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Dopamine dysregulation syndrome in Parkinson's disease patients: From reward to penalty

Parkinson’s disease (PD) is characterized primarily by loss of dopaminergic neurons in the substantia nigra pars compacta. An interesting pathophysiological feature of the disease is that in most patients with PD, dopaminergic neurons in the adjacent ventral tegmental area (VTA) are relatively spared. The ventral tegmental area neurons, together with their projections to the ventral striatum (nucleus accumbens) and the neurons of the nucleus accumbens, form the mesolimbic system. Over the past 20 years, a series of pharmacological, electrophysiological, and behavioral studies have greatly broadened our understanding of the complex role of the mesolimbic system. There is now ample evidence for its involvement in a variety of physiological behaviors, such as feeding and motivation, as well as pathological behaviors, such as substance abuse, gambling, and hypersexuality. Although several dopaminergic drugs are available for treatment of PD, finding the most effective combination of drugs and the proper doses for each remains a challenging task, especially with respect to the motor and behavioral side-effects. Dopamine dysregulation syndrome (DDS) is one such condition in which the PD patient develops a compulsive disorder to engage in drug-seeking behavior, in this case, L-dopa. It has been suggested that the use of these drugs in PD might abnormally stimulate the mesolimbic pathways, leading to a behavioral disorder similar to that associated with psychostimulant addiction. In this issue of Annals, Evans and colleagues evaluate L-dopa–induced alteration in dopamine neurotransmission in the ventral striatum in a subgroup of PD patients with DDS by using an in vivo molecular imaging technique. Specifically, positron emission tomography and the dopamine receptor radioligand Craclopride (RAC) were used to study the effect of L-dopa on endogenous dopamine levels. Each patient underwent two RAC positron emission tomography scans on two separate mornings after overnight drug withdrawal, both at baseline and then after an oral dose of Sinemet-275 (L-dopa 250mg, carbidopa 25mg). The percentage change in RAC binding potential after the drug challenge relative to the baseline state provided the estimate for endogenous dopamine level. The basal level of D2R availability, and the reduction in dorsal putaminal RAC binding potentials after administration of L-dopa were comparable in the DDS and control groups. In response to L-dopa, DDS patients showed a significantly greater reduction in RAC binding potentials, which indicating higher druginduced dopamine levels in this group than in controls. These results suggest that ventral tegmental area neurons releasing DA in the ventral striatum might be sensitized to exogenous dopamine in DDS patients. Similar observations have been made in the ventral striatum of rodents where drug-induced dopamine release is increased after behavioral sensitization to drugs of abuse. The widely studied phenomenon of behavioral sensitization (see definition later in this editorial) produced by repeated exposure to drugs of abuse was originally observed more than 70 years ago in humans and rodents. One popular theory postulates that behavioral sensitization reflects an increase in the incentive salience assigned to a drug and to stimuli associated with the drug, which ultimately would lead to compulsive drug “wanting,” dissociated from drug “liking.” For these reasons, behavioral sensitization is regarded as a valid behavioral index of drug craving. Of particular interest to us is the evidence that, in rodent models, it is possible to produce behavioral sensitization not only to common drugs of abuse, such as psychostimulants, but also to L-dopa. Similarly, in humans, pathological behaviors such as dyskinesias or punding (see definition later in this editorial) have been suggested to be a consequence of sensitization to chronic exposure to L-dopa therapy. These behaviors likely depend on an abnormal stimulation of the mesolimbic system. As mentioned earlier, DDS is characterized by severe dopamine addiction where patients ask for more medication and often report tolerance to the beneficial effects of L-dopa. Over time, instead of experiencing any improvement in their motor symptoms, patients enter a vicious cycle of increasing drug tolerance and distressing “off” periods in which the patients demand more medication. When Evans and colleagues examined the association between drug use and occurrence of various reward processes in DDS patients, more patients reported L-dopa “wanting” in the DDS group compared with the control subjects. Surprisingly, no significant association was seen with L-dopa “liking,” which is the basis for the reinforcing properties of L-dopa, independent of its ability to alleviate motor signs. Furthermore, L-dopa neurotransmission in the ventral striatum correlated with improvement in motor scores in the two