preproenkephalin and Parkinson-Disease--Secondary

Topics: Animals; Disease Models, Animal; Dopamine; Dystonia; Enkephalins; Parkinson Disease, Secondary; Protein Precursors

We investigated the effect of early vs. late initiation of levodopa treatment on dyskinetic movements, rotational behavior and molecular markers in hemiparkinsonian rats. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Rats were divided into three groups treated with: (i) levodopa (6 mg/kg) twice daily for 22 days starting at 4 weeks after 6-OHDA (Early group); (ii) levodopa at the same dose, regimen and duration but starting at 12 weeks after 6-OHDA (Late group), and (iii) saline starting at 4 weeks after 6-OHDA and continuing until the Late group finished treatment. Dyskinesias were quantified on days 1 and 22 of levodopa treatment. Striatal expression of preproenkephalin and preprodynorphin mRNAs, subthalamic cytochrome oxidase mRNA, and glutamate decarboxylase 67 mRNA in the pars reticulata of the substantia nigra was measured by in-situ hybridization. After 22 days of levodopa treatment, the percentage of rats showing dyskinesia was lower in the Early group than in the Late group (60% vs. 100%, respectively). No significant differences in total dyskinesia score were observed between both groups with the exception of the orolingual dyskinesias that were significantly less frequent in the Late group (P < 0.01). No significant differences were observed in the molecular markers between the Early and Late groups. Prompt initiation of levodopa treatment might be able to delay some of the basal ganglia molecular and circuitry changes underlying the development of dyskinesia but, once developed, they are behaviorally and molecularly similar to those appearing after late initiation of levodopa.

Topics: Animals; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dynorphins; Dyskinesias; Electron Transport Complex IV; Enkephalins; Glutamate Decarboxylase; Immunohistochemistry; In Situ Hybridization; Levodopa; Male; Neurons; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substantia Nigra; Subthalamic Nucleus

In Parkinson's disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.

Topics: Adenosine A2 Receptor Antagonists; Animals; Caffeine; Cell Count; Dynorphins; Enkephalins; Globus Pallidus; Immunohistochemistry; In Situ Hybridization; Male; Microinjections; Neostriatum; Neural Pathways; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; RNA, Messenger; Stereotyped Behavior; Substantia Nigra; Sympatholytics; Tyrosine 3-Monooxygenase

This study examined the cellular correlates of the akinetic deficits produced in Wistar rats by discrete bilateral 6-hydroxydopamine (6-OHDA) striatal infusions in the dorsolateral striatum, mimicking the preferential denervation of the motor striatal territory in early symptomatic stage of Parkinson's disease (PD). Intraneuronal gene expression of cytochrome oxidase subunit I (COI), a metabolic index of neuronal activity, was increased in the subthalamic nucleus, substantia nigra pars reticulata and decreased in frontal cortical areas, but paradoxically unchanged in the striatum, globus pallidus, entopeduncular nucleus and ventrolateral thalamic nucleus. Neither preproenkephalin A nor preprotachykinin mRNA expression, markers of striatal projection neurons, were modified in the denervated striatal area despite 90% loss of dopamine (DA) terminals. Preproenkephalin A mRNA expression was however, decreased in the nondepleted striatal region, suggesting compensatory increase of dopamine tone from those spared areas. A chronic treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethylnyl)-pyridine (MPEP), which alleviated the akinetic disorders produced by the lesion, reversed the lesion-induced variations of COI gene expression, moderately increased this marker in the structures unaffected by the lesion and did not modify the striatal neuropeptides gene expression. These data suggest that the expression of akinetic deficits in early parkinsonism is associated with focused metabolic changes in the cortico-basal ganglia-cortical loop downstream of the striatum and pallidal complex.

Topics: Animals; Basal Ganglia; Cerebral Cortex; Denervation; Dopamine Uptake Inhibitors; Electron Transport Complex IV; Enkephalins; Excitatory Amino Acid Antagonists; In Situ Hybridization; Male; Mazindol; Neostriatum; Nerve Net; Neurons; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; RNA, Messenger; Sympatholytics; Tachykinins; Thalamus

Using in situ hybridization, it was found that subchronic treatment with levodopa/benserazide increased preproenkephalin-A and preproenkephalin-B mRNAs in the dopamine-depleted striatum. In order to examine whether dysfunction of the endogenous opioid system may underlie the development of levodopa-induced dyskinesias, the effect of naloxone, an opioid antagonist, on dyskinesias was investigated in two models of parkinsonism in the common marmoset. MPTP-treated monkeys were administered a daily oral dose of levodopa/benserazide which relieved the parkinsonian symptoms but induced severe and reproducible dyskinetic movements. Naloxone (0.1, 0.2 or 0.5 mg/kg) was given subcutaneously (s.c.) during peak-dose dyskinesia, which reduced the dyskinesias significantly using the highest dose, normalized the motor activity, but did not modify the antiparkinson effect. Unilaterally 6-OHDA -lesioned marmosets received apomorphine s.c., which caused a contralateral turning behavior that could be reduced up to 35 percent by concomitant administration of naloxone. Taken together the present results suggest a possible role for the endogenous opioid system in the pathogenesis of levodopa-induced dyskinesia in primates.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benserazide; Callithrix; Dopamine; Dopamine Agents; Dopamine Antagonists; Dyskinesia, Drug-Induced; Enkephalins; Female; In Situ Hybridization; Levodopa; Male; Motor Activity; Naloxone; Narcotic Antagonists; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; RNA; Rotation; Stereotyped Behavior; Sympathectomy, Chemical

The substituted phenylpiperidine (-)-OSU6162 is a novel modulator of the dopaminergic systems with low affinity for dopamine D(2) receptors and potent normalizing effects on l-DOPA-induced dyskinesias. We studied the effects of coadministration of (-)-OSU6162 with l-DOPA on the regulation of striatal preproenkephalin (PPE) and prodynorphin (PDyn) mRNA expression in the primate brain by in situ hybridization histochemistry. Common marmoset monkeys sustaining unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received l-DOPA/carbidopa, l-DOPA/carbidopa plus (-)-OSU6162, or vehicle over 14 days. In vehicle-treated animals, PPE mRNA levels were markedly increased in the sensorimotor territory of the lesioned striatum. By contrast, a rather uniform lesion-induced reduction of PDyn mRNA levels was found in the vehicle group. Subchronic l-DOPA treatment induced a further increase in PPE mRNA expression in a number of sensorimotor and associative subregions of the denervated striatum. Coadministration of (-)-OSU6162 with l-DOPA partially reversed the lesion- and l-DOPA-induced elevation of PPE expression and, by affecting PPE mRNA expression differentially on the intact and lesioned striatum, markedly reduced the side-to-side difference in PPE mRNA expression. The effects on PPE mRNA expression were apparent throughout the rostrocaudal extent of the putamen and the dorsal portions of the caudate nucleus. l-DOPA treatment resulted in an enhancement in PDyn mRNA expression in all functional compartments of the striatum. Coadministration of (-)-OSU6162 had no apparent influence on these l-DOPA-induced changes in PDyn mRNA expression. The present results suggest that (-)-OSU6162 acts primarily by modifying striatal output via the indirect pathway.

Topics: Animals; Autoradiography; Callithrix; Caudate Nucleus; Corpus Striatum; Disease Models, Animal; Dopamine Agents; Drug Administration Schedule; Drug Therapy, Combination; Enkephalins; Female; In Situ Hybridization; Injections, Subcutaneous; Levodopa; Ligands; Male; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Protein Precursors; Putamen; RNA, Messenger; Tritium

The cAMP response element-binding protein (CREB) is believed to play a pivotal role in dopamine (DA) receptor-mediated nuclear signaling and neuroplasticity. Here we demonstrate that the significance of CREB for gene expression depends on the experimental paradigm. We compared the role of CREB in two different but related models: l-DOPA administration to unilaterally 6-hydroxydopamine lesioned rats, and cocaine administration to neurologically intact animals. Antisense technology was used to produce a local knockdown of CREB in the lateral caudate-putamen, a region that mediates the dyskinetic or stereotypic manifestations associated with l-DOPA or cocaine treatment, respectively. In intact rats, CREB antisense reduced both basal and cocaine-induced expression of c-Fos, FosB/DeltaFosB, and prodynorphin mRNA. In the DA-denervated striatum, CREB was not required for l-DOPA to induce these gene products, nor did CREB contribute considerably to DNA binding activity at cAMP responsive elements (CREs) and CRE-like enhancers. DeltaFosB-related proteins and JunD were the main contributors to both CRE and AP-1 DNA-protein complexes in l-DOPA-treated animals. In behavioral studies, intrastriatal CREB knockdown caused enhanced activity scores in intact control animals and exacerbated the dyskinetic effects of acute l-DOPA treatment in 6-OHDA-lesioned animals. These data demonstrate that CREB is not required for the development of l-DOPA-induced dyskinesia in hemiparkinsonian rats. Moreover, our results reveal an unexpected alteration of nuclear signaling mechanisms in the parkinsonian striatum treated with l-DOPA, where AP-1 transcription factors appear to supersede CREB in the activation of CRE-containing genes.

Topics: Animals; Antiparkinson Agents; Cocaine; Corpus Striatum; Cyclic AMP Response Element-Binding Protein; Denervation; DNA; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Administration Routes; Enkephalins; Female; Gene Expression; Levodopa; Oligonucleotides, Antisense; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription Factor AP-1

Loss of striatal dopamine has been associated with an increase in striatal enkephalin expression. However, the relationship between increased striatal enkephalin expression and the manifestation of parkinsonian motor deficits is not clear. Administration of MPTP to cats produces a severe parkinsonian condition from which the animals spontaneously recover. Using in situ hybridization histochemistry, preproenkephalin (PPE) mRNA expression was examined in the striatum of cats when normal, symptomatic for or spontaneously recovered from MPTP-induced parkinsonism. In all areas of the striatum, PPE mRNA levels were significantly elevated in animals exhibiting severe parkinsonian motor deficits and remained elevated even after recovery of gross motor functioning. These results show that striatal PPE gene expression and parkinsonian motor deficits are not directly correlated.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Cats; Caudate Nucleus; Corpus Striatum; Dopamine Agents; Enkephalins; Female; Gene Expression; Male; Motor Activity; Parkinson Disease; Parkinson Disease, Secondary; Protein Precursors; Recovery of Function; RNA, Messenger

Induction of dopamine D3 receptor gene expression in 6-hydroxydopamine-lesioned rats by repeated administration of levodopa had been suggested to be responsible for behavioural sensitization developing in these animals. Using double in situ hybridization techniques, we show that D3 receptor mRNA induction after repeated administration of levodopa took place mainly in dynorphin/substance P-expressing neurons of the direct striatonigral pathway. In agreement, induction of D3 receptor binding sites was evidenced, using 7-[3H]hydroxy-N,N-di-propyl-2-aminotetralin ([3H]7-OH-DPAT), in substantia nigra pars reticulata, the projection area of the direct nigrostriatonigral pathway. Changes in D3 receptor binding and behavioural sensitization during intermittent administration of levodopa paralleled changes in prodynorphin/preprotachykinin rather than preproenkephalin/prodynorphin and preproenkephalin/preprotachykinin mRNA ratios. Behavioural sensitization, induction of D3 receptor binding and changes in prodynorphin/preprotachykinin ratio were all prevented together when levodopa was continuously delivered or intermittently delivered in combination with R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390), a selective D1 receptor antagonist. Our results indicate that functional changes of the direct striatal output pathway, possibly through an interaction between D1 and D3 receptors at the level of terminals in the substantia nigra pars reticulata, are important for the development of behavioural sensitization.

Topics: Animals; Antiparkinson Agents; Benzazepines; Binding, Competitive; Corpus Striatum; Denervation; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Enkephalins; Excitatory Amino Acid Antagonists; Gene Expression; Levodopa; Male; Neural Pathways; Neurons; Opioid Peptides; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger; Substantia Nigra; Sympatholytics; Tachykinins; Tetrahydronaphthalenes; Tritium; Ventral Tegmental Area

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeated l-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However, de novo administration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1-17 and B1-13, leucine-enkephalin, and alpha-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeated L-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeated L-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlying L-DOPA- and dopamine agonist-induced dyskinesia. In contrast to l-DOPA, de novo administration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeated l-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalize

Topics: Animals; Autoradiography; Behavior, Animal; Bromocriptine; Dopamine Agents; Dopamine Agonists; Dopamine Uptake Inhibitors; Enkephalins; In Situ Hybridization; Levodopa; Lisuride; Male; Mazindol; Medial Forebrain Bundle; Neostriatum; Oligonucleotide Probes; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Radioligand Assay; Rats; Rats, Sprague-Dawley; RNA, Messenger

This study examined the extent of striatal dopamine (DA) denervation and coincident expression of preproenkephalin (PPE) mRNA in monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Some animals (n = 4) became moderately parkinsonian after receiving large doses of MPTP over short periods of time and were symptomatic for only a short period of time (1-3 months; acute parkinsonian group). Other animals became moderately parkinsonian after receiving either escalating doses of MPTP over long periods (4-6 months; n = 5) or a high dose of MPTP over a short period (<1 month; n = 1) and remained symptomatic for an extended period (>8 months; chronic parkinsonian group). Despite similar symptomatology and similar degrees of striatal DA denervation at the time of their deaths, only acute parkinsonian animals had significantly increased PPE expression in sensorimotor striatal regions. PPE expression in chronic parkinsonian animals was either not changed or significantly decreased in most striatal regions. These findings suggest that the duration and not the extent of striatal DA denervation is a critical factor in modulating changes in striatal PPE expression. Furthermore, these results question the role of increased activity in the enkephalin-containing indirect striatopallidal pathway in the expression of parkinsonian symptoms.

Topics: Acute Disease; Animals; Autoradiography; Behavior, Animal; Chronic Disease; Corpus Striatum; Enkephalins; Gene Expression Regulation; Globus Pallidus; In Situ Hybridization; Macaca fascicularis; Male; Mazindol; Neural Pathways; Parkinson Disease, Secondary; Protein Precursors

The effect of chronic treatment with the D2 dopamine agonist U91356A or L-DOPA therapy on the regulation of preproenkephalin (PPE) mRNA was investigated in the caudate-putamen of previously drug-naive cynomolgus monkeys Macaca fascicularis rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In MPTP monkeys, pulsatile treatment with either L-DOPA or U91356A relieved parkinsonian symptoms but caused progressive sensitization to treatment and, as expected, induced choreic dyskinesias. In contrast, U91356A given in a continuous mode led to partial behavioral tolerance without appearance of dyskinesias. Using in situ hybridization histochemistry, lesioning was shown to produce elevation of PPE mRNA levels in the lateral and medial parts of the putamen and in the lateral part of the caudate nucleus compared to control animals at the three rostrocaudal regions analyzed. In general, no change of PPE mRNA levels were observed in the medial caudate after MPTP lesioning with or without L-DOPA or U91356A treatments in the three rostrocaudal regions measured except for an increase in the caudal part of L-DOPA-treated MPTP monkeys. In the putamen and lateral caudate nucleus, elevated PPE mRNA expression by MPTP generally was not corrected (or only partially corrected) by chronic L-DOPA treatment except for the rostral medial putamen where correction to control values was observed. In general, pulsatile administration of U91356A partially corrected the lesion-induced elevation of PPE mRNA levels in the putamen and lateral caudate nucleus whereas the correction was more pronounced and widespread when MPTP monkeys received the continuous administration of this drug. These results indicate that the mode of administration of a D2 dopamine receptor agonist, such as U91356A, although at a roughly equivalent dosage influences the extent of inhibition of the expression of PPE in the denervated striatum of monkeys. In addition, the general lack of correction of the MPTP-induced increase of PPE mRNA in the striatum of L-DOPA-treated monkeys compared to the decreases observed with the D2 agonist treatments suggest that the D1 agonist component of L-DOPA therapy opposes the D2 agonist activity. Hence, D1 receptor agonist activity would stimulate PPE mRNA expression whereas D2 receptor agonists inhibit the expression of this peptide. Increases in PPE expression in the striatum may be implicated in the induction of dyskinesias since both groups of treated MP

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aminoquinolines; Animals; Caudate Nucleus; Dopamine Agonists; Enkephalins; Female; Imidazoles; In Situ Hybridization; Levodopa; Macaca fascicularis; Ovariectomy; Parkinson Disease, Secondary; Protein Precursors; Putamen; Receptors, Dopamine D2; RNA, Messenger; Transcription, Genetic

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Autoradiography; Dopamine; Dopamine Agents; Enkephalins; Gene Expression Regulation; Immunohistochemistry; Neostriatum; Neuropeptides; Parkinson Disease, Secondary; Protein Precursors; Saimiri; Tachykinins; Tyrosine 3-Monooxygenase

The cellular expression of the genes encoding the neuropeptides enkephalin and substance P were examined in the caudate nucleus and putamen of parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys by in situ hybridization using radioactive antisense oligonucleotides coupled with computer-assisted image analysis. Behavioural evaluation of the animals revealed two levels of motor impairment; one group moderately impaired and the other severely disabled. A marked increase in the cellular content of preproenkephalin A messenger RNA was observed in medium-sized (106 +/- 9 microns2) cells in the caudate-putamen of all MPTP animals when compared with controls, the increase being greatest in the most severely impaired animals. By contrast, a marked reduction in the cellular abundance of preprotachykinin gene expression was detected in striatal cells (101 +/- 16 microns2) of these same MPTP animals. These changes in neuropeptide gene expression were not associated with a change in the density (approximately 10 cells per mm2) of messenger RNA-expressing cells. L-DOPA treatment of two of the severely-impaired MPTP monkeys resulted in a dissociation of expression of these two genes: the cellular abundance of preproenkephalin A remained elevated whilst preprotachykinin levels were normalized and comparable with controls. No change in the cellular abundance of preprotachykinin messenger RNA was observed in cells of the insular cortex or a small discrete population of large cells (208 +/- 27 microns2) in the ventral putamen. These results demonstrate that MPTP treatment of primates results in a marked potentiation in preproenkephalin messenger RNA coupled with a attenuation in preprotachykinin messenger RNA in the dopamine-denervated caudate-putamen. L-DOPA therapy given on an intermittent schedule reverses the decrease in preprotachykinin messenger RNA, but fails to reverse the increase in preproenkephalin messenger RNA in the same animal. These observations suggest that a dissociation of the activity of these two neuropeptide systems may underlie the improvement in motor skill that accompanies dopamine replacement therapy and that this dissociation may be instrumental in the long-term complications associated with L-DOPA therapy.

Topics: Animals; Antiparkinson Agents; Caudate Nucleus; Dopamine Agents; Enkephalins; Gene Expression; In Situ Hybridization; Levodopa; Macaca fascicularis; MPTP Poisoning; Neostriatum; Oligonucleotides, Antisense; Parkinson Disease, Secondary; Protein Precursors; Putamen; RNA, Messenger; Tachykinins

Levels of preproenkephalin (PPE) mRNA were measured in different sectors of the striatum with in situ hybridization histochemistry in both normal and parkinsonian (MPTP-treated) squirrel monkeys. In parkinsonian monkeys, a marked increase in PPE mRNA levels was noted in the dorsolateral third of the precommissural putamen and in most of the postcommissural putamen. These regions largely correspond to the sensorimotor striatal territory. The other striatal sectors, including the caudate nucleus, did not exhibit significant changes, despite the fact that the loss of the dopaminergic input was severe in most of the striatum. These results reveal that PPE mRNA expression is specifically altered in striatal regions involved in sensorimotor processing in parkinsonian monkeys.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Dopamine; Enkephalins; Gene Expression; Histocytochemistry; In Situ Hybridization; Parkinson Disease, Secondary; Protein Precursors; Reference Values; RNA, Messenger; Saimiri

In order to elucidate the importance of the striatal GABAergic neurones in mediating functional effects of exogenously applied brain-derived neurotrophic factor (BDNF) in the basal ganglia, we performed daily injections of BDNF or vehicle into the dopamine-depleted striatum of unilaterally 6-hydroxydopamine-lesioned rats for 1 week. In situ hybridization revealed that BDNF exacerbated the lesion-induced up-regulation of preproenkephalin (PPE) mRNA, and completely reversed the lesion-induced decrease of preprotachykinin (PPT) mRNA. In contrast, striatal levels of trkB mRNA were not significantly affected by BDNF administration. Up-regulation of PPE and PPT mRNA was also observed in unlesioned BDNF-injected animals. We conclude that exogenously applied BDNF increases neuropeptide mRNA expression in striatal neurones independently of the presence of a dopaminergic innervation.

Topics: Animals; Brain-Derived Neurotrophic Factor; Corpus Striatum; Dopamine; Enkephalins; Female; Gene Expression Regulation; In Situ Hybridization; Injections; Nerve Tissue Proteins; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Ciliary Neurotrophic Factor; Receptors, Growth Factor; RNA, Messenger; Tachykinins