Depletion of dopamine in the striatum as an experimental model of parkinsonism: direct effects and adaptive mechanisms

Abstract

It is well known that a depletion of striatal DA is a pathological substrate of Parkinsonism. Furthermore, an experimental depletion of DA in the striatum of mammals is widely regarded as a valid model for Parkinsonism. The purpose of this study is to review the data on the effects of experimental depletions of striatal DA. Emphasis is placed on the discussion of mechanisms which are involved in the compensation for the arising deficits. Results from striatal DA depletions induced by lesions and by pharmacological agents are considered. Lesions of the nigrostriatal DA system in monkeys, with additional destruction of parts of the red nucleus, replicate the cardinal symptoms of Parkinsonism—akinesia, rigidity and tremor. These data on non-human primates show the validity of the Parkinsonian model. However, several neurological and biochemical differences between the disease and the model in primates are noted which remain at present unexplained. The long history of each individual case of idiopathic Parkinsonism, in contrast to the rapid experimental lesion, might be one contributing factor. The immediate neurochemical effect of a lesion of the nigrostriatal DA system consists of an increase in DA synthesis. This is probably due to decreased end-product inhibition of TH after the arrest of impulse flow. Increased amounts of DA enter the extraneuronal space while the membranes disintegrate during the death of the neurones, and cause behavioural effects. Two to three days after the lesion the DA terminals and DA itself disappear from the striatum and the degeneration has reached its final state. Striatal DA content never recovers afterwards. Shortly after the lesion, probably already during the actual degeneration, compensatory reactions begin to evolve. Even with minor striatal DA depletions nigrostriatal DA neurones increase the metabolic activity in their terminals, as evidenced by increased synthesis, metabolism and turnover. The absence of striatal DA terminals after lesions results in a decreased uptake of DA and consequently an increased effect of DA or extrinsically administered DOPA. This mechanism presumably plays a role at all levels of DA depletion and is termed “presynaptic supersensitivity”, in analogy to the comparable mechanism in the peripheral vegetative nervous system. A true postsynaptic receptor-mediated supersensitivity to DA agonists becomes operational following severe DA depletions, with less than 20% of DA remaining. This is seem from behavioural, neurochemical and electrophysiological indices of striatal DA function. The underlying molecular mechanisms are unclear at present. Behavioural data and results from studies of adenylate cyclase activity often show a shift of the dose response curves to the left, indicating an increased receptor affinity. Binding studies, however, point to an increased number of receptor sites. The receptors examined in the two different neurochemical methods are most probably not identical, a fact which might explain the variance of the data. Postsynaptic supersensitivity develops slower than metabolic hyperactivity and presynaptic supersensitivity. After a lesion it increases markedly during the first two to three weeks, exhibits some augmentation thereafter, and remains present during the whole lifetime of the animal. There is some suggestion of the existence of two more possible compensating mechanisms. Sprouting of collaterals from remaining DA terminals has been shown in some brain structures after lesions of heterosynaptic input, but was never reported for the striatum after nigrostriatal lesions. Other intrinsic or extrastriatal neuronal systems, not directly related to the DA terminals or the DA receptors, most probably change their functional states. The existing evidence from neurological, neurochemical and electrophysiological data, however, need to be more clearly elaborated in order to assess their role as adaptive mechanisms. Parkinsonism becomes neurologically manifest only after about three quarters of the nigrostriatal DA neurones have degenerated, which take place during a time span of approximately 20–30 years in the idiopathic form of this disease. The striatal DA functions of normal humans also decrease with age. The number of DA neurones, the striatal DA content and the number of striatal DA receptors are diminished by about 50% in the elderly human when compared to the young adult. This decrease, however, is less severe than in Parkinsonism and does not lead to overt neurological symptoms. It is suggested that the brain uses the same compensating mechanisms in this age-related decay of striatal DA function as in the pathological situation of beginning Parkinsonism, those mechanisms that were experimentally elaborated using the animal model. The pathology of Parkinsonism may therefore be viewed as being a decompensated form of an otherwise normally occuring striatal DA deficiency. This does not imply that Parkinsonism reflects an exaggerated aging process. The pathogenic factors of this disease remain unknown.