NEUROPHARMACOLOGY OF PARKINSONS-DISEASE - BASIC ASPECTS AND RECENT ADVANCES

Among the best identified pathological consequences of dopamine neurot ransmission dysfuntion is Parkinson's disease. The major clinical char acteristics of the disease include akinesia, rigidity, tremor, postura l deficiencies and speech impairments. Other afflictions observed incl ude visuo-spatial deficiencies, difficulty maintaining a mental set an d impairment of frontal lobe functions such as alternation and sequenc ing. Dopaminergic cell damage, as found in postmortem studies, has bee n replicated in experimental models of Parkinson in an attempt to unde rstand the various areas of the brain implicated in the disease and to establish alternative treatments. The neurotoxin MPTP (1-methyl-4-phe nyl-1,2,3,6-tetrahydropyridine) causes a condition resembling, but not identical, to Parkinson's disease in humans and some experimental ani mals. The mechanism by which a single dose of this compound can cause selective destruction of nigrostriatal dopaminergic neurons has genera ted three hypothesis on the origin of the disease, which may complemen t each other. These hypotheses emphasize the role of a progressive acc umulation of noxious stimuli to dopaminergic systems- Neurotoxins, for med as byproducts of environmental or endogenous substances appear rel ated to inhibition of mitochondrial oxidative phosphorylation. The los s of ATP-generating capacity has damaging consequences in the ability to maintain membrane potential and calcium ion homeostasis with a cons equent generation of free radicals which may cause neuronal degenerati on. However, the significance of these processes in relation to idiopa thic Parkinson's disease is not clear. The time-course and pattern of neuronal degeneration induced by neurotoxins such as MPTP cast doubts on the value of the neurotoxin models. It is apparent however, that in Parkinson's a state of oxidative stress exists in the dopaminergic su bstantia nigra where free radical scavenging mechanisms are reduced. I n the present review, processes associated with dopamine metabolism: s ynthesis, release, uptake and catabolism will be examined. So long as different pharmacodynamic and pharmacokinetic processes are identified , more therapeutic opportunities can arise On the one hand, the anatom ical electrophysiological and neurochemical characterization of dopami ne receptors which has enabled the development of new and more potent and specific agonist and antagonist drugs will be discussed. On the ot her hand, the molecular biology of dopamine receptors which has improv ed the conceptualization of the dopamine receptor as a family of at le ast five different subtypes will be presented. A prolonged treatment w ith antipsychotic agents such as phenotiazines and butyrophenones can induce symptoms similar to Parkinson's. Differences in the dyskinetic patterns have been clarified thanks to recent data on dopamine recepto r subtypes. The role of other neurotransmitters in Parkinson's disease will be mentioned briefly During the past decade considerable progres s has been made in the understanding of the interaction of dopamine wi th other neurotransmitter systems. The role of different drugs used in the treatment of the disease, from the classic L-Dopa treatment to th e use of systemic dopamine antagonists, devoted of central action, use d to block undesired peripheral side-effects, will also be mentioned. Enzymatic inhibitors of dopamine decarboxylase, MAO and COMT as well a s other dopaminergic receptor agonists such as the amantadine, aporphi nes, ergolines, selergine and anticholinergic agents will be described . This review will conclude with a brief description of possible treat ments to other noncardinal symptoms in Parkinson's disease and a discu ssion on possible new perspectives of modern neuropharmacology to the study of this disease that has contributed so much to the understandin g of cerebral functioning.