Nigrostriatal Denervation Research Articles

Postural disorders in Parkinson’s disease

Posture is often affected in Parkinson's disease. Postural abnormalities belong to the motor axial involvement. Generally, postural dysfunction induces clinical impairment at the latest stages of the disease, except in late-onset idiopathic Parkinson's disease and in atypical parkinsonian syndromes. Posture may be affected in its orientation component (stooped posture, camptocormia, Pisa syndrome) or in its balance component (loss of postural reflexes). Overall, postural impairment is poorly improved by levodopa, which implies that it is unlikely due to the nigrostriatal dopaminergic denervation. Several methods of investigation have been proposed but are generally not available in clinical practice. Medical treatment and deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus pars interna are less efficient on axial than on distal motor signs. The pedonculopontine nucleus seems promising as a new target for DBS in combination with the subthalamic nucleus. Physical therapy is, in most cases, the best way to improve postural dysfunction.

Role of central dopaminergic circuitry in pain processing and nitroglycerin-induced hyperalgesia

Experimental evidence shows that dopaminergic transmission within the basal ganglia is involved in the modulation of nociceptive information. Epidemiological studies show that in some disease states inherent pathophysiological mechanisms that involve degenerative changes (Parkinson's disease; PD) can also impact negatively on other unrelated functional systems (i.e. nociception). Delayed Fos expression in response to nitroglycerin (NTG) administration is a procedure used to identify the neuroanatomical substrates of the migraine condition. In this study, we investigated the influence of dopaminergic nigrostriatal denervation, obtained by intrastriatal injection of 6-hydroxydopamine (6-OHDA), on this response in Sprague–Dawley rats. We also explored the effects on the NTG-induced hyperalgesic response to painful stimuli (formalin and tail-flick tests). Nigrostriatal lesion prevented the neuronal activation typically induced by NTG in sub-cortical areas involved in pain perception, autonomic control and neuroendocrine functions, such as hypothalamic nuclei, periaqueductal grey, parabrachial nucleus and the medullary nuclei. In addition, 6-OHDA-induced lesion inhibited NTG-induced hyperalgesia. Our data show that integrity of central dopaminergic neurotransmission is required for the NTG-induced activation of sub-cortical areas involved in the expression of migraine symptoms, as well as for the hyperalgesic response to painful stimuli elicited by the drug.

Suppression of autophagy precipitates neuronal cell death following low doses of methamphetamine

Methamphetamine abuse is toxic to dopaminergic neurons, causing nigrostriatal denervation and striatal dopamine loss. Following methamphetamine exposure, the number of nigral cell bodies is generally preserved, but their cytoplasm features autophagic-like vacuolization and cytoplasmic accumulation of alpha-synuclein-, ubiquitin- and parkin-positive inclusion-like bodies. Whether autophagy is epiphenomenal or it plays a role in the mechanism of methamphetamine toxicity and, in the latter case, whether its role consists of counteracting or promoting the neurotoxic effect remains obscure. We investigated the signaling pathway and the significance (protective vs. toxic) of autophagy activation and the convergence of the autophagic and the ubiquitin-proteasome pathways at the level of the same intracellular bodies in a simple cell model of methamphetamine toxicity. We show that autophagy is rapidly up-regulated in response to methamphetamine. Confocal fluorescence microscopy and immuno-electron microscopy studies demonstrated the presence of alpha-synuclein aggregates in autophagy-lysosomal structures in cells exposed to methamphetamine, a condition compatible with cell survival. Inhibition of autophagy either by pharmacologic or genetic manipulation of the class III Phosphatidylinositol-3 kinase-mediated signaling prevented the removal of alpha-synuclein aggregates and precipitated a bax-mediated mitochondrial apoptosis pathway.

Ciliary Neurotrophic Factor Mediates Dopamine D2Receptor-Induced CNS Neurogenesis in Adult Mice

Neurogenesis continues in the adult forebrain subventricular zone (SVZ) and the dentate gyrus of the hippocampal formation. Degeneration of dopaminergic projections in Parkinson's disease and animals reduces, whereas ciliary neurotrophic factor (CNTF) promotes, neurogenesis. We tested whether the dopaminergic system promotes neurogenesis through CNTF. Astrocytes of the SVZ and dentate gyrus expressed CNTF and were close to dopaminergic terminals. Dopaminergic denervation in adult mice reduced CNTF mRNA by approximately 60%, whereas systemic treatment with the D2 agonist quinpirole increased CNTF mRNA in the SVZ and hippocampal formation, and in cultured astrocytes by 1.5-5 fold. The effect of quinpirole in vitro was blocked by the D2 antagonist eticlopride and did not cause astroglial proliferation or hypertrophy. Systemic quinpirole injections increased proliferation in wild-type mice by approximately 25-75% but not in CNTF-/- littermates or in the SVZ of mice infused with CNTF antibodies. Quinpirole increased the number of neuroblasts in wild-type but not in CNTF-/- littermates. Neurogenesis was reduced by approximately 20% in CNTF-/- mice, confirming the endogenous role of CNTF. Nigrostriatal denervation did not affect SVZ proliferation in CNTF-/- mice, suggesting that the dopaminergic innervation normally regulates neurogenesis through CNTF. Quinpirole acted on postsynaptic receptors as it reversed the reduced proliferation seen after dopaminergic denervation in wild-type mice. Thus, CNTF mediates dopaminergic innervation- and D2 receptor-induced neurogenesis in the adult forebrain. Because CNTF is predominantly expressed in the nervous system, this mechanism and the ability to pharmacologically modulate it have implications for Parkinson's disease and cell-replacement therapies for other disorders.

Exogenous l-DOPA induce no dopamine immuno-reactivity in striatal astroglias and microglias of adult rats with extensive nigro-striatal dopaminergic denervation

The aim of this study was to determine whether striatal glial cells of adult rats with extensive nigro-striatal dopaminergic denervation are induced to contain dopamine by injection of exogenous l-DOPA. At 2 weeks after injection of 6-hydroxydopamine into the medial forebrain bundle of rats, immuno-reactivity of glial cells was detected with antibodies against glial fibrillary acidic protein (GFAP) or ionized calcium binding adapter molecule 1 (Iba1) in the intact and lesioned striatum. Double-labeling immunofluorescence method was secondly performed. In the lesioned striatum, immuno-reactivity of GFAP was significantly increased, whereas immuno-reactivity of Iba1 was significantly increased except for ventral portion. Exogenous l-DOPA induced DA immuno-reactivity in the striatum, which was independently detected from GFAP immuno-positive astroglial cells or Iba1 immuno-positive microglial cells in the intact side as well as in the lesioned side. These findings suggest that the proliferation of glial cells in the striatum is the response to the loss of dopaminergic terminals but the glial cells do not compensate for the lost dopaminergic terminals.

Grooved pegboard test as a biomarker of nigrostriatal denervation in Parkinson's disease

Recent pharmacotherapy trials in Parkinson's disease (PD) using dopaminergic neuroimaging as outcome parameter failed to show significant relationships between imaging and clinical results. One possible explanation is that there is a non-linear relationship between striatal denervation and motor performance reflecting a statistical "floor" effect in the imaging data with advanced disease. Both the motor manifestations and the striatal dopamine denervation of idiopathic PD, however, are typically asymmetric and more meaningful associations may be found by comparing data from the least denervated striatum with motor performance in the corresponding body side. PD patients (n=28) underwent [11C]beta-CFT dopamine transporter (DAT) positron emission tomography (PET) and grooved pegboard testing. Voxel-based analysis of DAT PET and bimanual pegboard scores demonstrated significant correlation clusters within the bilateral striata (P<0.001). However, findings were most prominent in the least denervated striatum. There was a significant inverse correlation between pegboard scores of the least affected arm and DAT binding of the least denervated striatum (Rs=-0.69, P<0.0001) but no significant correlation between pegboard scores of the clinically most affected arm and DAT binding of the most denervated striatum (Rs=-0.15, ns). These data indicate that the robustness of the grooved pegboard test as a biomarker for nigrostriatal denervation in PD mainly reflects the relationship between test performance of the clinically least affected limb and the least denervated striatum. These findings indicate that there is both a statistical "floor" and "ceiling" effect for the most affected striatal and body sides that must be considered when employing imaging as an outcome measure in clinical trials in PD.

Striatal dopamine transporter binding in patients with Parkinson's disease and severe occupational hydrocarbon exposure

We used 123I-Ioflupane SPECT to study striatal dopamine transporter (DAT) binding in 36 Parkinson's disease (PD) patients with history of severe occupational exposure to hydrocarbons. Data were compared with 38 PD patients without exposure history as well as healthy controls. Both PD cohorts showed significant striatal uptake decrements compared with controls. We found significantly lower values in the whole striatum of exposed compared with non-exposed patients (0.83 +/- 0.25 vs. 1.05 +/- 0.39; P = 0.004), more pronounced in the putamen (0.61 +/- 0.24 vs. 0.85 +/- 0.42; P = 0.004). We conclude that severe occupational exposure to hydrocarbons may modify disease course and ultimately accelerate nigro-striatal denervation.

Imaging of Cholinergic and Monoaminergic Neurochemical Changes in Neurodegenerative Disorders

Positron emission tomography (PET) or single photon emission computer tomography (SPECT) imaging provides the means to study neurochemical processes in vivo. These methods have been applied to examine monoaminergic and cholinergic changes in neurodegenerative disorders. These investigations have provided important insights into disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The most intensely studied monoaminergic transmitter is dopamine. The extent of presynaptic nigrostriatal dopaminergic denervation can be quantified in PD and may serve as a diagnostic biomarker. Dopaminergic receptor imaging may help to distinguish idiopathic PD from atypical parkinsonian disorders. Cholinergic denervation has been identified not only in AD but also in PD and more severely in parkinsonian dementia. PET or SPECT can also provide biomarkers to follow progression of disease or evaluate the effects of therapeutic interventions. Cholinergic receptor imaging is expected to play a major role in new drug development for dementing disorders.

Selective hyposmia and nigrostriatal dopaminergic denervation in Parkinson’s disease

Olfactory dysfunction is a frequent and early feature of Parkinson's disease (PD), often preceding the motor symptoms by several years. Assessment of olfactory deficits may be used in the diagnostic assessment of PD. In this study we investigated the relationship between selective deficits in smell identification and nigrostriatal dopaminergic denervation in patients with PD. Twenty-seven PD patients (Hoehn and Yahr stages I-III) and 27 healthy controls matched for gender and age underwent olfactory testing using the 40-odor University of Pennsylvania Smell Identification Test (UPSIT). PD patients underwent (11)C-beta-CFT dopamine transporter (DAT) positron emission tomography (PET) imaging and clinical motor examination. We found that total UPSIT scores were significantly lower in the PD than in the control subjects (z=4.7, p<0.0001). Analysis of the individual smell scores identified 3 odors with an accuracy of >0.75 for the diagnosis of PD. These odors were banana, licorice, and dill pickle. A PD-specific smell identification score (UPSIT-3) was calculated for these 3 odors. Analysis of the patient PET data demonstrated significant correlations between dorsal striatal DAT activity and the UPSIT-3 (R(S)=0.53, p=0.0027) and total UPSIT (R(S)=0.44, p=0.023) scores. UPSIT-3 (R(S)=0.43, p=0.027) but not total UPSIT (R(S)=0.20, ns) correlated with nigral DAT activity. We conclude that patients with PD have selective hyposmia. A simplified UPSIT smell identification test consisting of 3 PD-selective odors had more robust correlation with nigral and dorsal striatial dopaminergic activity compared with the full UPSIT scores in patients with PD. Assessment of selective olfactory deficits may be used as a simplified olfactory screening test in the evaluation of subjects with possible PD.

Metabolic activity of cerebellar and basal ganglia-thalamic neurons is reduced in parkinsonism

We have examined whether degeneration of nigrostriatal dopaminergic neurons causes dysfunction of both the basal ganglia-thalamic and cerebello-thalamic pathways. Changes in the activity of thalamic neurons receiving input from the basal ganglia or the cerebellum were examined in two models of Parkinson's disease, 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Metabolic activity of the neurons was evaluated at the cellular level by quantitative in situ hybridization, using the expression of messenger RNA for subunit I of cytochrome oxidase (COI), encoded by the mitochondrial genome, as the marker. COI mRNA expression decreased significantly in thalamocortical neurons receiving input from the substantia nigra (-50.6%) or the cerebellum (-45%) in 6-OHDA-lesioned rats compared with controls. The decrease was observed in all thalamic neurons whether or not they were retrogradely labelled with a tracer injected into the motor cortex. Similarly, COI mRNA expression decreased in projection neurons and interneurons of the thalamus receiving input from the substantia nigra (-39 and -38%, respectively), the internal pallidum (-20 and -42.4%, respectively) and the cerebellum (-36.2 and -50%, respectively) of MPTP-treated monkeys compared with controls. These decreases in COI mRNA levels show that nigrostriatal denervation results in a decrease in the metabolic activity of thalamic neurons in the territories innervated by the substantia nigra, pallidum and cerebellum, which in turn is indicative of a decrease in their neuronal activity. The decrease did not concern the entire thalamus, however, since metabolic activity was unchanged in two thalamic nuclei considered to be limbic structures, the laterodorsal nucleus in 6-OHDA-lesioned rats and the anterior nucleus in MPTP-treated monkeys. Hypoactivity of both the basal ganglia-thalamic and cerebellar-thalamic pathways might therefore be implicated in the development of parkinsonian symptoms.

Impaired long‐term potentiation–like plasticity of the trigeminal blink reflex circuit in Parkinson's disease

We investigated the hypothesis that Parkinsons's disease (PD) is associated with abnormal plasticity of the neuronal circuits mediating blink reflex. We induced long-term potentiation (LTP)-like plasticity in trigeminal wide dynamic range neurons of the blink reflex circuit by pairing an high-frequency train of electrical stimuli over the right supraorbital nerve (SO) coincident with the R2 response elicited by a preceding SO stimulus. The facilitation of the R2 response after the induction protocol was markedly decreased in patients relative to controls. Treatment with dopaminergic drugs normalized the LTP-like plasticity of the R2 response. We conclude that nigrostriatal denervation disrupts LTP-like plasticity in the trigeminal reflex circuit.

Impaired behavioural and molecular adaptations to dopamine denervation and repeated L‐DOPA treatment in Nur77‐knockout mice

We have previously shown that dopamine (DA) denervation and repeated L-DOPA treatment modulate the pattern of Nur77 mRNA expression in the striatum. However, the exact role of this nuclear receptor in L-DOPA-induced molecular and behavioural adaptations observed in animal models of Parkinson's disease is still unknown. In the present study, we investigated the effects of Nur77 gene deletion on the development of behavioural sensitization and on changes in the regulation of neuropeptides and DA D(3) receptor expression following DA denervation and repeated L-DOPA treatment in Nur77+/+ and Nur77-/- hemiparkinsonian mice. One week postsurgery, hemiparkinsonian mice were treated with L-DOPA (10 mg/kg) plus benserazide (3 mg/kg) once a day for 7 days. Despite similar extents of nigrostriatal denervation, L-DOPA-induced rotational response was exacerbated in Nur77-/- mice compared to Nur77+/+ ones. However, the rate of increase of the rotational behaviour after repeated L-DOPA injections was similar in the two mouse strains. Lesioning the nigrostriatal pathway increased enkephalin (ENK) and neurotensin (NT) mRNA levels in both mouse strains. However, the up-regulation of these neuropeptides was significantly reduced in Nur77-/- mice. There was no difference in the modulation of D3 receptor density and dynorphin (DYN) mRNA expression between the two mouse strains. The present results suggest that Nur77 is involved in setting the threshold level for L-DOPA-induced rotational behaviour, rather than controlling the development of behavioural sensitization. This specific behavioural change is associated with a selective regulation of neuropeptide expression specifically in the indirect striatal output pathway.

Consequences of unilateral nigrostriatal denervation on the thalamostriatal pathway in rats

The position of the caudal intralaminar nuclei within basal ganglia circuitry has largely been neglected in most studies dealing with basal ganglia function. During the past few years, there has been a growing body of evidence suggesting that the thalamic parafascicular nucleus in rodents (PF) exerts a multifaceted modulation of basal ganglia nuclei, at different levels. Our aim was to study the activity of the thalamostriatal pathway in rats with unilateral dopaminergic depletion. The experimental approach comprised first unilateral delivery of 6-OHDA in the medial forebrain bundle. Thirty days post-lesioning, animals showing a clear asymmetry were then subjected to bilateral injection of Fluoro-Gold (FG) within the striatum. Subsequently, expression of the mRNA encoding the vesicular glutamate transporter 2 (vGLUT2) was detected within thalamostriatal-projecting neurons (FG-labeled) by in situ hybridization and the results were confirmed by laser-guided capture microdissection microscopy followed by real-time PCR. The data showed that there was a marked neuronal loss restricted to PF neurons projecting to the dopamine-depleted striatum. Moreover, PF neurons innervating the dopamine-depleted striatum were intensely hyperactive. These neurons showed a marked increase on the expression of vGLUT2 mRNA as well as for the mRNA encoding the subunit I of cytochrome oxidase as compared with those neurons projecting to the striatum with normal dopamine content. Thus, the selective neurodegeneration of PF neurons innervating the striatum together with the increased activity of the thalamostriatal pathway coexist after nigrostriatal denervation.

Disfunción frontal en la enfermedad de Parkinson idiopática

In his description of the disease in his original work, James Parkinson claimed that the 'senses remained intact', but later reports began to identify cognitive impairment that ranged from dementia to barely identifiable subclinical deteriorations. Research carried out in recent decades has revealed that cognitive disorders form part of the clinical symptoms of Parkinson's disease (PD) and point to the frontal lobes as being the most affected areas; a great deal of controversy, however, still surrounds their definition, epidemiology and pathology.To determine and classify the frontal deficits associated to this disease and to relate this cognitive performance with certain characteristics of the disease.The sample utilised in the study was made up of 222 subjects divided into two groups according to their diagnosis: 111 subjects with idiopathic PD and 111 control subjects. The neuropsychological examination was performed using the Frontal Assessment Battery, the copy of the Rey-Osterrieth complex figure and the digit test for determining frontal functioning.We prove the existence of a frontal dysfunction that is characterised by impaired working memory, with visuospatial and executive dysfunction, which suggests greater involvement of the dorsolateral prefrontal cortex and cingulate. According to our findings, because working memory and visuospatial functioning are correlated to the motor status and the time elapsed since the onset of the disease, they could share the same underlying neuroanatomical foundations--the nigrostriatal denervation. This is not the case of executive function, which was not found to be related to the characteristics of the disease under study.

Levodopa‐induced dyskinesia in MPTP‐treated macaques is not dependent on the extent and pattern of nigrostrial lesioning

The extent of nigrostriatal denervation is presumed to play a role in the genesis of levodopa-induced dyskinesia. Yet some parkinsonian patients who have been treated over a long period do not develop dyskinesia, raising the possibility that the pattern of denervation is as important as the extent of lesioning as a risk factor. Here we study the extent and pattern of nigrostriatal denervation in a homogeneous population of parkinsonian macaque monkeys chronically treated with levodopa. Based on the characteristics of the lesioning, non-dyskinetic animals could not be differentiated from those with dyskinesia. Indeed, the number of tyrosine-hydroxylase (TH)-immunopositive neurons in the substantia nigra pars compacta, striatal dopamine transporter (DAT) binding and TH immunostaining, as well as the overall TH striatal content measured by Western blotting were identical. Moreover, the patterns of lesioning assessed by a detailed analysis of the TH- and DAT-immunopositive striatal fibers were comparable in all functional quadrants and at all rostro-caudal levels considered. These data indicate that neither the extent nor the pattern of nigrostriatal lesioning are sufficient to explain the occurrence of levodopa-induced dyskinesia.

Cellular distribution of interleukin-1α-immunoreactivity after MPTP intoxication in mice

In young rodents, peripheral injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in a dopaminergic nigrostriatal denervation (during the first week after injection), followed by a spontaneous dopaminergic reinnervation. Sprouting from residual neurons has been proposed to account for this event. It has been shown that an inflammatory process takes place during striatal dopaminergic denervation but its consequences remain controversial. Some clues notably indicate that interleukin (IL)-1α may participate in MPTP-induced inflammation and promote recovery. We therefore studied the immunohistochemical localization of IL-1α expression in the striatum and ventral mesencephalon at different times (1, 3, 6, 16, and 30 days) after MPTP injection in mice. IL-1α-immunoreactivity (ir) was observed in striatum, substantia nigra pars compacta, and ventral tegmental area. Apart from a few localization in mesencephalic activated microglia, IL-1α was almost exclusively found in activated astrocytes. However, in the striatal parenchyma, another component of IL-1α-ir colocalized with tyrosine hydroxylase (TH)-ir, a marker for dopaminergic neurons. Moreover, some parenchymal TH-positive axons were also found to express the growth cone-associated protein (GAP)-43, a marker for axonal growth cones. In the striatum, IL-1α-ir was also detected in a non-astrocytic perivascular component, with a distribution similar to GAP-43-ir. IL-1α could thus directly or indirectly influence striatal reorganization after MPTP.

Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered l-DOPA

The aim of this study was to determine whether raphe-striatal serotonergic neurons of adult rats with extensive nigro-striatal dopaminergic denervation are induced by injection of exogenous l-DOPA to contain dopamine. Double-labeling immunofluorescence study was conducted. In the lesioned striatum of rats that received l-DOPA, serotonergic hyperinnervation was observed, and dopamine was detected in serotonergic varicose fibers. These findings suggest that striatal serotonergic hyperinnervation can compensate for the lost function of dopaminergic neurons.

Naltrexone in the short-term decreases antiparkinsonian response to l-Dopa and in the long-term increases dyskinesias in drug-naïve parkinsonian monkeys

Nigrostriatal dopaminergic denervation and levodopa therapy in animal models and in parkinsonian patients are associated with an enhanced opioid transmission in the striatum. The functional role of this increase has always been a subject of debate. In this study two groups of drug-naïve macaque monkeys with MPTP-induced parkinsonism were treated daily, during four weeks, with l-Dopa alone or l-Dopa plus naltrexone, a non-selective opioid receptor antagonist. The improvement of parkinsonism in all animals treated with l-Dopa alone was clearly displayed from the first day of treatment. By contrast, naltrexone co-treatment blocked the antiparkinsonian action of l-Dopa for 7–14 days. As soon as the therapeutical action of l-Dopa appeared in naltrexone-treated monkeys, the magnitude and duration of the antiparkinsonian response were similar in both groups. Furthermore, in animals treated with l-Dopa plus naltrexone the beginning of the therapeutical effect of l-Dopa was accompanied by the appearance of dyskinesias. In this group, the severity of dyskinesias during the third and fourth weeks of treatment was significantly higher than the group treated with l-Dopa alone. The results of the present study demonstrate that in de novo MPTP parkinsonian monkeys antagonizing the action of opioid receptors worsens the motor response to l-Dopa.

Occurrence of neuronal inclusions combined with increased nigral expression of α-synuclein within dopaminergic neurons following treatment with amphetamine derivatives in mice

In recent years several clinical and research findings have demonstrated the involvement of the presynaptic protein α-synuclein in a variety of neurodegenerative disorders which are known as synucleinopathies. Although the function of this protein in the physiology of the cell remains unknown, it is evident that both genetic alterations or a mere overexpression of the native molecule produces a degeneration of nigral dopamine-containing neurons leading to movement disorders, as demonstrated in inherited Parkinson's disease. In the present study, we investigated whether widely abused drugs such as methamphetamine and methylenedioxymethamphetamine (ecstasy), which are known to damage the nigrostriatal dopamine pathway of mice, increase the expression of α-synuclein within dopamine neurons of the substantia nigra pars compacta. The results of this study demonstrate that nigrostriatal dopamine denervation and occurrence of intracellular inclusions in nigral neurons produced by amphetamine derivatives are related to increased expression of α-synuclein within dopamine neurons of the substantia nigra. This lends substance to the hypothesis that increased amounts of native α-synuclein may be per se a detrimental factor for the dopamine neurons.

Regulation of dopamine receptor and neuropeptide expression in the basal ganglia of monkeys treated with MPTP

In Parkinson's disease (PD), striatal dopamine deficiency has been associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. In this study, we simultaneously analyzed the regulation of D 1 and D 2 dopamine receptors and levels of the neuropeptides, substance P, and enkephalin (ENK) in various basal ganglia nuclei following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic denervation of striatum in nonhuman primates. Both unilateral and bilateral lesioned animals were used for this study. Striatal dopamine deficiency resulted in distinct alterations in D 1, D 2, substance P, and enkephalin levels and distribution: (1) Both D 1 and D 2 protein levels were significantly up-regulated in striatum. (2) There was an overall up-regulation of striatal substance P expression following dopamine denervation. (3) Substance P distribution was ‘reversed’ in dopamine depleted striatum: striosomes, which normally express higher levels of substance P, showed decreased expression, whereas substance P expression was up-regulated in the matrix. (4) Substance P expression was up-regulated in the internal segment of the globus pallidus (GPi), but remained unchanged in substantia nigra (SN). (5) Enkephalin levels were increased in striatum and the external segment of the globus pallidus (GPe), but not in substantia nigra. All the changes were more pronounced in the bilateral lesioned monkeys, though the data represent a pooled statistical evaluation of unilateral and bilateral lesioned monkeys. Our studies indicate that D 1 and D 2 dopamine receptors and substance P and enkephalin undergo regulatory changes in response to nigrostriatal dopamine denervation. Simultaneous study of the alterations in these various components of the ‘direct’ and ‘indirect’ pathways in the same animals will enable better understanding of the pathophysiology of PD and its therapeutic targets.