Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis).
The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from monkeys which had received unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing loss of dopamine-containing neurones of the substantia nigra pars compacta. The monkeys developed hemi-parkinsonian symptoms (tremor, bradykinesia) in limbs contralateral to the side of the toxin infusion. Administration of apomorphine (0.05-0.25 mg/kg) caused contralateral rotational behaviour, and reversal of the parkinsonian symptoms. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A reduction in these sites of 97% (mean brain value) in the caudate nucleus, and 91% in the putamen, as compared with binding values from untreated control monkeys, was accompanied by a significant increase in the binding of [3H]sulpiride (D2) in these structures. In contrast, in the same animals there was no similar increase in [3H]SCH 23390 binding to D1 receptors in the denervated areas. These results suggest that in the parkinsonian brain, where the dopaminergic innervation of the caudate nucleus and putamen has been lost, D2 receptors may be more susceptible than D1 receptors to changes, revealed here as an increase in [3H]sulpiride binding sites.
Department of Cell and Structural Biology, University of Manchester, U.K.
W C
WC
Graham
C E
CE
Clarke
S
S
Boyce
M A
MA
Sambrook
A R
AR
Crossman
G N
GN
Woodruff
D000818:Animals; D001552:Benzazepines / Q000378:metabolism*; D020267:MPTP Poisoning; D008252:Macaca fascicularis; D008297:Male; D010302:Parkinson Disease, Secondary / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D013469:Sulpiride / Q000378:metabolism*
D001552:Benzazepines; D011954:Receptors, Dopamine; D013469:Sulpiride