated the relationship between the disease related changes of expressed dopamine D₂/D₃ receptor density and the corresponding intracellular signal transduction route in cortical and sub-cortical brain structures in the human brain. Dopamine D₂/D₃ receptor autoradiography (ARG), using [³H]raclopride, and agonist stimulated [³⁵S]GTPγS (guanosine 5'-O-[γ-thio]triphosphate) binding autoradiography have been performed in human striatum, cingulate gyrus and medial frontal gyrus samples obtained from six deceased PD patients and six age matched control subjects. Receptor densities were expressed as fmol/gram tissue protein for [³H]raclopride; agonist stimulated [³⁵S]GTPγS binding was expressed in fmol/gram tissue and its change was expressed in percentage values above basal binding. Our results indicate that whereas there is a decrease of the dopamine D₂/D₃ receptors in the striatum demonstrated by classical receptor autoradiography (controls and PD: 24.08±2.06 fmol/gram (mean±SEM) and 18.43±2.82 fmol/gram, respectively; p<0.05), the corresponding agonist stimulated [³⁵S]GTPγS binding autoradiography shows unchanged basal [³⁵S]GTPγS binding (controls and PD: 199±17 fmol/g and 198±21 fmol/g, respectively; n.s.) and, at the same time, no change in stimulation (controls and PD: 0.40±4.57% and 1.51±2.27%, respectively; n.s.). In cingular gyrus and medial frontal gyrus neither the dopamine D₂/D₃ receptor densities nor the [³⁵S]GTPγS binding displayed significant differences between PD and age matched control brain samples, whereas the [³⁵S]GTPγS binding values were markedly higher in PD. These preliminary findings may indicate a possible compensatory mechanism in striatal regions of PD brains: the loss of the dopamine receptors in the striatum appears to be compensated by an increased post-synaptic intracellular signal transduction route activity. However, the accurate interpretation of the present findings requires detailed further studies.
authors.affiliation: Department of Neurology, University of Debrecen Medical and Health Science Center, H-4012 Debrecen, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Farkas
authors.forename: Katalin
authors.initials: K
authors.lastname: Nagy
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Jia
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: László
authors.initials: L
authors.lastname: Csiba
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001345:Autoradiography; D003342:Corpus Striatum / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006179:Gyrus Cinguli / Q000378:metabolism*; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000378:metabolism*; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020891:Raclopride