We used two analytic methods (a multichannel coulometric electrode array with high-performance liquid chromatography, and gas chromatography-mass spectrophotometry) to measure CSF dopamine (DA) and its metabolites in mildly affected, unmedicated subjects with Parkinson's disease (PD). The mean (+/- SD) concentration of homovanillic acid (HVA), the most abundant product of DA turnover, was 164.57 +/- 95.05 nM. As sequential aliquots of CSF were collected from the first to 23rd ml, CSF HVA concentration almost doubled. After HVA, 3-O-methyldopa (3-O-MD) was the next most abundant compound. The summed concentrations of 3-O-MD, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, DA, DA-3-sulfate, homovanillol, and levodopa (LD) amounted to 12.6% of HVA. Concentrations of the DA metabolites did not correlate to a variety of indices of PD severity. The presence of LD and 3-O-MD may be indicators of DA synthesis and possibly could reflect compensatory processes among surviving dopaminergic neurons of the PD brain.

Because cocaine effectively increases extracellular levels of both dopamine (DA) and serotonin (5HT), it might be expected that this agent would inhibit transmitter biosynthesis in these monoamine neurons by activation of autoregulatory feedback pathways. This possibility was tested by measuring the effect of cocaine on 3,4-dihydroxyphenylalanine accumulation (DA synthesis) and 5-hydroxytryptophan accumulation (5HT synthesis) in vivo and in vitro after inhibition of aromatic amino acid decarboxylase with NSD-1015. In vivo, cocaine suppressed both DA and 5HT synthesis in a dose-dependent (10-60 mumols/kg, i.p.) and time-dependent fashion (maximum 60 min after administration, recovery by 120-150 min). Inhibition of DA and 5HT synthesis ranged from 35% to 60% depending on the brain region and was apparent in dopaminergic fields such as the medial prefrontal cortex, nucleus accumbens, piriform cortex, striatum, and in noradrenergic fields, such as the hippocampus and temporal cortex. Inhibition of DA, but not 5HT, synthesis was blocked by the D2 antagonist sulpiride in brain areas containing DA nerve terminals. Procaine (30 mumols/kg) did not inhibit DA or 5HT synthesis and prior treatment with reserpine diminished the effectiveness of cocaine in the medial prefrontal cortex, but not in the striatum. Cocaine did not reverse the gamma-butyrolactone-induced increase in striatal DA synthesis nor did cocaine block the ability of the D2 agonist quinpirole to reverse the increase. In vitro, cocaine inhibited DA synthesis in depolarized (K+ = 30 mM) striatal brain slices, an effect that was reversed by the D2 antagonist eticlopride. These results suggest that DA and 5HT neurons compensate in situ for cocaine-induced increases in synaptic transmitter levels by a transient inhibition of transmitter biosynthesis. Acute suppression of transmitter synthesis (and release) in mesoprefrontal DA neurons may represent the principal compensatory mechanism in this group of neurons.

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Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 micrograms/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 micrograms/ml. LD plasma concentrations fluctuating around 0.9 micrograms/ml may result in the "on/off" effects seen in Parkinson's disease.

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