Orphan neurones and amine excess: the functional neuropathology of Parkinsonism and neuropsychiatric disease

The aetiology and treatment of Parkinsonism is currently conceptualised within a dopamine (DA) deficiency-repletion framework. Loss of striatal DA is thought to cause motor impairment of which tremor, bradykinaesia and rigidity are prominent features. Repletion of deficient DA should at least minimise parkinsonian signs and symptoms. In Section 2, based on extensive pre-clinical and clinical findings, the instability of this approach to Parkinsonism is scrutinised as the existing negative findings challenging the DA deficiency hypothesis are reviewed and reinterpreted. In Section 3it is suggested that Parkinsonism is due to a DA excess far from the striatum in the area of the posterior lateral hypothalamus (PLH) and the substantia nigra (SN). This unique area, around the diencephalon/mesencephalon border (DCMCB), is packed with many ascending and descending fibres which undergo functional transformation during degeneration, collectively labelled `orphan neurones'. These malformed cells remain functional resulting in pathological release of transmitter and perpetual neurotoxicity. Orphan neurone formation is commonly observed in the PLH of animals and in man exhibiting Parkinsonism. The mechanism by which orphan neurones impair motor function is analogous to that seen in the diseased human heart. From this perspective, to conceptualise orphan neurones at the DCMCB as `Time bombs in the brain' is neither fanciful nor unrealistic [E.M. Stricker, M.J. Zigmond, Comments on effects of nigro-striatal dopamine lesions, Appetite 5 (1984) 266–267] as the DA excess phenomenon demands a different therapeutic approach for the management of Parkinsonism. In Section 4the focus is on this novel concept of treatment strategies by concentrating on non-invasive, pharmacological and surgical modification of functional orphan neurones as they affect adjacent systems. The Orphan neurone/DA excess hypothesis permits a more comprehensive and defendable interpretation of the interrelationship between Parkinsonism and schizophrenia and other related disorders.