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B J Hoffer

Publications and source records attributed to B J Hoffer.

At least 55 records · Page 3Linked to original sources
PubMed1997

Intracerebroventricular glial cell line-derived neurotrophic factor improves motor function and supports nigrostriatal dopamine neurons in bilaterally 6-hydroxydopamine lesioned rats.

In order to evaluate the efficacy of glial cell line-derived neurotrophic factor (GDNF) in a model of advanced Parkinson's disease, we studied rats with extensive bilateral lesions of the nigrostriatal pathway. Adult male F344 rats were injected bilaterally into the medial forebrain bundle with the neurotoxin 6-hydroxydopamine. Locomotor ability as measured by total distance traveled in an open field over 20 min, as well as von Frey hair testing of sensorimotor neglect, was monitored weekly. Rats demonstrating severe motor impairment and sensorimotor neglect were used for this study and were sorted to achieve similar average behavioral scores between the two treatment groups. After 2 weeks of pretesting, the rats received 250 microg GDNF or vehicle injected into the right lateral cerebral ventricle. Three weeks later, an additional 500 microg GDNF or vehicle was injected into the contralateral ventricle. The rats were monitored for another 2 weeks prior to sacrifice. Behavioral results indicated that von Frey hair scores were inconsistent between tests for each rat and were unchanged following GDNF treatment. However, GDNF recipients demonstrated significant improvement in locomotor ability compared to vehicle recipients. High-pressure liquid chromatography-electrochemical detection analysis of neurotransmitter levels revealed a significant increase in dopamine content within the substantia nigra and ventral tegmenta, but not the striata, of GDNF-treated rats. Further, immunohistochemical staining of tissues from matched pairs of rats revealed increased numbers of tyrosine hydroxylase-positive ventral mesencephalic neurons in one of the two pairs of rats examined. These results suggest that intracerebroventricular GDNF administration improves motor ability and supports nigrostriatal dopaminergic neurons in a model of severe Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

In vivo microdialysis studies on somatodendritic dopamine release in the rat substantia nigra: effects of unilateral 6-OHDA lesions and GDNF.

Dopamine (DA) release and metabolism within the substantia nigra (SN) were studied in normal rats, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions, and 6-OHDA-lesioned rats treated with glial cells line-derived neurotrophic factor (GDNF). Animals with > 99% DA depletions, as determined by apomorphine-induced circling behavior, also showed significant deficits in several measures of spontaneous motor activity. In vivo microdialysis recordings in the SN were carried out in normal and unilaterally 6-OHDA-lesioned rats. Basal levels of DNA were detectable only in the dialysates of normal animals, and basal levels of t he primary DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were found to be significantly reduced in the SN of 6-OHDA-lesioned animals. In the presence of d-amphetamine, either alone or in combination with potassium, significant reductions in DA release were observed in the SN of 6-OHDA-lesioned animals compared to normal animals. Potassium-evoked DA release alone was not significantly different between the groups. A single intranigral administration of GDNF into 6-OHDA-lesioned animals elicited a significant reduction in apomorphine-induced rotation behavior and a significant increase in spontaneous motor activities. These behavioral changes were apparent at 1 week and persisted through 4 weeks following treatment. In vivo microdialysis showed that, although DA metabolism was altered 1 week following GDNF treatment, DA release was not significantly affected until 4 weeks following treatment.

Animals↗
PubMed1997

In vivo electrochemical measurements of serotonin clearance in rat striatum: effects of neonatal 6-hydroxydopamine-induced serotonin hyperinnervation and serotonin uptake inhibitors.

Diffusion and clearance of extracellular serotonin (5-HT) was examined using in vivo chronoamperometry with "delayed-pulse" recordings after pressure ejections of 1 to 60 picomoles 5-HT into rat striatum at a fixed distance from a Nafion-coated carbon fiber electrode. Signals obtained were identified based on the signal characteristics to consist of 5-HT. Clearance times of 5-HT decreased, while amplitudes and rise times increased with serotonergic hyperinnervation induced by neonatal 6-hydroxydopamine (6-OHDA) lesions of dopamine (DA) neurons. Local applications of the 5-HT uptake inhibitors zimelidine or fluoxetine, in conjunction with 5-HT ejections, produced increased clearance times in both normal and 6-OHDA-treated animals. Thus, direct in vivo evidence was obtained for the importance of high affinity nerve terminal uptake as a key mechanism for clearance of 5-HT from the extracellular space. Inhibitors of 5-HT uptake appear to prolong the extracellular presence of 5-HT by increasing its clearance time.

Animals↗
PubMed1997

Cellular and developmental patterns of expression of Ret and glial cell line-derived neurotrophic factor receptor alpha mRNAs.

Glial cell line-derived neurotrophic factor (GDNF) has recently been shown to signal by binding to GDNF receptor-alpha (GDNFR-alpha), after which the GDNF-GDNFR-alpha associates with and activates the tyrosine kinase receptor Ret. We have localized Ret messenger RNA (mRNA) in the developing and adult rodent and compared with to the expression of GDNF and GDNFR-alpha mRNA. Ret mRNA is strongly expressed in dopamine neurons and alpha-motor neurons as well as in thalamus, ruber and occluomotor nuclei, the habenular complex, septum, cerebellum, and brain stem nuclei. Ret mRNA was also found in several sensory systems, in ganglia, and in nonneuronal tissues such as teeth and vibrissae. Very strong Ret mRNA signals are present in kidney and the gastrointestinal tract, where Ret and GDNF mRNA expression patterns are precisely complementary. The presence of Ret protein was confirmed in adult dopamine neurons using immunohistochemistry. GDNFR-alpha mRNA was strongly expressed in the developing and adult dopamine neurons. It was also found in neurons in deep layers of cortex cerebri, in hippocampus, septum, the dentate gyrus, tectum, and the developing spinal cord. In the kidney and the gastrointestinal tract, GDNFR-alpha mRNA and Ret mRNA distribution overlapped. Dorsal root ganglia, cranial ganglia, and developing peripheral nerves were also positive. GDNFR-alpha was additionally found in sensory areas and in developing teeth. Sensory areas included inner ear, eye, olfactory epithelium, and the vomeronasal organ, as well as developing tongue papillae. The temporospatial pattern of expression of GDNFR-alpha mRNA did not always match that of Ret mRNA. For instance, GDNFR-alpha mRNA was also found in the developing ventral striatum, including the olfactory tubercle, and in hippocampus. These areas seemed devoid of Ret mRNA, suggesting that GDNFR-alpha might also have functions unrelated to Ret.

Animals↗
PubMed1997

Glial cell line-derived neurotrophic factor improves survival of ventral mesencephalic grafts to the 6-hydroxydopamine lesioned striatum.

One approach to replace lost dopaminergic neurons in Parkinson's disease is to transplant fetal mesencephalic tissue into the striatum. In an attempt to expand the developmental window useful for grafting of mesencephalic tissue and increase the fiber outgrowth from grafted dopaminergic neurons, we have pretreated fetal mesencephalic tissue with the dopaminotrophic factor glial cell line-derived neurotrophic factor (GDNF). Mesencephalic tissue pieces from embryonic day 18-19 Fischer 344 rats were preincubated for 20 min with GDNF (1 microg/microl) or vehicle. Two tissue pieces were then transplanted into the striatum of rats that had been unilaterally lesioned by medial forebrain bundle injections of 6-hydroxydopamine. The animals were tested for apomorphine-induced rotations prior to intracranial grafting. Host rats received intrastriatal injections of 10 microg GDNF or control solution at 10 days and 4 weeks postgrafting. The animals were tested in the rotometer twice monthly following transplantation. Despite the fact that these transplants were from a suboptimal donor stage, the rotations were significantly decreased in both transplanted groups. Immunohistochemical evaluation of the host brains revealed that the overall size of transplanted mesencephalic tissue was significantly increased in the GDNF-treated animals, and that the average size of transplanted tyrosine hydroxylase (TH)-positive neurons was also increased. Furthermore, we found that the innervation density of surrounding host striatal tissue was significantly increased in the GDNF-treated group, as compared with controls. Taken together, these results suggest that treatment of intrastriatal ventral mesencephalon grafts with GDNF can optimize the conditions for intracranial grafting and thus improve the chances for functional recovery following the intrastriatal grafting procedure.

Animals↗
PubMed1996

Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy.

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment. Intraventricular administration of NGF is necessary because NGF will not cross the blood-brain barrier (BBB). Here we have used a novel carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. In our experiment, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate or a control solution (a mixture of unconjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF injections resulted in a significant improvement in spatial learning in previously impaired rats but disrupted the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatial learning. These results indicate the potential use of the transferrin receptor antibody delivery system for treatment of CNS disorders with neurotrophic proteins.

Aging↗
PubMed1996

Defects in enteric innervation and kidney development in mice lacking GDNF.

Glial-lial-cell-line-derived neurotrophic factor (GDNF) has been isolated as neurotrophic factor for midbrain dopaminergic neurons. Because of its neurotrophic activity on a wide range of neuronal populations in vitro and in vivo, GDNF is being considered as a potential therapeutic agent for neuronal disorders. During mammalian development, it is expressed not only in the nervous system, but also very prominently in the metanephric kidney and the gastrointestinal tract, suggesting possible functions during organogenesis. We have investigated the role of GDNF during development by generating a null mutation in the murine GDNF locus, and found that mutant mice show kidney agenesis or dysgenesis and defective enteric innervation. We demonstrate that GDNF induces ureter bud formation and branching during metanephros development, and is essential for proper innervation of the gastrointestinal tract.

Animals↗
PubMed1996

Glial cell line-derived neurotrophic factor reverses motor impairment in 16-17 month old rats.

Aging is accompanied with declines in motoric function which may be the result of deficits in central nervous system dopaminergic function. Glial cell line-derived neurotrophic factor (GDNF) has been shown to have neuroprotective and restorative effects on dopaminergic neurons of the nigrostriatal pathway in young rats. In this study, 10, 40, or 60 micrograms GDNF or vehicle was injected intrastriatally in 16-17 month old Fischer 344 rats. Coordination and muscle strength as determined by performance on an inclined balance beam and a wire grip strength test were monitored for up to 5 weeks post-injection. GDNF elicited dose-dependent improvements in motor coordination without concurrent increases in strength. The highest dose tested produced > 79% improvement in motor coordination, resulting in performance scores approaching those achieved by 3 month old rats tested concurrently. These findings indicate GDNF produces profound improvement in the motoric function of mature rats, which may be related to dopaminergic circuits.

Aging↗
PubMed1996

Interactions of neurotrophic factors GDNF and NT-3, but not BDNF, with the immune system following fetal spinal cord transplantation.

Glial cell line-derived neurotrophic factor (GDNF) is known to stimulate survival of dopaminergic and spinal cord motor neurons. However, little is known of the possible immune sequelae of GDNF exposure, or that of other putative trophic factors. To address these questions we utilized in oculo grafts of spinal cord, wherein we could induce different levels of immune responses via allogeneic vs. syngeneic combinations. Adult female Sprague-Dawley and Fisher rats were used as hosts for allogeneic and syngeneic grafts, respectively. Embryonic age 14-15-day-old fetuses were taken from pregnant dams of each strain, and cervical spinal cords were removed and dissected. Pieces of the spinal cord were transplanted into the anterior chamber of the eye within each strain. At 5-day intervals, 0.5 microgram of GDNF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or cytochrome c (CC) was injected into the anterior chamber of the eye and the sizes of the transplants were measured for the Sprague-Dawley rats. The same injections and measurements, but only for GDNF and CC, were carried out using Fisher rats. As expected, GDNF increased transplant survival and growth in both the Sprague-Dawley and Fisher animals. At day 41-42, all rats were sacrificed. Cameral graft appearance was evaluated by cresyl violet and immunohistochemically using antibodies against neurofilament (NF), calcitonin gene-related peptide (CGRP) and glial fibrillary acidic protein (GFAP). To monitor immune responses, the following monoclonal antibodies were used: OX38 against CD4, OX18 against MHC class I (MHCI), OX8 against CD8, OX6 against MHC class II (MHCII), OX42 against CD11b, R73 against alpha and beta T cell receptor (TcR), and ED1. In the Sprague-Dawley grafts, significantly higher amounts of CD8+, T lymphocyte+, MHCI+ and MHCII+ antigen-presenting cells (APC) were observed in GDNF-treated transplants. These markers were also increased in NT-3-treated groups. There were two types of OX-42+ cells, one was the ordinary ramified microglial cell, the other appeared to be a phagocytic cell, looking like the interstitial proliferating variety. Interestingly, the phagocytic OX-42+ cells had the same distribution as ED1+ and MHCII+ cells. In contrast, there were few immunoreactive cells after GDNF treatment in the inbred Fisher animals, similar to the CC control group. These results suggest that GDNF and to some extent NT-3, can activate the immune system in allogeneic graft combinations, but that these trophic factors do not produce overt rejection, and do not per se induce immune responses.

Animals↗
PubMed1996

Functional recovery in parkinsonian monkeys treated with GDNF.

Parkinson's disease results from the progressive degeneration of dopamine neurons that innervate the striatum. In rodents, glial-cell-line-derived neurotrophic factor (GDNF) stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons. Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally in rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The recipients of GDNF displayed significant improvements in three of the cardinal symptoms of parkinsonism: bradykinesia, rigidity and postural instability. GDNF administered every four weeks maintained functional recovery. On the lesioned side of GDNF-treated animals, dopamine levels in the midbrain and globus pallidus were twice as high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density. The results indicate that GDNF may be of benefit in the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Microglial cell responses to fetal ventral mesencephalic tissue grafting and to active and adoptive immunizations.

Microglia express cytokines, major histocompatibility (MHC) loci, and several other immunologically important constituents. The aim of this study was to detect immunological responses of microglial cells following allogeneic dopaminergic transplantation using active and adoptive immunizations. Adult inbred Fisher 344 (F344 RT1) rats were unilaterally dopamine (DA) depleted in striatum by injection of 6-hydroxydopamine. The degree of degeneration was assessed by recording the rotational response to apomorphine. Fetal ventral mesencephalic tissue containing DA neuroblasts from Wistar-Furth (WF, RT1u) rat donors (9-12 mm CRL) were later implanted in striatum on the lesioned side. Lymph nodes and spleen cells were collected aseptically, resuspended, and diluted for isovolumetric injections. Animals selected for active immunization were injected intraperitoneally with varying amounts of WF lymphocytes. Animals selected for adoptive immunization (transferred immunity) were intraperitoneally injected with 10(8) F344 lymphocytes prepared from animals actively immunized 3 weeks previously. Monoclonal antibodies against CD4 (OX38), CD8 (OX8), CD11b (OX42), MHC class I (OX18), monomorphic MHC class II (OX-6), and ED1 and polyclonal antibodies against tyrosine hydroxylase (TH) were used for immunohistochemistry. We found that the degree of ED1-positive cell proliferation was well correlated to the immunization patterns. Groups that were actively immunized with or without prior adoptive immunization had a larger amount of reactive microglial proliferation. ED1 immunohistochemistry revealed patterns of immunolabeling of engrafted areas: 8-12 weeks after grafting in nonimmunized and adoptively immunized groups reactive microglial proliferation occurred only at the graft periphery. Active and adoptive + active immunization led to ED1-IR within the grafts themselves. At early stages nonimmunized groups had an ED1 pattern which was partially inside the grafts. At early time points nonimmunized groups contained ameboid microglial cells within the grafts which disappeared at later stages and were absent in the immunized groups. ED1-positive ameboid microglial cells within the grafts may be of graft origin and constitute a part of a continued normal development of the fetal tissue.

Animals↗
PubMed1996

Effects of GDNF on fetal septal forebrain transplants in oculo.

Glial cell line-derived neurotrophic factor (GDNF) is a member of the TGF-beta superfamily of growth factors with marked neurotrophic activity on midbrain dopaminergic neurons. To investigate whether this trophic activity is shared by central cholinergic neurons, we investigated the effects of GDNF treatment during development of the medial septal area in rats. Adult Fischer 344 rats received intraocular transplants of fetal septal forebrain tissue (embryonic Day 17) which was preincubated for 20 min with either GDNF or vehicle. The two treatment groups subsequently received weekly intraocular injections of either GDNF (0.5 microgram in 5 microliters/injection) or vehicle for 6 weeks following transplantation. Transplants treated with GDNF grew twice as large as control grafts treated with vehicle. Immunohistochemical evaluations of the transplants revealed that there was no difference between the two groups in terms of acetylcholinesterase or low affinity neurotrophin receptor (p75) staining. In contrast, a significant increment in the number of GABA-ergic neurons was observed in transplants that received GDNF, as compared to vehicle-treated grafts. The overall number of neurons within the transplanted tissue was also elevated in the experimental group. There was no difference between the two groups in the distribution or density of astrocytes in the grafted tissue, as evidenced by immunohistochemistry with antibodies directed against glial fibrillary acidic protein. These results indicate that basal forebrain GABA-ergic neurons may be dependent on GDNF for their survival and/or for GABA synthesis, but that the cholinergic neurons in this area appear to be unaffected by GDNF administration during development.

Animals↗
PubMed1996

6-hydroxydopamine induces the loss of the dopaminergic phenotype in substantia nigra neurons of the rat. A possible mechanism for restoration of the nigrostriatal circuit mediated by glial cell line-derived neurotrophic factor.

Intraparenchymal injections of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle in rats destroys the dopaminergic neurons in the pars compacta of the substantia nigra. In other transmitter systems it has been found that axotomy or neurotoxin exposure produces an initial loss of neurotransmitter phenotype, with cell death occurring over a much slower time course. To determine whether this also occurs in dopamine neurons after 6-OHDA, two approaches were utilized. First, the effect of injections of 6-OHDA into the medial forebrain bundle on nigral dopaminergic neurons was studied using combined fluorogold and immunocytochemical labeling. Four weeks after the 6-OHDA injection, there was an 85% reduction in the number of tyrosine hydroxylase (TH)-immunoreactive cells on the lesioned side. In contrast, there was only a 50% reduction in the number of fluorogold-labeled cells on the lesioned side. Second, the time course of the rescue of dopaminergic neurons after 6-OHDA by glial cell line-derived neurotrophic factor (GDNF) was determined using TH immunocytochemistry. Greater numbers of dopamine neurons were rescued 9 weeks after GDNF, compared with counts made 5 weeks after GDNF. Taken together, these results suggest loss of dopaminergic phenotype is greater than cell loss following 6-OHDA injections, and that GDNF restores the phenotype of affected cells.

Animals↗
PubMed1996

Cellular expression of GDNF mRNA suggests multiple functions inside and outside the nervous system.

Glial-cell-line-derived neurotrophic factor (GDNF) is a distant member of the transforming growth factor-beta family and has potent neurotrophic effects on several classes of neurons including dopamine neurons and motoneurons. Here, we have used in situ hybridization to describe the development of the cellular expression of GDNF mRNA pre- and postnatally. Consistent with dopaminotrophic activity, GDNF mRNA is expressed in the developing basal ganglia and the olfactory tubercle. It is also found in a thalamic nucleus, in neurons of the substantia innominata, in the developing Purkinje neurons and the developing locus coeruleus area, and in trigeminal brainstem nuclei. In the spinal cord, neuronal expression is found in Clarke's column. GDNF mRNA is also expressed in the dorsal horns during development. Additional GDNF mRNA expression in the head region includes the carotid body, the retina, the vibrissae, the inner ear, the ear canal, and epithelium in the nasal cavity. Prominent expression is also found in the developing teeth. The widespread expression of GDNF in developing skeletal muscle is consistent with trophic activity on alpha-motoneurons. The smooth muscle layers of the gastrointestinal tract are also strongly positive. A very strong signal is found in the outer mesenchyme of the developing metanephric kidney. We conclude that GDNF mRNA is expressed in many different cellular systems inside and outside the central nervous system during development, suggesting multiple functions of GDNF in the developing organism.

Animals↗
PubMed1996

GDNF triggers fiber outgrowth of fetal ventral mesencephalic grafts from nigra to striatum in 6-OHDA-lesioned rats.

Previous reports have indicated that grafting of fetal ventral mesencephalic tissue to the nigra region of animals unilaterally lesioned with 6-hydroxydopamine (6-OHDA), in conjunction with kainate injection between the nigra and striatum, restores nigrostriatal tyrosine hydroxylase immunoreactivity. Glial-cell-line-derived neurotrophic factor (GDNF), a potent trophic factor for dopaminergic neurons, has been found to be upregulated by kainate. We have investigated the bridging effect of GDNF injection on intra-nigral transplants. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-OHDA into the medial forebrain bundle. The completeness of lesions was tested by measuring methamphetamine-induced rotations. Some 1-2 months after 6-OHDA administration, fetal ventral mesencephalic tissues were grafted into the lesioned nigral area followed by injection of 100 microg GDNF, along a tract from the nigra to striatum. Animals receiving transplantation and GDNF injection showed a significant decrease in rotation 1-3 months after grafting. Immunocytochemical studies indicated that tyrosine-hydroxylase-positive neurons and fibers were present in the nigra and striatum, respectively, after grafting. No effects of similarly injected brain-derived neurotrophic factor were seen. These results indicate that fetal nigral transplantation and GDNF injection restore the nigrostriatal dopaminergic pathway in Parkinsonian animals and support the hypothesis of trophic activity of GDNF on midbrain dopaminergic neurons.

Animals↗
PubMed1996

In vivo electrochemical studies of dopamine overflow and clearance in the striatum of normal and MPTP-treated rhesus monkeys.

Rapid chronoamperometric recordings, using Nafion-coated carbon-fiber electrodes (30-90 microns o.d.), were used to investigate overflow and uptake of dopamine (DA) in the striatum of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys. The monkeys were anesthetized with isoflurane and placed in a stereotaxic apparatus. Magnetic resonance imaging-guided sterile stereotaxic procedures were used for implantations of the electrochemical electrodes coupled with single-barrel micropipettes that were used to apply potassium or DA locally. Potassium evoked a robust overflow of DA-like electrochemical signals into the brain extracellular space in the unlesioned or normal putamen and caudate nucleus of the rhesus monkeys. In contrast, potassium did not produce any detectable changes (> 97% depletion) of DA in the MPTP-lesioned striatum. In addition, the diffusion/clearance of locally applied DA was markedly altered in the lesioned caudate nucleus and putamen compared with unlesioned striatum. Cell counts of the number of residual tyrosine hydroxylase-positive neurons in MPTP-treated monkeys, in conjunction with whole-tissue levels of DA and its metabolites, showed that the MPTP lesions produced extensive damage of the nigrostriatal DA system. These data indicate that residual dopaminergic fibers remaining after MPTP lesions are dysfunctional and have a greatly diminished capacity for high-affinity DA uptake.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Functional effects of GDNF in normal rat striatum: presynaptic studies using in vivo electrochemistry and microdialysis.

The functional effects of a single dual-site intranigral administration (10 micrograms) of glial cell line-derived neurotrophic factor (GDNF) on dopamine (DA) neurons in the basal ganglia of young Fischer 344 rats were investigated. A combination of behavioral, in vivo electrochemical, microdialysis and high-performance liquid chromatography methods were used to study the effects of this novel peptide. Behaviorally, significant changes in spontaneous locomotor activity were found 1 week, but not 3 weeks, after GDNF treatment. However, the velocity of movements was increased in the GDNF-treated animals 3 weeks after GDNF administration, a result that corresponded to significant enhancement of stimulus-evoked release of DA. Two-fold increases in potassium-evoked DA overflow were seen throughout the striatum by means of high-speed chronoamperometry 3 weeks after GDNF injection. No significant change in basal levels of DA was measured by microdialysis, although both potassium-evoked and d-amphetamine-induced DA overflow were significantly increased 3 weeks after treatment. Finally, significant changes in whole-tissue levels of DA were seen in the substantia nigra 1 week, but not 3 weeks, after GDNF administration. These data represent the first studies demonstrating that GDNF has long-lasting functional presynaptic effects on DA-containing neurons in the rat striatum.

Animals↗