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Symptomatic characteristics and recent advances in understanding the pathophysiology of tardive dyskinesias and levodopa-induced dyskinesias were reviewed. After the advent of atypical antipsychotics, tardive dyskinesias became less frequent, at least as observed during a short-term follow up. The dopamine supersensitivity hypothesis stating that blockade of dopamine D2 receptors by antipsychotics makes D2 receptors more sensitive to dopamine, has long been proposed. However, the true mechanisms remain to be determined. Three types of levodopa-induced dyskinesias-peak-dose dyskinesia, off-period dystonia and diphasic dyskinesia-were described. The pathomechanisms of peak-dose dyskinesia have been demonstrated in recent years. The priming process involved in peak-dose dyskinesia is as follows: (1) marked fluctuation of dopamine concentration occurs in the synaptic clefts of striatal neurons after each levodopa dose, (2) cortico-striatal synapses of the striatal spiny neurons of the direct pathway become supersensitive, (3) there is increased production of GABA in the spiny neurons and excessive storage of GABA in their axon terminals, (4) following this, each dose of levodopa causes excessive release of GABA into the output nuclei of the basal ganglia, resulting in abnormal firing of the neurons in these nuclei. Thus, peak-dose dyskinesia occurs after levodopa dose.

It has recently been reported that the human striatum, especially its ventral part, the nucleus accumbens, contains numerous neurons immunoreactive for aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme), but not for tyrosine hydroxylase (TH; the first-step catecholamine synthesizing enzyme) or tryptophan hydroxylase (TPH; the first-step serotonin synthesizing enzyme). These AADC (+)/TH(-)/TPH(-) neurons are named D-neurons. AADC is also the rate-limiting synthesizing enzyme of phenylethylamine (PEA). Although the functions of striatal D-neurons are yet unclear, their functions were discussed in the present review based on recent findings in the literature. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors, including L-dopa or droxidopa (L-threo-DOPS), and by converting them to dopamine (DA) or noradrenaline (NA), respectively. Because the nucleus accumbens is one of the brain regions involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration. Further studies should be conducted to elucidate the functions of this unique cell group in the human striatum.

The existence of L-3,4-dihydroxyphenylalanine (L-DOPA) immunoreactivity is demonstrated for the first time in some neurons in the human mesencephalic region, using an immunohistochemical method with a newly raised, highly specific anti-L-DOPA antiserum. In this study, we have found many L-DOPA-positive/dopamine (DA)-positive neurons. On the other hand, we observed a few L-DOPA-positive/DA-negative cell bodies in the dopaminergic regions in the midbrain. The present results suggest the possibility of the existence of more than one neuronal group in the human mesencephalic ventral tegmental area region. L-DOPA in one group is an intermediate metabolite for decarboxylation to DA and in another group may exist as an end-product. L-DOPA in the latter group could be a neuromodulator and/or neurotransmitter. Thus, we suggest that L-DOPA plays an important role besides being an intermediate of DA in the human mesencephalon.

Levodopa was released by depolarizing stimuli from rat striata in a transmitter-like manner in vitro and in vivo. Exogenous nanomolar levodopa stereoselectively facilitated the release of dopamine and noradrenaline via presynaptic beta-adrenoceptors in brain slices even under inhibition of aromatic L-amino acid decarboxylase. This facilitation was competitively antagonized by levodopa methyl ester, whereas it was non-competitively antagonized by propranolol. Furthermore, picomolar levodopa stereoselectively potentiated the isoproterenol-induced facilitation of the noradrenaline release. Levodopa methyl ester selectively antagonized this potentiation, while propranolol antagonized both the facilitation by isoproterenol alone and its potentiation by levodopa. The recognition site for levodopa could be differentiated from the carrier proteins for levodopa transport, because nanomolar levodopa methyl ester abolished the levodopa-induced facilitation of the noradrenaline release, whereas a 30 times higher concentration of L-phenylalanine or L-leucine produced no antagonism. Microinjection of levodopa into the nucleus tractus solitarii led to dose-dependent decreases in arterial blood pressure and heart rate in rats in a levodopa methyl ester-sensitive manner. Based on these findings, we propose that levodopa itself is an endogenous neurotransmitter in the CNS.

In the present study, we obtained genetically manipulated non-neuronal cells which synthesize a catecholamine precursor for future use in the intracerebral grafting. Human type 1 tyrosine hydroxylase (TH, EC 1. 14. 16. 2) cDNA was inserted into eukaryotic expression vector pKCRH2 and was co-transfected into C6 cells with plasmid pSV2neo. Expression of the TH minigene was screened by immunocytochemical staining with TH antibody and immunoblotting analysis. Several clones of the C6 transfectants that produce TH molecules were obtained. These cells showed TH activity and the product, L-DOPA, was detected intracellularly due to the absence of L-amino acid decarboxylase (AADC, EC 4. 1. 1. 28) activity. It was found that a large amount of L-DOPA was released from the cells into the culture medium. These transfectants were transplanted into rat brain and the expression of TH was examined immunohistochemically. At the 10th day following transplantation, a mass of C6 cells which was heavily stained with TH antibody was observed in the brain. These findings may provide us an opportunity to investigate the effects of intracerebral transplantation of non-neuronal cells that produce catecholamine or its precursor.