Cocaine use is associated with a range of movement disorders [3], and has complex effects on the central nervous system. Possible ways to categorize these effects is based on time characteristics, i.e. neurologic complications with acute or chronic use, or whether the patient is an active user, early or late abstinent. The main acute pharmacological effect of cocaine is dopamine (DA) reuptake inhibition, which elevates synaptic DA levels.
Literature information about cocaine’s effect on dopamine transporter (DAT) level expression in human is scarce and available information from experimental animal studies are also contradictory at times. There are two possible mechanism supported by the literature, by which we tried to interpret our findings, i.e. the low DAT binding, which later normalized.
On one hand, in response to the elevated DA levels, DAT downregulation might take place, as a compensatory mechanism [17]. This compensatory mechanism decreases the acute DA elevation with the use of cocaine, but on the long term it leads to DA deficiency in the caudate nucleus and frontal cortex as DA synthesis and reuptake is both needed for synaptic storage [18]. In acute cocaine abstinence the DATs start to upregulate as shown by other DaTscan studies [19]. This might explain our results, why we have seen decreased DAT binding, which later normalized. In this scenario we hypothesize that DaTscan in our patient was performed in a time window when DAT levels are still decreased; however, the patient was already abstinent. As an acute withdrawal symptom decreasing DA level results in psychological symptoms, restlessness and tremor [20]. Long term use of cocaine however also results in DAT decrease, and this might explain Parkinsonian features in abstinence as a result of DA depletion.
On the other hand, other studies in the literature suggest, that cocaine increases DAT expression, and abstinence of cocaine intake for a prolonged period of time decreases DAT level [5]. In this scenario, we can hypothesize that we have seen the decreased DAT-binding, because the patient was already abstinent for a long time, and this change in the expression later normalized.
It should be mentioned that the above described mechanisms are speculative and the effects of cocaine on the nervous system is complex. We also need to consider changes in D2 receptor expression [21] and possible long-term structural damage to dopaminergic synaptic terminals [18]. Effects might be dose and formulation dependent, as neurologic complications are more common with the smokable alkaloidal form of cocaine, known as „crack” [22]. Acute blood pressure elevations and cerebral vasospasm might also cause cerebrovascular events, such as acute ischemic stroke, or aneurysm rupture [23], but small subclinical ischemic events may also cause structural damage in the brain. Chronic cocaine abuse lead to increased age-dependent temporal lobe cortical atrophy [24], and decreased frontal white matter connectivity [25] shown by imaging studies.
The association of cocaine use with Parkinsonism is nevertheless complicated, and the literature information is scarce. On one hand, the acute elevation of synaptic DA levels may ameliorate “off” periods in Parkinson’s disease patients [26]. On the other hand chronic use was associated with Parkinsonian features in many case reports [20], although this was not confirmed by the epidemiological study of Callaghan et al. [27]. The above described mechanism suggests a pharmacological, reversible form of secondary Parkinsonism in our case. However, a further possible, non-pharmacologic link between Parkinsonism and chronic cocaine use might exist. Chronic cocaine exposure triggers alpha-synuclein overexpression [10], which might be an acute protective mechanism against increased oxidative stress, but which eventually lead to formation of Lewy bodies (LBs), and accelerated neurodegeneration. Besides, cocaine also physically binds to alpha-synuclein, which might cause deleterious conformational changes [8]. However, it is not probable, that these changes will cause reversible pathology on the DaTscan.
The long-term cocaine use has not the same effect as dopamine receptor blocking agents - DRBA, however these can induce also parkinsonism. Drug-induced Parkinsonism (DIP) should resolve after the causative agent has been withdrawn. Lim et al. [28] reported that Parkinsonism might persist for more than 6 months after discontinuation of the DRBA, and DaTscan showed normal striatal dopamine transporter binding at that time. Nine months after the discontinuation of the dopamine receptor blocking agent, Parkinsonism was significantly improved in their patients but not completely resolved [28].
In a number of patients, with DIP symptoms persist or may even worsen over time, suggesting the development of concomitant PD. There are speculations that the possible neurotoxic effect of neuroleptics exerted on a susceptible dopaminergic system would lead to a progressive process. To which extent a personal susceptibility plays a role remains to be determined and further genomic studies in patients exposed to neuroleptics who develop DIP or PD could eventually identify a genetic background of susceptibility [29]. Even if the pathomechanism is not the same in the cocaine induced Parkinsonism and DIP the personal susceptibility can be an important factor.
In our case the PD associated genes were investigated since the patient has movement disorders in his family. We detected only one genetic risk variant, which was previously associated with PD. The presence of this homozygous LRRK2 polymorphism (S1647 T) has a very mild association with PD, with a low odds ratio (in our cohort OR: 1.787, 95%, CI: 0.8052 to 3.96 – Illes et al., unpublished data). In the presence of this genetic risk variant, even in homozygous status, appearance of Parkinsonism is not likely, but hypothetically in the presence of some environmental factors, which may influence dopamine level it may present itself. Similar mechanism was suggested by Lin et al. [30] in a Taiwanese population, where the S1647 T variant was only associated to Parkinsonism when environmental exposures were included in the logistic regression model. Further published studies indicated also significant interactive effects between environmental factors and genetic variants [31]. These kind of interactions are well described in the case of the serotonin transporter polymorphism association with depression [32]. However, it should be kept in mind that proof of the additional effect of LRRK2 S1647 T polymorphism and cocaine abuse goes beyond the framework of our case study.
It is interesting, that in our patient, the MRI already showed some structural changes (absence of the swallow tail sign), indicating the damage of nigrostriatal pathway, and thus the acute pharmacological effect of cocaine might be also altered. The family history of hand tremor in the father and restless-leg syndrome in the child also suggest some already existing non-pharmacologic risk at the patient.
In summary, this case report may raise the possibility of a gene-environment interactions in the background of our patient’s symptoms. Our result suggests that some of these effects in the early state might partially reversible, as after a period of abstinence the patient’s Parkinsonian symptoms resolved. However, the patient needs longitudinal follow-up, as PD might later reoccur, as the consequence of the chronic effects of cocaine, and the additive effects of the LRRK2 alteration. Further studies of S1647 T alteration and environmental interaction in a larger Hungarian cohort and functional studies in in vivo models are warranted to validate our hypothesis.
