The neurochemistry of therapeutics: Levodopa pharmacodynamics in Parkinson's disease

Parkinson’s disease (PD), the most common neurodegenerative movement disorder, has enjoyed a recent explosion of treatment options available for its symptomatic management. Despite these recent introductions, PD remains a progressive disorder, with the majority of patients experiencing significant disability in its more advanced stages. One aspect of PD leading to disability is the development of unsatisfactory symptomatic responses to precursor loading therapy with levodopa (LD). Typical PD patients respond initially to LD with a sustained (several hours) improvement in resting tremor, bradykinesia, and rigidity. This response initially outlasts the plasma levels of LD and has been assumed to rely on conversion to dopamine in remaining striatal monoaminergic terminals, with subsequent storage in and release from synaptic vesicles. In more advanced PD, the response from an individual dosage becomes progressively shortened until it closely parallels the plasma LD level. Furthermore, the clinical response to LD in advanced PD is often complicated by unpredictable losses of therapeutic effect and by choreoathetoid dyskinesias at times of peak LD effect. There is limited mechanistic understanding of these complications, with attendant controversy surrounding the relationship of prior medication history to their risk of development. In the present issue of The Annals, de la Fuente-Fernandex et al have applied positron emission tomography (PET) to the investigation of levodopa pharmacodynamics in PD patients with regard to the subsequent development of end-ofdosage “wearing off” of LD effect. The studies reported by de la Fuente-Fernandez et al are based mechanistically on prior investigations from a number of laboratories that have identified apparent effects of endogenous neurotransmitter on the in vivo binding of dopamine D2-type receptor antagonist radioligands (see Laurelle for a recent review). Initial studies suggesting an effect of endogenous dopamine on binding of D2 antagonists such as [ C]raclopride (RAC) and [I]iodobenzamide employed interventional challenges with the dopamine releaser amphetamine. Paired, within-subject studies demonstrated significant reductions in RAC binding after intravenous amphetamine compared to baseline in normal subjects. Detailed investigations of this effect in nonhuman primates indicate that the magnitude of the PET binding reduction correlated with the magnitude of dopamine release, as assessed by in vivo microdialysis. Further evidence in support of the role of endogenous dopamine as the mediator of the effect is the observation that it is abolished by prior dopamine depletion. Human patient studies employing the amphetamine challenge paradigm indicate potential presynaptic dopaminergic abnormalities in neuropsychiatric disorders. Several investigators have examined the effect of amphetamine on D2 receptor binding in schizophrenic patients. In comparison to normal control subjects, schizophrenics frequently demonstrate exaggerated responses (greater reduction of D2 radioligand binding after amphetamine), suggesting increased presynaptic dopamine stores or abnormal regulation of synaptic dopamine disposition. In addition, dopamine depletion after alphamethyltyrosine administration reveals increased D2 radioligand binding in schizophrenics that exceeds that in normal subjects, suggesting increased D2 receptor occupancy at baseline in unmedicated schizophrenia. Although findings are only preliminary, the possibility of altered presynaptic dopaminergic regulation in Tourette syndrome is supported by exaggerated amphetamine response in D2 radioligand imaging studies as well. Can apparent synaptic dopamine changes induced by interventions other than amphetamine be measured by the D2 receptor radioligand binding competition paradigm? Amphetamine administration results acutely in up to 100-fold increases in dopamine release from nerve terminals compared with baseline levels. Thus, it is reasonable to question whether more modest stimuli have detectable effects on the in vivo binding of RAC. To the affirmative, investigators have demonstrated similar apparent competitive effects of dopamine reuptake inhibitors such as methylphenidate. Furthermore, it has been observed that putative trans-synaptic effects of acetylcholine, serotonin, and glutamate modulations lead to altered in vivo RAC binding, presumed to be mediated by the competitive effect of endogenous dopamine. Finally, Tedroff et al have demonstrated previously in PD that acute administrations of LD result in decreased RAC binding (Fig). It is this specific competitive radioligand-binding paradigm that was investigated further by de la FuenteFernandez et al.