Metabolic mapping of the pharmacological and toxicological effects of dopaminergic drugs in experimental animals.
Functional consequences of pharmacological and toxicological manipulations of the dopaminergic systems were evaluated by means of the 2-[14C]deoxyglucose (DG) method for measuring local rates of cerebral glucose utilization. Administration of dopamine agonist drugs modifies glucose metabolism in selected brain areas. Several factors, such as the compound used, the dose, length, and modality of the treatment, and the interval of time between the end of the treatment and the measurement of glucose utilization, contribute to define the topography and intensity of the changes. The differences refer to distinct activation of subtypes of dopamine receptors, to secondary involvement of other neurotransmitter receptor systems, and to modification of the receptor sensitivity occurring during the treatment. Other variables that interfere with the motivated behavior induced by psychostimulants may also affect the metabolic pattern. A few changes in glucose utilization are, however, common to most dopamine agonist drugs. High doses, which induce stereotypic behavior, produce metabolic changes in the extrapyramidal system. Low doses of psychostimulants, which elicit locomotion and exploratory behavior and produce reinforcement, increase glucose metabolism in the limbic system, particularly in the nucleus accumbens. Metabolic mapping in monkeys bearing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced lesions of the dopaminergic areas in the brainstem contributed to define the key role of the striatopallidal pathway in the production and maintenance of the motor abnormalities that characterize parkinsonism. Metabolic patterns associated with unilateral 6-hydroxydopamine lesion of the nigrostriatal neurons in the rat are modified by dopamine agonist drugs. Specific changes are produced by selective D1 or D2 agonists. In rats bearing unilateral 6-hydroxydopamine lesion, the DG method also revealed functional effects produced by the interaction between D1 and N-methyl-D-aspartate receptors.
Orzi
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F
Dipartimento di Scienze Neurologische, Università di Roma La Sapienza, Italia.
Morelli
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M
Fieschi
C
C
Pontieri
F E
FE
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D001931:Brain Mapping; D002250:Carbon Radioisotopes; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003847:Deoxyglucose; D015259:Dopamine Agents / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism; D011877:Radionuclide Imaging
D002250:Carbon Radioisotopes; D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D003847:Deoxyglucose