devazepide and Parkinson-Disease--Secondary

Cholecystokinin (CCK) receptors were visualized autoradiographically using [125I]Bolton Hunter CCK8 ([125I]BHCCK8) in the fore- and midbrain of 3 monkeys rendered hemi-parkinsonian by unilateral intra-carotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). More specifically, CCK-A receptors were detected using [3H]MK-329 (devazepide), a peripheral-type (CCK-A) receptor antagonist. In the substantia nigra pars compacta, ipsilateral to the toxin infusion, where dopamine D2 receptors (labelled with [3H]sulpiride) were lost, there was a decrease in the binding of both [125I]BHCCK8 and [3H]MK-329. Binding of the two CCK ligands was also reduced in the ipsilateral nucleus accumbens and most medial part of the caudate nucleus, whereas 3H-sulpiride binding was increased in the lateral caudate nucleus and putamen. These results indicate that CCK-A receptors may be located on dopaminergic cells within the substantia nigra, which are lost in the parkinsonian brain, and may also be present on dopaminergic terminals within restricted regions of nigral/ventral tegmental area projection sites.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Autoradiography; Benzodiazepinones; Cholecystokinin; Devazepide; Indicators and Reagents; Iodine Radioisotopes; Macaca fascicularis; Mazindol; Parkinson Disease, Secondary; Prosencephalon; Receptors, Cholecystokinin; Sincalide; Substantia Nigra; Succinimides; Sulpiride; Tegmentum Mesencephali; Tritium

We examined the ability of selective CCK-A and CCK-B receptor antagonists to induce or modulate the locomotor stimulant effects of dopamine agonists in MPTP-treated squirrel monkeys. Administration of 1-100 micrograms/kg i.p. of either the selective CCK-A receptor antagonist devazepide (MK-329) or the CCK-B receptor antagonist L-365,260 alone failed to stimulate a locomotor response in parkinsonian monkeys. In contrast, treatment with L-365,260 caused a 50-60% potentiation of the locomotor stimulatory effects of L-DOPA or (+)-PHNO. No such modulatory effects were observed following pretreatment with devazepide. We suggest that CCK-B receptor antagonists may be useful adjuncts to existing dopamine replacement therapy for improved management of Parkinson's disease.

Topics: Animals; Benzodiazepinones; Carbidopa; Cholecystokinin; Devazepide; Dopamine Agents; Levodopa; Male; Motor Activity; MPTP Poisoning; Oxazines; Parkinson Disease, Secondary; Phenylurea Compounds; Receptors, Cholecystokinin; Saimiri