Testing the contributions of striatal dopamine loss to the genesis of parkinsonian signs
Highlights
► Is focal striatal dopamine loss sufficient to elicit parkinsonian signs in primates? ► D1/D2 antagonist infusion into putamen variably elicited akinesia and bradykinesia. ► Akinesia was most severe for self-initiated non-rewarded reaching movements. ► Acute focal blockade of putamenal dopamine is sufficient to induce akinesia. ► Elicting individual signs in isolation suggests they have distinct pathophysiologies.
Introduction
Given the spectacular therapeutic efficacy of dopamine-replacement therapies (Hornykiewicz and Kish, 1987), there is little doubt that the core motor signs of Parkinson's disease (akinesia, bradykinesia, rigidity and tremor) arise from a loss of dopamine (DA) in the central nervous system. Historically, loss of DA from the posterolateral striatum (i.e., the skeletomotor region of the putamen) has been thought to be the primary factor that leads to parkinsonism (Damier et al., 1999, Forno, 1996). Indeed, the largest loss of DA in absolute terms is from the posterior putamen (Ehringer and Hornykiewicz, 1960, Kish et al., 1988) and symptom severity does correlate with the level of putamenal DA depletion (Bernheimer et al., 1973, Morrish et al., 1996, Nandhagopal et al., 2009, Seibyl et al., 1995). Putamenal DA depletion, however, is not a perfect predictor of symptom severity or symptom progression in individual patients (Gallagher et al., 2011, Pavese et al., 2011, Pirker, 2003), suggesting that factors other than putamenal DA influence the genesis of parkinsonian symptoms. Dopamine loss in PD is not restricted to the striatum (reviewed by Rommelfanger and Wichmann, 2010), but has also been observed in the subthalamic nucleus, thalamus, globus pallidus, and cortex (Francois et al., 2000, Freeman et al., 2001, Jan et al., 2000, Scatton et al., 1982, Scatton et al., 1983). Thus, the minimal pathologic defect necessary to induce parkinsonian signs remains unknown.
The diverse topography of DA loss in PD is mirrored by a variety of motor signs, which can be broken down into relatively independent groupings (Parkinson, 1817). Akinesia is a multi-component sign, characterized by a poverty of willed movement, slowness to initiate sensory-triggered movement (i.e., lengthened reaction times, RTs), and particular difficulty initiating movements in the absence of external sensory cues (Flowers, 1976, Morris et al., 1996, Oliveira et al., 1997). Freezing episodes, a facet of akinesia characterized by a temporary inability to initiate movement (Fahn, 1995, Jankovic, 2008, Nieuwboer et al., 2009) are difficult to treat, but can often be overcome with the help of external sensory cues (Arias and Cudeiro, 2008, Dietz et al., 1990, Marchese et al., 2000, Praamstra et al., 1998). Bradykinesia refers exclusively to slowed execution of movement (measurable as prolonged movement durations, MDs, Hallett and Khoshbin, 1980), while rigidity and tremor manifest as increased muscular resistance to passive joint movement and involuntary 4–6 Hz tremulous movements of one or more body part, respectively (Jankovic, 2008). Each of these parkinsonian signs varies independently in severity, rate of progression, and response to therapy (Espay et al., 2009, Evarts et al., 1981, Jankovic, 2008, Jordan et al., 1992, Kimber et al., 1999, Kishore et al., 2007, Meyer, 1982, Nieuwboer et al., 1998, Selikhova et al., 2009, Temperli et al., 2003, Zetusky and Jankovic, 1985), implying that different parkinsonian signs may have unique pathophysiologic substrates. Similarly, the fact that anatomically-segregated regions of the striatum are devoted to skeletomotor, associative and limbic functions (Alexander et al., 1990, Kelly and Strick, 2004, Worbe et al., 2009) has prompted proposals that dissociable symptoms of PD arise from loss of DA from separate functional regions of the striatum (Alexander et al., 1986, Joel and Weiner, 1994, Wichmann et al., 2011). It is therefore important to determine whether DA loss in specific striatal regions elicits separate parkinsonian signs.
Here, we sought to establish whether acute focal blockade of striatal DA neurotransmission is sufficient to induce behavioral changes that reflect parkinsonian signs. This question is not amenable to current DA-targeted neurotoxin approaches (i.e., using 6-OHDA or MPTP, Emborg, 2007). Administration of these agents leads to degeneration of dopaminergic somata in the substantia nigra compacta (Oiwa et al., 2003, Sauer and Oertel, 1994) and of their extensive multi-nuclear axonal arborizations (Debeir et al., 2005, Freeman et al., 2001, Pifl et al., 1991) even when the neurotoxin is infused directly into the striatum (Debeir et al., 2005, Freeman et al., 2001). Neurotoxin models, therefore, cannot rule out the potential roles of extra-striatal DA loss, degeneration of the somata of dopaminergic neurons, or chronic DA depletion in the development of parkinsonian signs.
An alternative approach involves the selective blockade of DA receptors in the striatum. Infusions of DA receptor antagonists into the striatum are known to elicit catalepsy in rodents (Amalric and Koob, 1987, Ellenbroek et al., 1985, Hauber et al., 2001, Kaur et al., 1997, Salamone et al., 1993, Yoshida et al., 1994). It is difficult, however, to relate the cataleptic state, a nonspecific combination of abnormal posturing and immobility, to specific signs of human parkinsonism. To our knowledge, only one previous study examined the behavioral effects of intra-striatal DA blockade in non-human primates (Hikosaka et al., 2006). In that study, small intra-striatal infusions of D1- or D2-specific antagonists disrupted the normal relationship between oculomotor reaction times and size of rewards (Hikosaka et al., 2006), but overt signs of parkinsonism were not noted. By infusing large volumes of a non-specific D1/D2-receptor antagonist at various sites in the putamen, we tested whether acute blockade of striatal DA transmission is sufficient to cause changes in motor performance reflective of parkinsonian signs.
Section snippets
Animals and task
Two monkeys (Macaca mulatta; D, male ~ 7.5 kg; E, female ~ 6 kg) were used in the study. All aspects of animal care were in accord with the “National Institutes of Health Guide for the Care and Use of Laboratory Animals, the PHS Policy on the Humane Care and Use of Laboratory Animals, and the American Physiological Society’s Guiding Principles in the Care and Use of Animals”, and all procedures were approved by the institutional animal care and use committee. An animal was seated in a primate chair
Results
A total of 26 cis-flu injections were performed in three hemispheres across two monkeys (18 injections across two hemispheres in monkey D, 8 injections in one hemisphere in monkey E; Fig. 2B). Three saline injections into the putamen were also performed, one in each hemisphere (Table 1).
Discussion
For decades, the pathophysiology of PD has been routinely attributed to loss of DA from the skeletomotor region of the posterior putamen. It has become increasingly unclear, however, whether simple under-activation of DA receptors in this region is sufficient to induce Parkinsonian signs. Recent studies have suggested possible roles for loss of DA from non-skeletomotor striatal regions, chronic striatal DA depletion, and extra-striatal DA loss in the emergence of parkinsonian signs (Francois et
Conclusions
Our results indicate that acute, focal blockade of striatal DA receptors is sufficient to induce motor deficits reflective of specific parkinsonian signs. Intra-striatal infusion of a D1- and D2-receptor antagonist in awake, behaving macaques was found to slow the initiation of movement more than its execution. Paralleling observations in PD patients, the initiation of self-generated movements was impaired more severely than initiation of externally-cued movements. Additionally, motor deficits
Acknowledgments
We wish to thank Mary Watach and Angela Cowan for expert assistance with animal care and surgery. Dr. Benjamin Pasquereau provided invaluable advice and assistance throughout the project. Dr. Kwan-Jin Jung of the University of Pittsburgh Brain Imaging Research Center provided advanced directional image filtering of the MRI images that enhanced the contours of the basal ganglia. This research was supported by the National Institute of Neurological Disorders and Stroke at the National Institutes
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2020, Experimental NeurologyCitation Excerpt :One may argue that our observations were made in mice and hence may not be applicable to human PD patients. However, literature data have firmly established that DA critically stimulates motor function in all vertebrate animals (Grillner and Robertson, 2016), and the profound DA dependence of motor function in mammalian animals is amply demonstrated by the motor function loss caused by toxin-induced DA loss in rodents, monkeys and humans (Langston, 2017; Liang et al., 2008; Nonnekes et al., 2018; Schwarting and Huston, 1996), by DA receptor blockade (Franco and Turner, 2012), and by TH deletion (Zhou and Palmiter, 1995). Indeed, clinical opinions are swinging back in favor of L-dopa over DA agonists (Chaudhuri et al., 2019; Olanow, 2019).
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2017, International Review of NeurobiologyCitation Excerpt :Accordingly, novel evidence supports the high dopamine reserve of striatum owing to the compensatory response by the collateral axonal sprouting from the surviving dopaminergic neurons and by the postsynaptic cells of the striatum (Arkadir, Bergman, & Fahn, 2014; Deumens et al., 2002). On the other hand a direct administration of the toxin into the striatum in a fixed stereotaxic coordinates produces a selective destruction of the dopaminergic system inducing a denervation of the posterolateral striatum and the subsequent loss of dopaminergic neurons in SN (Franco & Turner, 2012). This lesion provides a suitable partial model to elucidate the optimal time to initialize the treatment (Agid, Javoy, & Glowinski, 1973; Jankovic, Shoulson, & Weiner, 1994; Przedborski et al., 1991; Sarre et al., 2004).
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2016, Handbook of Behavioral NeuroscienceCitation Excerpt :Future studies are needed to determine if D1-MSNs in different striatal subregions converge onto the same SNr GABA neurons. The nigrostriatal DA system has profound motor-stimulating effects: animals including humans immediately become akinetic when DA is depleted and quickly regain their mobility when DA is restored (Ballard et al., 1985; Franco and Turner, 2012; Li and Zhou, 2013). D1Rs on the D1-MSN somata, dendrites, and striatonigral axon terminals all contribute to the DA's motor stimulation and other behavioral effects.
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