[handbook of behavioral neuroscience] handbook of basal ganglia structure and function volume 20 ||...

Compensatory Mechanisms in Experimental and Human Parkinsonism: Potential for New Therapies

Chapter 37

Erwan Bezard1, Grégory Porras1, Javier Blesa2 and José A. Obeso2,3

1Université Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, Bordeaux, France,2Neuroscience Center and Centro Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), University of Navarra, Spain,3Department of Neurology, Clinica Universitaria and Medical School, Pamplona, Spain

I. IntroductionII. overview of compensation,

classic conceptsIII. Striatal Mechanisms

A. Pre- and Postsynaptic Changes in Dopaminergic Activity

B. Re-Innervation

C. Serotonin CompensationD. Volume Transmission and

Passive StabilizationIV. Basal Ganglia-Mediated

compensationV. thalamo-cortical-Mediated

compensation

VI. dopamine compensation reappraised

VII. conclusions – compensation vs. Sensing dopamine depletion

references

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Handbook of Basal Ganglia Structure and FunctionCopyright © 2010 Elsevier B.V. All rights reserved.2010

I. IntroductIon

Parkinson’s disease (PD) is a widespread neurodegen-erative disorder, the major pathologic feature of whichis the profound loss of pigmented dopamine (DA) neu-rons, mainly in the pars compacta of the substantia nigra(SNc) (Hassler, 1938; Ehringer and Hornykiewicz, 1960)(see also Chapter 34). The cardinal features of PD, thatis, tremor, rigidity and bradykinesia (Singh et al., 2007),typically arise when DA neuronal death reaches a criticalthreshold: 70–80% of striatal nerve terminals and 50–60%of SNc perikarya (Bernheimer et al., 1973). This dissocia-tion between the onset of parkinsonian motor features andthe presence of large DA depletions is understood as a con-sequence of compensatory mechanisms (Zigmond et al.,1990; Bezard and Gross, 1998; Bezard et al., 2003). Thus,compensatory mechanisms can delay the clinical onset ofPD and could also play a role in the progression of motordeficits. Indeed, it is quite possible that compensatory

mechanisms continue to take place after clinical features become noticeable; however the interaction between ongo-ing compensatory mechanisms and the effect of standard symptomatic treatment, i.e., l-DOPA, has not been stud-ied and is not necessarily synergistic. It is also likely that compensatory mechanisms are implicated in the onset of clinical manifestations associated with advanced PD such as cognitive impairment, autonomic disturbances or dise-quilibrium. Currently, the available data is limited to motor symptoms and signs.

The model commonly accepted to explain the compen-sation that follows nigral lesion was proposed by Zigmond and co-workers (Zigmond et al., 1990; Zigmond, 1997) and indicates that surviving DA neurons undergo func-tional changes aimed at preserving DA release in the stria-tum (Zigmond et al., 1990). However, the sole importance of such a mechanism has been questioned on the basis of findings in the MPTP monkey model (Bezard et al., 1997c). In this model, repeated administration of low doses

Handbook of Basal Ganglia Structure and Function642

of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)to non-human primate initiates a process of neurodegener-ation reminiscent of that seen in PD (Bezard et al., 2001c).The novelty of the model accrues from the fact that theprotocol produces a reproducible, progressive DA cell lossover a time course of approximately one month (Bezardet al., 2001c). Findings in the MPTP monkey model haverevealed compensatory mechanisms beyond the nigrostriatalDA system.

In this review, we describe these different compensa-tory mechanisms, discuss the evidence sustaining their rel-ative importance and examine the practical implications ofthese findings for defining conceptually novel approachesto the diagnosis and treatment of PD.

II. oVerVIew of coMpenSatIon, claSSIc conceptS

The appearance of parkinsonian signs is supposed toclosely reflect the breakdown of striatal DA homeostasis.In patients this process occurs over several years (meanestimation 7 years) and post-mortem analysis of parkinso-nian brains indicates that extensive loss of DA in the puta-men and in the caudate nucleus can still be accompaniedby only minor clinical manifestations (Bernheimer et al.,1973; Agid, 1991). In animal models of PD even higherdegrees of striatal DA depletion are tolerated (Zigmond andStricker, 1973; Bezard et al., 1997a; Bezard et al., 1997c).

At the beginning of DA cell loss, DA efficiency is suchthat modest reduction of SNc neurones does not neces-sitate any adaptive response (Abercrombie et al., 1990;Garris et al., 1997). Discrete compensation of striatal DAcould occur because the profuse DA striatal innervationshas some degree of redundancy or, more likely, becauseDA diffuse by volume transmission (Fuxe and Agnati,1991) from lesser affected areas. However, once a criti-cal threshold of neurodegeneration has been reached, itbecomes essential to regulate DA release. This regulationof DA activity is homeostatically controlled and impliesadaptive changes in the synthesis and release of DA, andin the response of the striatal neurones (Zigmond, 1993).Increased neuronal firing and DA turnover, once believedto be a major homeostatic mechanism, has recently beenshown to occur only to a modest degree and only when DAdepletion is substantial (Bezard et al., 2001c; Bezard et al.,2003; Rodriguez et al., 2003). Indeed, in the early stages ofSNc degeneration, other compensatory mechanisms havebeen identified, intrinsic and extrinsic to the basal ganglia,

that are not directly related to modifications in levels of extracellular DA and do not actively compensate for DA loss in the classically understood manner. In the following sections we review findings regarding striatal mechanisms, including evidence in favour and against changes in DA availability, and other basal ganglia and thalamo-cortical mechanisms also possibly involved in compensating DA reduction in PD.

III. StrIatal MechanISMS

a. pre- and postsynaptic changes in dopaminergic activity

There are several putative mechanisms by which the nigrostriatal system may adapt to restore or maintain DA activity within limits compatible with an apparently nor-mal motor performance (Fig. 37.1). These include the following: (i) increased SNc neuronal activity leading to increase DA release and turnover (Zigmond et al., 1990); (ii) reduced DA transporter (DAT) expression to aug-ment DA synaptic availability; (iii) increased DA receptor sensitivity.

1. Increased DA Activity

The preferential implication of the nigrostriatal DA path-way in the compensatory preservation of DA function has been supported by studies showing an increase in DA release, DA turnover, DA uptake and tyrosine hydroxylase activity/protein after nigrostriatal damage in animal mod-els and in the brain of patients with PD (Bernheimer et al., 1973; Onn et al., 1986; Snyder et al., 1990; Zigmond et al., 1990; Hornykiewicz, 1998; Pifl and Hornykiewicz, 2006; Perez et al., 2008) (Fig. 37.1). Indeed, it was the seminal work of Hornykiewicz in the brain of a few PD patients where it was first shown that the ratio of DA to its striatal metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was increased in patients with mild symptoms (Bernheimer et al., 1973; Zigmond et al., 1990). It was suggested that such up-regulation of DA transmission might be a possible mechanism opera-tive in the preclinical stages of the disease attempting to compensate for DA loss in PD (Hornykiewicz, 1993; Pifl and Hornykiewicz, 2006) However, in the progressive MPTP-lesioned primate model of PD discussed above, the up-regulation of DA metabolism is unchanged in the pre-symptomatic period and only occurs at the very end stage of the symptomatic part of the progression. The finding

643chapter | 37 Compensatory Mechanisms in Experimental and Human Parkinsonism

fIGure 37.1 Schematic summary of basal ganglia compensatory mechanisms in Parkinson’s disease. (A) Main basal ganglia connections in the “normal” state. Black arrows correspond to the dopaminergic nigrostriatal and nigro-subthalamic projections. Red and green arrows indicate inhibitory GABAergic and excitatory glutamatergic projections, respectively. The thickness of the arrows indicates relative functional activity. Black dots symbol-ize released dopamine (DA). (B) Proposed compensatory mechanisms in the presymptomatic stage of Parkinson’s disease. (1) Nigrostriatal compensa-tory mechanisms: increased DA release and turnover, increased receptor sensitivity, sprouting, and reduced DA re-uptake by DAT. (2) Increased PPE-A mRNA expression: increased enkephalin release in GPe may reduce GABA release through enhanced activation of delta opioid receptors and keep activity of GPe within normal limits. (3) Loss of dopaminergic projections may lead to hyperactivity of the STN, before DA depletion in the putamen reaches an extent that alters the putamen-GPe projection, leading to increased GPe activity which in turn inhibits GPi/SNr, thus maintaining normal output activity. (C) Further dopamine loss in the putamen reaches a level that cannot be compensated. This causes decreased inhibitory activity in the “direct” strio-GPi/SNr projection and excessive inhibitory activity in the “indirect” projection and GPe hypoactivity. The latter leads to further hyper-activity of the STN and GPi, accounting for the onset of parkinsonian motor features. DAT, dopamine transporter; PPE, pre-proenkephalin A; SNc, substantia nigra pars compacta; STN, subthalamic nucleus; GPe, globus pallidus external segment; GPi, globus pallidus internal segment. To view a color version of this image please visit http://www.elsevierdirect.com/companion/9780123747679

that most of the remaining SNc neurons of PD patients exhibit lower rather than high tyrosine hydroxylase mRNA expression (Javoy-Agid et al., 1990) further challenges the effectiveness of this compensatory mechanism.

Zigmond et al. (1990) posited that surviving neurons and terminals compensate by releasing more DA follow-ing denervation. Complementary views have been proposed

(Bergstrom and Garris, 2003; Bezard et al., 2003) on the basis of both rodent and primate investigations. However, it is noteworthy that experimental findings on this area are vari-able and may even be contradictory. Thus, on the one hand, the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease demonstrates that dialysate DA levels col-lected in the striatum are normal until the loss of DA terminals


is nearly complete (Zhang et al., 1988; Abercrombie et al., 1990; Robinson et al., 1994). Furthermore, the fact that endogenous DA release was not increased in severely lesioned mice suggests that augmented DA release does not constitute a pre-synaptic compensatory mechanism (Bezard et al., 2000). On the other hand, a 300% increment in endog-enous striatal DA release was encountered in moderately lesioned MPTP monkeys (Perez et al., 2008) and nicotine-evoked [3 H]DA release was maintained at or near control levels in the ventromedial striatum after MPTP treatment, despite 50% declines in DA. Moreover, although DA release was reduced to about 10% of control in the dorso-lateral striatum with denervation, it was still greater than the DA levels (1% of control) in this region. These results con-trast with other studies using real-time voltammetry to probe neurotransmitter dynamics which did not find changes in pre-synaptic DA release, but additionally suggested a down-regulation of DA uptake (Garris et al., 1997; Rothblat and Schneider, 1999; Dentresangle et al., 2001).

2. Reduced DAT Expression

The absence of up-regulated release is striking, but reduced DA uptake by the DA transporter (DAT) could as well be compensatory (Fig. 37.1). Earlier post-mortem studies in PD patients described down-regulation of DAT mRNA (Uhl et al., 1994; Joyce et al., 1997), after symptoms have appeared, but the relevance for functional compensation in the preclinical phase was not clear and in most instances patients have received dopaminergic drugs, which probably modifies DAT expression. In models of preclinical phase, DAT was not found down-regulated (Bezard et al., 2000; Bezard et al., 2001c; Dentresangle et al., 2001). However, a number of more recent findings using positron emission tomography (PET) do suggest a very important role for DAT regulation in early PD. A PET study with three radioligands to assess vesicular monoamine transport, plasma membrane DA transport and synthesis of DA in patients with early and advanced PD were consistent with increased activity of aromatic L-aminoacid decarboxylase and down-regulation of DAT (Lee et al., 2000; Adams et al., 2005). A similar approach has recently been applied by the same study group in the 6-OHDA rat’s model, where a very positive correla-tion was found between reduced labeling for DAT (by PET) and denervation (Sossi et al., 2009). DAT down-regulation appears to be functionally capable of maintaining fairly constant and normal DA synaptic levels up to 75% of DA lost. In the same way, as low as 5% of normal striatal DA

levels is sufficient for normal motor performance in non-human primates (Elsworth et al., 2000). It is therefore, quite conceivable that reduction in uptake mechanism associated with moderate denervation could lead to longer-range diffu-sion of DA away from its site of release, increasing tonic DA activity in a modest but sufficient amount to maintain striatal physiology within normal levels.

3. DA Receptor Changes

The role of changes in DA receptors has also been explored as a possible compensatory mechanism (Fig. 37.1). Thus, increased affinity of D2 receptors for DA could mask an effect of neurotransmitter loss on binding. Primate studies suggest that increases in D2 receptors might act as adap-tive mechanisms in the early stages of disease progression (Bezard et al., 2001c). The relationship between D2-like receptor binding and both DAT binding and DA content is not linear but instead is best represented by equations com-bining the synergistic actions of two processes (Bezard et al., 2001c). D2-like receptors are located on both the pre-synaptic DA terminals and the postsynaptic striatal neurons. Thus, the quadratic correlation can be explained by the ini-tial decrease in D2 receptor binding reflecting only disap-pearance of the DA terminals while the subsequent increase represents a compensatory response occurring postsynapti-cally. The transition between these two phenomena occurs in the middle of the presymptomatic period, These findings suggest not only that presymptomatic increase in D2 recep-tor binding might be a compensatory mechanism but also that the breakdown of striatal DA homeostasis occurs ear-lier than expected. In addition, findings in the rat and mon-key models indicate that DA depletion is associated with an increase in the fraction of D2-like receptors in a high-affin-ity state (Seeman et al., 2005; Chefer et al., 2008). Another possible mechanism leading to an increase in D2 receptor affinity for DA could be a translocation of these receptors from the intracellular pool to the membrane surface (Chefer et al., 2008). Confirmation of early changes in D2 receptors number or affinity state in patients could lead to a presymp-tomatic diagnosis of PD.

B. re-Innervation

Regeneration or sprouting of terminals from unaffected DA cell groups is a potential compensatory mechanism (Fig. 37.1). Certainly, in animal models sprouting has been shown to occur in animals with partial lesions, and several


neurotrophic agents act through this mechanism (Blanchard et al., 1996; Song and Haber, 2000). Extensive work has been carried out with beautiful morphological analyses of nigrostri-atal DA axons in rats with different degrees of DA depletion by 6-OHDA; such studies reported significant axonal sprout-ing in the DA terminal arbors (Finkelstein et al., 2000; Stanic et al., 2003), an effect that would normally be inhibited by a tonic stimulation of D2 autoreceptors (Parish et al., 2002). This homeostatic mechanism is overcome when 70% of nigral DA neurons are lost (Finkelstein et al., 2000; Stanic et al., 2003). Re-innervation is accompanied by behavioral recovery in MPTP monkeys, marked increases in DA levels and modest elevations of metabolic activity (HVA/DA ratio) (Elsworth et al., 2000). However, PD is a progressive degener-ative process where the capacity for healthy neurons to sprout is probably diminished. In this regard, it is interesting that one study in human brains showed non-melanised neurons in the ventral tegmental area displaying a significantly higher expression of TH mRNA than melanised neurons in the same PD brains and control subjects (Tong et al., 2000), consistent with up-regulation of TH expression in these neurons.

c. Serotonin compensation

Monkeys intoxicated with MPTP systemically show a clear tendency to recover spontaneously unless treatment is con-tinued until a large enough lesion is achieved. Using this model, it has been shown that recovered monkeys displayed more DA and serotoninergic fibres than those with stable motor symptoms in sensorimotor and associative territories of striatum and more DA fibres in the GPi (Mounayar et al., 2007). Such serotonergic sprouting (Gaspar et al., 1993) could be seen as related with competition due to reduced number of DA fibres or could be a real compensatory mechanism. Studies in 6-OHDA lesion rats have produced inconsistent results, reporting either increased or decreased serotonergic striatal innervations (Takeuchi et al., 1991; Zhou et al., 1991). Recently however, more direct data by microdialysis in MPTP-treated monkeys indicate that recovery of motor symptoms is associated with increased serotonin striatal levels (~370%) (Boulet et al., 2008).

d. Volume transmission and passive Stabilization

There are two principal mechanisms of striatal DA release (see also Chapter 17): (i) “phasic release”, which is associ-ated with abrupt increases in SNc neuron firing leading to

activation of D1 and D2 receptors located within the syn-apse; such DA is subjected to intense uptake and metabolic degradation (Parent et al., 1995); and (ii) tonic release, which is independent of SNc firing, primarily excites extra-synaptically located D1 receptors on neurons of the “direct” pathway (see Chapter 1) by non-synaptic diffusion transmission (Onn et al., 2000). This “volume transmis-sion” (Zoli et al., 1999) would appear to play a far more important role in pathological conditions. In animal mod-els of PD, DA transmission is in part restored by volume transmission of the neurotransmitter from intact to dener-vated regions (Bezard and Gross, 1998; Zoli et al., 1999).

These well established mechanisms have recently been challenged by analysis of steady-state levels of extracellular DA, which mimics the normal dynamics of DA-mediated tone (Garris et al., 1997; Bergstrom and Garris, 2003). In these studies, kinetic analysis demon-strated that DA transmission was maintained without plas-ticity of release or clearance mechanisms suggesting that the primary mechanisms controlling extracellular DA lev-els were not actively altered. This so-called “passive sta-bilization” is mediated by the simple physical principles of diffusion and steady state, and forms the basis for a new compensation model of preclinical parkinsonism. Would the regulation of uptake be not necessary, the observation that only 5% of normal DA levels are able to restore nor-mal motor performance in non-human primates (Elsworth et al., 2000) would support the “passive stabilization” the-ory and would not be in support of the down-regulation of DA uptake. This provocative theory would actually provide an elegant explanation to both the high redundancy in the system and the sharpness and brutality of the threshold for symptom appearance.

IV. BaSal GanGlIa-MedIated coMpenSatIon

According to the classic pathophysiological model of the basal ganglia (Alexander and Crutcher, 1990), DA defi-ciency leads to reduced inhibition of gamma-aminobutyric acid (GABA)-ergic striatal neurons in the indirect path-way and decreased facilitation of GABA-ergic neurons in the direct pathway (Albin et al., 1989; DeLong, 1990) (see Chapter 1). Reduced inhibition of neurons in the indirect pathway would lead sequentially to over-inhibition of the globus pallidus pars externalis (GPe), disinhibition of the subthalamic nucleus (STN), and thus, overactivity of basal ganglia outputs from the internal segment of the globus


pallidus (GPi) and the substantia nigra pars reticulata (SNr) (Mitchell et al., 1989; DeLong, 1990). Similarly, decreased activation of neurons in the direct pathway reduces its inhibitory influence on GPi/SNr and contributes to the excessive basal ganglia output activity.

The striato-GPe projection uses enkephalins, derived from the precursor pre-proenkephalin-A (PPE-A), as co-transmitters with GABA (see also Chapter 29). A wealth of evidence suggests that the activity of both the GABAergic and enkephalinergic components of this pathway is increased in the parkinsonian MPTP-treated monkey (Asselin et al., 1994; Herrero et al., 1995; Levy et al., 1995; Morissette et al., 1999). However, both the role of this co-transmission in the generation of parkinsonian symptoms and the nature of any functional interaction between GABA and enkephalin are not clear. It has recently been shown that PPE-A mRNA levels are elevated before the appearance of parkinsonian motor features in the progressive MPTP model of degen-eration in the primate (Bezard et al., 2001b). Importantly, this up-regulation is restricted to motor regions of the basal ganglia circuitry. The increased PPE-A mRNA expression observed in asymptomatic, but DA-depleted animals pro-vide further support for the hypothesis that the breakdown of striatal DA homeostasis is dissociated from the clinical signs appearance (Fig. 37.1).

The functional significance of this presymptomatic up-regulation of enkephalinergic transmission remains subject to debate. Increased PPE-A mRNA levels could represent an endogenous mechanism attempting to reduce an overactive inhibitory GABAergic input from the stria-tum to the GPe (Maneuf et al., 1994) (see also Chapter 29). Enhanced enkephalin release in GPe may thus reduce GABA release through enhanced activation of delta-opioid receptors by met-enkephalin and keep activity of GPe nor-mal. This compensatory mechanism, intrinsic to the basal ganglia circuitry, but outside the nigrostriatal pathway, may be responsible of the absence of changes in GPe neu-ronal activity at any stage of parkinsonism (Herrero et al., 1996; Vila et al., 1997; Bezard et al., 1999). When looking at the relationship between DAT binding and the expres-sion level of PPE-A mRNA, it appears that up-regulation of enkephalinergic transmission starts early in the degen-erative process, at a stage comparable to the D2 recep-tor up-regulation. Further support for the concept that an elevation of PPE-A expression might be a presymptomatic compensatory mechanism is provided by the finding that, once symptoms appear, the up-regulation of PPE-A does not remain indefinitely (Schneider et al., 1999).

While current imaging technologies might have diffi-culty imaging an up-regulation of PPE-A expression, the idea of using enhanced enkephalin transmission as a bio-marker for presymptomatic PD is not without possibili-ties. For instance, a potential non-imaging approach might involve the administration of an opioid antagonist to elicit parkinsonian symptoms in presymptomatic PD. A short acting antagonist combined with sensitive electromyo-graphic measurement of rigidity and tremor might permit the development of a test that would cause minimal dis-comfort. Such a strategy would however never be accepted without a cure available (or at least a significantly neuro-protective drug) for obvious ethical reasons.

Although the notion that levels of gene expression are tightly coupled to levels of physiological activity is sim-plistic, the presymptomatic increase in PPE-A expression level is nonetheless suggestive of changes in the activity of striatal medium spiny neurons before symptoms appear. The question of presymptomatic changes in the electro-physiological activity of basal ganglia nuclei has thus emerged.

Changes in activity in the STN and in GPi have been assessed, using multiunit electrophysiological record-ings, in monkeys intoxicated with MPTP according to the progressive regimen (Bezard et al., 1999, 2002) (see also Chapters 25 and 38 for reviews of changes in basal ganglia circuit activities in MPTP models). In this model, both overactivity of STN and GPi actually occur before the appearance of symptoms and thus might be related to presymptomatic compensation (Bezard et al., 1999, 2002). Similar results were reported in the 6-OHDA-treated rat model of PD where early changes in the firing frequency of STN neurons occur before it is possible to induce rota-tions in those animals (Vila et al., 2000).

The increase in the activity of GPi, in the latter stages of the presymptomatic period, has recently been con-firmed using multi-channel single unit recordings in the same MPTP monkey model (Boraud et al., 2001; Leblois et al., 2006; Leblois et al., 2007). These results are sugges-tive of dissociation between the changes in the basal gan-glia activity and the appearance of the parkinsonian motor abnormalities. Thus, there appears to be very early striatal DA homeostasis breakdown highlighted by the early up-regulation of both DA D2 receptor and enkephalin pre-cursor expression and a comparatively later increase in the activity of the basal ganglia output structures. Indeed, the breakdown of the DA homeostasis occurs before the changes in the basal ganglia electrophysiological activity,


further supporting the existence of non-DA compensatory mechanisms intrinsic to the basal ganglia.

Though STN and GPi are both overactive before the appearance of symptoms, both changes in neural activity are not necessarily presymptomatic compensatory mecha-nisms. However, overactivity of the STN could be a com-pensatory mechanism initially (Fig. 37.1). Blockade of the subthalamic excitation of surviving DA neurons in the presymptomatic period can provoke the emergence of par-kinsonian symptoms (Bezard et al., 1997a, b; Obeso et al., 2004). Thus, it appears that by increasing the firing rate of surviving DA neurons the overactive STN might be able to enhance remaining DA transmission and delay the appear-ance of symptoms until relatively late in the progression. An alternative view regarding the functional modulation of the STN after DA depletion has been recently proposed (Obeso et al., 2004). The hyperactivity of the STN and related glu-tamatergic nuclei arises early in the course of PD, before striatal DA depletion has become significant (Vila et al., 2000; Bezard et al., 2003). At this time (in the presymptom-atic state), DA loss in the caudal putamen is still not large enough (50%) to increase activity in the striatal inhibitory projection to the GPe. As a result, increased STN activity exerts a powerful excitatory effect on the GPe that leads to increased inhibition of the GPi and maintains the output of the motor circuit within normal limits. In that fashion, the “internal” STN-GPe–GPi circuit compensates itself (Obeso et al., 2000). Increased STN activity could increase GPi fir-ing by its direct excitatory projection (Whone et al., 2003), but this can be compensated by the still-normal inhibitory projection to the GPi (i.e., “direct” pathway). In PD, where the changes occur slowly, excessive STN drive onto the GPi might also be compensated by way of the nigro-pallidal DA projection, which has been shown to increase during the presymptomatic phase, by fluorodopa positron emission tomography (PET) (Shink et al., 1996).

In humans it has been suggested that GPi in particular could be implicated in compensatory mechanisms (Whone et al., 2003). The 18F-dopa uptake increases in early phase of PD in the GPi and additionally a modification of tyrosine hydroxylase (TH) labeling has been noticed in GPi of MPTP-intoxicated monkeys (Jan et al., 2000; Mounayar et al., 2007). Although this change in TH labeling is less marked in the pallidal complex than in the striatum, suggesting that the pallidal omplex could contribute to compensation, there is no evidence, or theoretical basis, for a mechanism by which overactive GPi (driven by overactive STN) could represent a presymptomatic compensatory mechanism.

V. thalaMo-cortIcal-MedIated coMpenSatIon

Overactivation of lateral premotor areas has also been reported in PD patients, generally interpreted as a com-pensation for deficiencies in the midline motor system during internally generated tasks (Cunnington et al., 1999; Berardelli et al., 2001). Recent studies in MPTP-treated monkey have revealed the involvement of non-basal gan-glia structures, throwing light upon putative cortical compensatory mechanisms (Bezard et al., 2001a; Escola et al., 2003; Huang et al., 2007; Mounayar et al., 2007). Although it is likely that many cortical or subcortical regions are involved in the pathophysiology of motor signs (Hirsch et al., 2000; Pahapill and Lozano, 2000; Berardelli et al., 2001), the pivotal position of the supplementary motor area (SMA) between the prefrontal and motor cor-tical areas makes it probable that these structures play an essential role, particularly in the origin of bradykinesia, in the pathophysiology of PD.

The 2-deoxyglucose (2-DG) metabolic mapping tech-nique has been applied to identify changes in neuronal met-abolic activity that occur before and after the appearance of parkinsonian motor abnormalities, in the MPTP model that recapitulates the progression of the disease (Mitchell et al., 1989; Bezard et al., 2001a). 2-DG levels were assessed in the whole basal ganglia, the motor thalamic nuclei, and the SMA (Alexander and Crutcher, 1990; DeLong, 1990). It was shown that decreased metabolic rate in the SMA only appears when MPTP-treated monkeys become fully parkin-sonian (Bezard et al., 2001a). These changes occur after the early changes in the electrophysiological activity described above. Therefore, neural activity in SMA is normal in presymptomatic animals but decreased in parkinsonian monkeys (Escola et al., 2003). The decrease in metabolic activity in SMA accompanying motor symptoms of fully parkinsonian animals was similar to that reported in previ-ous in vivo and ex vivo functional imaging studies in PD patients (Palombo et al., 1990; Jenkins et al., 1992; Rascol et al., 1992; Playford et al., 1993; Eidelberg et al., 1995; Rascol et al., 1998). Altogether these observations suggest that PD symptoms are closely linked to changes in SMA activity. In itself, overactivity of basal ganglia outputs does not necessarily lead to the generation of symptoms while impairment of SMA metabolic activity does. It thus appears that compensatory mechanisms outside the basal ganglia exist to prevent the appearance of symptoms even though the basal ganglia are in a parkinsonian-like state.


Other territories could be implicated in the phenom-enon of recovery and, furthermore, in the compensatory mechanisms in early phases of PD, as well. The parafas-cicular–centromedian complex of the thalamus (Orieux et al., 2000) and the pedunculopontine nucleus (PPN) in the brainstem (Pahapill and Lozano, 2000) are known to be hyperactive in the 6-OHDA rat model, (Orieux et al., 2000), while the motor cortex projection is hypoactive (Orieux et al., 2002). However, how hyperactivity ensues in these motor-related glutamatergic nuclei associated with STN is not understood (Hirsch et al., 2000; Obeso et al., 2000; Vila et al., 2000). If the PD process begins with the loss of DA cells in the SNc, as is the case in the animal models induced by neurotoxins, it appears likely that the glutamatergic hyperactivity would arise as a direct conse-quence of reduced DA input. In this regard, there is now considerable evidence indicating that DA exerts a modu-latory effect upon STN activity, and therefore it can be assumed that the effect of DA drugs is not limited to the striatum. One should not forget that degeneration in PD is multisystemic and affects among many other nuclei, the thalamus (Henderson, 2000; Jellinger, 1999). Therefore, we could not rule out this widespread lesioning as one of the many important factors that may counteract the defects associated with the DA denervation.

Finally, regarding the thalamo-cortical compensation mechanism, it has been suggested that the major dysfunc-tion after DA depletion at the early stages of PD could be the loss of functional segregation within cortico-basal ganglia circuits. This dysfunction appears to affect only the pallidal-nigral thalamus in the asymptomatic state, and to extend to the cerebellar thalamus coinciding with the appearance of PD motor features (Pessiglione et al., 2005). As the DA depletion becomes more severe, motor deficits characteristic of parkinsonism may be superimposed upon pre-existing executive deficits (Schneider and Kovelowski, 1990; Schneider and Pope-Coleman, 1995). In this context, the loss of functional segregation may first induce inter-ferences within the motor or associative circuit and then between motor and cognitive areas.

VI. dopaMIne coMpenSatIon reappraISed

Until recently, compensatory mechanisms associated with recovery from PD motor symptoms were thought to result principally from the adaptive properties of DA neurons (Zigmond, 1997). Studies on MPTP monkeys with motor

features of varying degrees of severity have shown that a limited DA loss can, in fact, be counterbalanced by an increase in DA release from the remaining fibers. “Passive stabilization” of the DA system may thus represents an active mechanism that maintains DA homeostasis with den-ervation (Garris et al., 1997; Bezard et al., 2000; Bergstrom and Garris, 2003) and contribute to presynaptic DA com-pensation. Also, a large body of evidence suggests that presynaptic DA-mediated compensation delays the appear-ance of parkinsonian symptoms with moderate nigrostriatal damage. This increased DA release from spared DA ter-minals could help to maintain DA homeostasis at the early stages of neuronal degeneration. With further degenerative changes, the continued loss of DA nerve terminal integrity may no longer support increased DA function (Pifl and Hornykiewicz, 2006; Perez et al., 2008).

The question thus remains: what compensates for DA degeneration? Our lack of understanding of the compensa-tion process itself may have been hampered because of a widely held belief in concepts for which solid support was not available, that is:

l the late appearance of parkinsonian motor features is due to failure of compensatory mechanisms thought to reside solely within the nigrostriatal pathway; and

l the appearance of parkinsonian signs closely reflects the breakdown of the striatal DA homeostasis, i.e., the failure of the above-mentioned DA compensa-tory mechanisms.

These views imply an intimate and causative relation-ship between the breakdown of the striatal DA homeo-stasis, changes in striatal activity (as well as in the other components of the basal ganglia) and the appearance of motor abnormalities.

Until now, it has proved difficult to ascertain the true nature of these relationships on the basis of changes in neurotransmission, DA or otherwise, observed in PD. DA depletion alters expression of multiple neurotransmitters, particularly the serotonergic system as recently suggested (Mounayar et al., 2007), neuropeptides and receptors pres-ent in the different compartments of the striato-pallidal and striato-nigral output pathways (see also Chapters 28 and 36). A combination of pre- and postsynaptic compensatory mechanisms most likely accounts for the delayed develop-ment of the motor symptoms characteristic of PD.

Consequently, it is reasonable to assume that the dis-ease process and aging in DA and non-DA structures involve a biologic interaction. Thus, studies about the


pathogenic abnormalities implicated in PD should further account not only for the relative selectivity of the disease process to the SN, but also for the widespread involvement of the whole brain in late clinical stages of the disease.

VII. concluSIonS – coMpenSatIon VS. SenSInG dopaMIne depletIon

Consensus arises for stating that compensation is multi-factorial, involving several neuromodulators and neuro-transmitter systems as well as occurring at several levels of the cortio-basal ganglia-thalamo-cortical loop. Considering compensation only under the angle of the nigrostriatal pathway is clearly not sufficient, although its paramount importance is recognized. As a last example, we would like to emphasize the marked plasticity of the SNc itself. Taking advantage of the progressive non-human primate model, we monitored transcriptional fluctuations in the SN using affymetrix microarrays in control (normal), saline-treated (normal), 6 day-treated (asymptomatic with 20% cell loss), 12 day-treated (asymptomatic with 40% cell loss) and 25 day-treated animals (fully parkinsonian with 85% cell loss) (Bassilana et al., 2005). Surprisingly, different profiles of gene regulation were defined using a hierarchical cluster-ing algorithm. Such profiles are likely to represent activa-tion/deactivation of mechanisms of different nature. The main conclusion of this work was the demonstration of (i) the existence of yet unknown compensatory mechanisms within the SN itself in the course of the degeneration; (ii) the putative triggering of a developmental program in the mature brain in reaction to progressing degeneration and finally; (iii) the activation of mechanisms leading eventu-ally to death in final stage (Bassilana et al., 2005). Thus, the SN itself is undergoing plastic, likely compensatory changes in the course of the degenerative process.

We would, however, like to conclude on a more con-ceptual note. Most, if not all previous studies on compen-sation have related changes in given markers, whatever the marker is, and a given level of nigrostriatal degenera-tion. The compensatory nature of these changes is merely hypothetical as almost none of them have been causally demonstrated as being compensatory. To do so, one should block or enhance the hypothesized mechanism resulting into worsening/appearance of motor symptoms or reduc-tion/masking of those symptoms, respectively. While the true compensatory nature of the glutamatergic inputs of the SNc was shown by blocking glutamatergic activity and revealing parkinsonian features earlier in the intoxication

process (Bezard et al., 1997b), similar approaches have not been formally undertaken for other markers/parameters. It is even possible that most of these “compensatory mecha-nisms” are not compensatory but simply represent the con-sequences of DA depletion or the network dysfunction. Manipulating these would thus bring new knowledge on the compensatory mechanisms at work. What is critically needed now is to reappraise the compensatory nature of the number of hypothesized mechanisms by formally testing the impact of their modulation upon symptom appearance or severity. Such a step constitutes the missing link before embarking on developing new strategies aiming at promot-ing compensatory mechanisms in a therapeutically relevant manner for PD patients.

acknowledGMentS

Research in this area is funded in France by ANR Young Researcher (EB) and in Spain by grants SAF2005-08416-C02-01 from the Spanish ministry of Science and Education, the CIBERNED (PIO31085, Spanish Ministry of Health), and FIMA (Fundacion Investigacion Medica Aplicada) – UTE(Union Temporal de Empresas) project in the University of Navarra (JO).

referenceS

Abercrombie ED, Bonatz AE, Zigmond MJ (1990) Effects of l-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopa-mine-treated rats. Brain Res 525:36–44.

Adams JR, van Netten H, Schulzer M, et al. (2005) PET in LRRK2 muta-tions: comparison to sporadic Parkinson’s disease and evidence for presymptomatic compensation. Brain 128:2777–2785.

Agid Y (1991) Parkinson’s disease: pathophysiology. Lancet 337:1321–1324.

Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375.

Alexander GE, Crutcher MD (1990) Functional architecture of basal gan-glia circuits: neural substrates of parallel processing. Trends Neurosci 13:266–271.

Asselin MC, Soghomonian JJ, Cote PY, Parent A (1994) Striatal changes in preproenkephalin mRNA levels in parkinsonian monkeys. Neuroreport 5:2137–2140.

Bassilana F, Mace N, Li Q, Stutzmann JM, et al. (2005) Unraveling substantia nigra sequential gene expression in a progressive MPTP-lesioned macaque model of Parkinson’s disease. Neurobiol Dis 20:93–103.

Berardelli A, Rothwell JC, Thompson PD, Hallett M (2001) Pathophysiology of bradykinesia in Parkinson’s disease. Brain 124:2131–2146.

Bergstrom BP, Garris PA (2003) “Passive stabilization” of striatal extra-cellular dopamine across the lesion spectrum encompassing the


presymptomatic phase of Parkinson’s disease: a voltammetric study in the 6-OHDA-lesioned rat. J Neurochem 87:1224–1236.

Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455.

Bezard E, Gross CE (1998) Compensatory mechanisms in experimen-tal and human parkinsonism: towards a dynamic approach. Prog Neurobiol 55:93–116.

Bezard E, Gross CE, Brotchie JM (2003) Presymptomatic compensation in Parkinson’s disease is not dopamine-mediated. Trends Neurosci 26:215–221.

Bezard E, Boraud T, Bioulac B, Gross CE (1997a) Presymptomatic rev-elation of experimental parkinsonism. Neuroreport 8:435–438.

Bezard E, Boraud T, Bioulac B, Gross CE (1997b) Compensatory effects of glutamatergic inputs to the substantia nigra pars compacta in experimental parkinsonism. Neuroscience 81:399–404.

Bezard E, Boraud T, Bioulac B, Gross CE (1999) Involvement of the sub-thalamic nucleus in glutamatergic compensatory mechanisms. Eur J Neurosci 11:2167–2170.

Bezard E, Crossman AR, Gross CE, Brotchie JM (2001a) Structures out-side the basal ganglia may compensate for dopamine loss in the pres-ymptomatic stages of Parkinson’s disease. FASEB J 15:1092–1094.

Bezard E, Boraud T, Bioulac B, Gross CE (2002) Evolution of the mul-tiunit activity of the basal ganglia in the course of experimental par-kinsonism. In: The Basal Ganglia VI (Graybiel A, Delang M, Kitaï S, eds), pp. 107–116. New York: Kluwer Academic Publishers.

Bezard E, Imbert C, Deloire X, Bioulac B, Gross CE (1997c) A chronic MPTP model reproducing the slow evolution of Parkinson’s dis-ease: evolution of motor symptoms in the monkey. Brain Res 766:107–112.

Bezard E, Ravenscroft P, Gross CE, Crossman AR, Brotchie JM (2001b) Upregulation of striatal preproenkephalin gene expression occurs before the appearance of parkinsonian signs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys. Neurobiol Dis 8:343–350.

Bezard E, Jaber M, Gonon F, Boireau A, Bloch B, Gross CE (2000) Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neu-rodegeneration in the mouse. Eur J Neurosci 12:2892–2900.

Bezard E, Dovero S, Prunier C, et al. (2001c) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 21:6853–6861.

Blanchard V, Anglade P, Dziewczapolski G, Savasta M, Agid Y, Raisman-Vozari R (1996) Dopaminergic sprouting in the rat striatum after par-tial lesion of the substantia nigra. Brain Res 709:319–325.

Boraud T, Bezard E, Bioulac B, Gross CE (2001) Dopamine agonist-induced dyskinesias are correlated to both firing pattern and fre-quency alterations of pallidal neurones in the MPTP-treated monkey. Brain 124:546–557.

Boulet S, Mounayar S, Poupard A, et al. (2008) Behavioral recovery in MPTP-treated monkeys: neurochemical mechanisms studied by intra-striatal microdialysis. J Neurosci 28:9575–9584.

Chefer SI, Kimes AS, Matochik JA, et al. (2008) Estimation of D2-like receptor occupancy by dopamine in the putamen of hemiparkinsonian Monkeys. Neuropsychopharmacology 33:270–278.

Cunnington R, Iansek R, Bradshaw JL (1999) Movement-related poten-tials in Parkinson’s disease: external cues and attentional strategies. Mov Disord 14:63–68.

DeLong MR (1990) Primate models of movement disorders of basal gan-glia origin. Trends Neurosci 13:281–285.

Dentresangle C, Le Cavorsin M, Savasta M, Leviel V (2001) Increased extracellular DA and normal evoked DA release in the rat striatum after a partial lesion of the substantia nigra. Brain Res 893:178–185.

Ehringer H, Hornykiewicz O (1960) Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems/[Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system.]. Klin Wochenschr 38:1236–1239.

Eidelberg D, Moeller JR, Ishikawa T, et al. (1995) Assessment of disease severity in parkinsonism with fluorine-18-fluorodeoxyglucose and PET. J Nucl Med 36:378–383.

Elsworth JD, Taylor JR, Sladek JR Jr., Collier TJ, Redmond DE Jr., Roth RH (2000) Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in old-world primates one year after MPTP treatment. Neuroscience 95:399–408.

Escola L, Michelet T, Macia F, Guehl D, Bioulac B, Burbaud P (2003) Disruption of information processing in the supplementary motor area of the MPTP-treated monkey: a clue to the pathophysiology of akinesia? Brain 126:95–114.

Finkelstein DI, Stanic D, Parish CL, Tomas D, Dickson K, Horne MK (2000) Axonal sprouting following lesions of the rat substantia nigra. Neuroscience 97:99–112.

Fuxe K, Agnati LF (1991) Two principal modes of electrochemi-cal communication in the brain: volume versus wiring transmis-sion. In: Volume Transmission in the Brain: Novel Mechanisms for Neural Transmission (Fuxe K, Agnati LF, eds), pp. 1–9. New-York: Raven Press.

Garris PA, Walker QD, Wightman RM (1997) Dopamine release and uptake rates both decrease in the partially denervated striatum in pro-portion to the loss of dopamine terminals. Brain Res 753:225–234.

Gaspar P, Febvret A, Colombo J (1993) Serotonergic sprouting in primate MTP-induced hemiparkinsonism. Exp Brain Res 96:100–106.

Hassler R (1938) Zur Pathologie der Paralysis Agitans und des postenz-ephalitischen Parkinsonismus. J Psychol Neurol 48:387–476.

Herrero MT, Augood SJ, Hirsch EC, Javoy-Agid F, Luquin MR, Agid Y, Obeso JA, Emson PC (1995) Effects of l-DOPA on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum. Neuroscience 68:1189–1198.

Herrero MT, Levy R, Ruberg M, et al. (1996) Consequence of nigros-triatal denervation and l-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum. Neurology 47:219–224.

Hirsch EC, Perier C, Orieux G, et al. (2000) Metabolic effects of nigros-triatal denervation in basal ganglia. Trends Neurosci 23:S78–S85.

Hornykiewicz O (1993) Parkinson’s disease and the adaptive capacity of the nigrostriatal dopamine system: possible neurochemical mecha-nisms. Adv Neurol 60:140–147.

Hornykiewicz O (1998) Biochemical aspects of Parkinson’s disease. Neurology 51:S2–S9.

Huang C, Tang C, Feigin A, Lesser M, Ma Y, Pourfar M, Dhawan V, Eidelberg D (2007) Changes in network activity with the progression of Parkinson’s disease. Brain 130:1834–1846.

Jan C, Francois C, Tande D, Yelnik J, Tremblay L, Agid Y, Hirsch E (2000) Dopaminergic innervation of the pallidum in the normal state, in MPTP-treated monkeys and in parkinsonian patients. Eur J Neurosci 12:4525–4535.


Javoy-Agid F, Hirsch EC, Dumas S, Duyckaerts C, Mallet J, Agid Y (1990) Decreased tyrosine hydroxylase messenger RNA in the sur-viving dopamine neurons of the substantia nigra in Parkinson’s dis-ease: an in situ hybridization study. Neuroscience 38:245–253.

Jenkins IH, Fernandez W, Playford ED, Lees AJ, Frackowiak RS, Passingham RE, Brooks DJ (1992) Impaired activation of the supple-mentary motor area in Parkinson’s disease is reversed when akinesia is treated with apomorphine. Ann Neurol 32:749–757.

Joyce JN, Smutzer G, Whitty CJ, Myers A, Bannon MJ (1997) Differential modification of dopamine transporter and tyrosine hydroxylase mRNAs in midbrain of subjects with Parkinson’s, Alzheimer’s with parkinsonism, and Alzheimer’s disease. Mov Disord 12:885–897.

Leblois A, Meissner W, Bezard E, Bioulac B, Gross CE, Boraud T (2006) Temporal and spatial alterations in GPi neuronal encoding might contribute to slow down movement in Parkinsonian monkeys. Eur J Neurosci 24:1201–1208.

Leblois A, Meissner W, Bioulac B, Gross CE, Hansel D, Boraud T (2007) Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism. Eur J Neurosci 26:1701–1713.

Lee CS, Samii A, Sossi V, et al. (2000) In vivo positron emission tomo-graphic evidence for compensatory changes in presynaptic dopa-minergic nerve terminals in Parkinson’s disease. Ann Neurol 47:493–503.

Levy R, Herrero MT, Ruberg M, et al. (1995) Effects of nigrostriatal denervation and l-dopa therapy on the GABAergic neurons in the striatum in MPTP-treated monkeys and Parkinson’s disease: an in situ hybridization study of GAD67 mRNA. Eur J Neurosci 7:1199–1209.

Maneuf YP, Mitchell IJ, Crossman AR, Brotchie JM (1994) On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus. Exp Neurol 125:65–71.

Mitchell IJ, Clarke CE, Boyce S, Robertson RG, Peggs D, Sambrook MA, Crossman AR (1989) Neural mechanisms underlying parkin-sonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 32:213–226.

Morissette M, Grondin R, Goulet M, Bedard PJ, Di Paolo T (1999) Differential regulation of striatal preproenkephalin and preprot-achykinin mRNA levels in MPTP-lesioned monkeys chronically treated with dopamine D1 or D2 receptor agonists. J Neurochem 72:682–692.

Mounayar S, Boulet S, Tande D, et al. (2007) A new model to study com-pensatory mechanisms in MPTP-treated monkeys exhibiting recov-ery. Brain 130:2898–2914.

Obeso JA, Rodriguez-Oroz MC, Rodriguez M, Lanciego JL, Artieda J, Gonzalo N, Olanow CW (2000) Pathophysiology of the basal ganglia in Parkinson’s disease. Trends in Neurosciences 23:S8–S19.

Obeso JA, Rodriguez-Oroz M, Marin C, et al. (2004) The origin of motor fluctuations in Parkinson’s disease: importance of dopaminergic innervation and basal ganglia circuits. Neurology 62:S17–S30.

Onn SP, West AR, Grace AA (2000) Dopamine-mediated regulation of striatal neuronal and network interactions. Trends Neurosci 23:S48–S56.

Onn SP, Berger TW, Stricker EM, Zigmond MJ (1986) Effects of intra-ventricular 6-hydroxydopamine on the dopaminergic innervation of striatum: histochemical and neurochemical analysis. Brain Res 376:8–19.

Orieux G, Francois C, Feger J, Hirsch EC (2002) Consequences of dopaminergic denervation on the metabolic activity of the cortical

neurons projecting to the subthalamic nucleus in the rat. J Neurosci 22:8762–8770.

Orieux G, Francois C, Feger J, Yelnik J, Vila M, Ruberg M, Agid Y, Hirsch EC (2000) Metabolic activity of excitatory parafascicular and pedunculopontine inputs to the subthalamic nucleus in a rat model of Parkinson’s disease. Neuroscience 97:79–88.

Pahapill PA, Lozano AM (2000) The pedunculopontine nucleus and Parkinson’s disease. Brain 123(Pt 9):1767–1783.

Palombo E, Porrino LJ, Bankiewicz KS, Crane AM, Sokoloff L, Kopin IJ (1990) Local cerebral glucose utilization in monkeys with hemipar-kinsonism induced by intracarotid infusion of the neurotoxin MPTP. J Neurosci 10:860–869.

Parent A, Cote PY, Lavoie B (1995) Chemical anatomy of primate basal ganglia. Prog Neurobiol 46:131–197.

Parish CL, Finkelstein DI, Tripanichkul W, Satoskar AR, Drago J, Horne MK (2002) The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice. J Neurosci 22:8034–8041.

Perez XA, Parameswaran N, Huang LZ, O’Leary KT, Quik M (2008) Pre-synaptic dopaminergic compensation after moderate nigrostriatal damage in non-human primates. J Neurochem 105:1861–1872.

Pessiglione M, Guehl D, Rolland AS, Francois C, Hirsch EC, Feger J, Tremblay L (2005) Thalamic neuronal activity in dopamine-depleted primates: evidence for a loss of functional segregation within basal ganglia circuits. J Neurosci 25:1523–1531.

Pifl C, Hornykiewicz O (2006) Dopamine turnover is upregulated in the caudate/putamen of asymptomatic MPTP-treated rhesus monkeys. Neurochem Int 49:519–524.

Playford ED, Jenkins IH, Passingham RE, Frackowiak RS, Brooks DJ (1993) Impaired activation of frontal areas during movement in Parkinson’s disease: a PET study. Adv Neurol 60:506–510.

Rascol O, Sabatini U, Chollet F, Celsis P, Montastruc JL, Marc-Vergnes JP, Rascol A (1992) Supplementary and primary sensory motor area activity in Parkinson’s disease. Regional cerebral blood flow changes during finger movements and effects of apomorphine. Arch Neurol 49:144–148.

Rascol O, Sabatini U, Brefel C, et al. (1998) Cortical motor overactiva-tion in parkinsonian patients with l-dopa-induced peak-dose dyskine-sia. Brain 121(Pt 3):527–533.

Robinson TE, Mocsary Z, Camp DM, Whishaw IQ (1994) Time course of recovery of extracellular dopamine following partial damage to the nigrostriatal dopamine system. J Neurosci 14:2687–2696.

Rodriguez M, Gonzalez J, Sabate M, Obeso J, Pereda E (2003) Firing regulation in dopaminergic cells: effect of the partial degeneration of nigrostriatal system in surviving neurons. Eur J Neurosci 18:53–60.

Rothblat DS, Schneider JS (1999) Regional differences in striatal dopa-mine uptake and release associated with recovery from MPTP-induced parkinsonism: an in vivo electrochemical study. J Neurochem 72:724–733.

Schneider JS, Kovelowski CJ 2nd (1990) Chronic exposure to low doses of MPTP. I. Cognitive deficits in motor asymptomatic monkeys. Brain Res 519:122–128.

Schneider JS, Pope-Coleman A (1995) Cognitive deficits precede motor deficits in a slowly progressing model of parkinsonism in the mon-key. Neurodegeneration 4:245–255.

Schneider JS, Decamp E, Wade T (1999) Striatal preproenkephalin gene expression is upregulated in acute but not chronic parkinsonian mon-keys: implications for the contribution of the indirect striatopallidal circuit to parkinsonian symptomatology. J Neurosci 19:6643–6649.


Seeman P, Weinshenker D, Quirion R, et al. (2005) Dopamine supersensi-tivity correlates with D2High states, implying many paths to psycho-sis. Proc Natl Acad Sci USA 102:3513–3518.

Shink E, Bevan MD, Bolam JP, Smith Y (1996) The subthalamic nucleus and the external pallidum: two tightly interconnected structures that control the output of the basal ganglia in the monkey. Neuroscience 73:335–357.

Singh N, Pillay V, Choonara YE (2007) Advances in the treatment of Parkinson’s disease. Progress in Neurobiology 81:29–44.

Snyder GL, Keller RW Jr., Zigmond MJ (1990) Dopamine efflux from striatal slices after intracerebral 6-hydroxydopamine: evidence for compensatory hyperactivity of residual terminals. J Pharmacol Exp Ther 253:867–876.

Song DD, Haber SN (2000) Striatal responses to partial dopami-nergic lesion: evidence for compensatory sprouting. J Neurosci 20:5102–5114.

Sossi V, Dinelle K, Topping GJ, et al. (2009) Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson’s: an in-vivo imaging study. J Neurochem 109(1):85–92.

Stanic D, Finkelstein DI, Bourke DW, Drago J, Horne MK (2003) Timecourse of striatal re-innervation following lesions of dopaminer-gic SNpc neurons of the rat. Eur J Neurosci 18:1175–1188.

Takeuchi Y, Sawada T, Blunt S, Jenner P, Marsden CD (1991) Effects of 6-hydroxydopamine lesions of the nigrostriatal pathway on striatal serotonin innervation in adult rats. Brain Res 562:301–305.

Tong ZY, Kingsbury AE, Foster OJ (2000) Up-regulation of tyrosine hydroxylase mRNA in a sub-population of A10 dopamine neurons in Parkinson’s disease. Brain Res Mol Brain Res 79:45–54.

Uhl GR, Walther D, Mash D, Faucheux B, Javoy-Agid F (1994) Dopamine transporter messenger RNA in Parkinson’s disease and control substantia nigra neurons. Ann Neurol 35:494–498.

Vila M, Levy R, Herrero MT, Ruberg M, Faucheux B, Obeso JA, Agid Y, Hirsch EC (1997) Consequences of nigrostriatal denervation on the functioning of the basal ganglia in human and nonhuman primates: an in situ hybridization study of cytochrome oxidase subunit I mRNA. J Neurosci 17:765–773.

Vila M, Perier C, Feger J, et al. (2000) Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements. Eur J Neurosci 12:337–344.

Whone AL, Moore RY, Piccini PP, Brooks DJ (2003) Plasticity of the nigropallidal pathway in Parkinson’s disease. Ann Neurol 53:206–213.

Zhang WQ, Tilson HA, Nanry KP, Hudson PM, Hong JS, Stachowiak MK (1988) Increased dopamine release from striata of rats after uni-lateral nigrostriatal bundle damage. Brain Res 461:335–342.

Zhou FC, Bledsoe S, Murphy J (1991) Serotonergic sprouting is induced by dopamine-lesion in substantia nigra of adult rat brain. Brain Res 556:108–116.

Zigmond MJ (1997) Do compensatory processes underlie the preclinical phase of neurodegenerative disease? Insights from an animal model of parkinsonism. Neurobiol Dis 4:247–253.

Zigmond MJ, Stricker EM (1973) Recovery of feeding and drinking by rats after intraventricular 6-hydroxydopamine or lateral hypothalamic lesions. Science 182:717–720.

Zigmond MJ, Abercrombie ED, Berger TW, Grace AA, Stricker EM (1990) Compensations after lesions of central dopaminergic neurons: some clinical and basic implications. Trends Neurosci 13:290–296.

Zigmond SH (1993) Recent quantitative studies of actin filament turnover during cell locomotion. Cell Motil Cytoskeleton 25:309–316.

Zoli M, Jansson A, Sykova E, Agnati LF, Fuxe K (1999) Volume trans-mission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol Sci 20:142–150.

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