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At least 19 recordsLinked to original sources

PubMed1992

Target-specific outgrowth from human mesencephalic tissue grafted to cortex or ventricle of immunosuppressed rats.

Human fetal mesencephalic tissue was grafted to rats with unilateral lesions of the nigrostriatal pathway. The animals were immunosuppressed with cyclosporine A. Grafts were placed either into the lateral ventricle ipsilateral to the lesion or in the cingulate cortex above corpus callosum. The grafts and newly formed fibers were visualized by immunohistochemistry with antibodies against tyrosine hydroxylase (TH) and the human Thy-1 glycoprotein. TH-positive fibers covered the total volume of striatum when the graft was placed either in the ventricle or in the cortex. When the transplant was located in the ventricle, TH-positive cells migrated from the graft into host striatum. No cell migration was seen into any other areas than striatum. Cortex and septum were sparsely reinnervated by the graft, but not to a density higher than that normally seen. Globus pallidus was totally devoid of TH-positive fibers. When the graft was placed in cingulate cortex, fiber bundles penetrated through corpus callosum into either striatum, to arborize in its dorsal parts, or followed the medial side of the lateral ventricle to ventral limbic areas, where a fiber network also was formed. Human specific Thy-1-immunohistochemistry revealed positivity only on the lesioned side. These data suggest that dopamine neurons in human mesencephalic tissue, grafted to the rat brain, can migrate specifically into host striatum. Furthermore, TH-positive fiber outgrowth occurred only into dopamine denervated areas of the host, avoiding areas that are normally not innervated by nigral neurons, but also able to reach distant target cells.

Animals↗

PubMed1992

Long distance directed axonal growth from human dopaminergic mesencephalic neuroblasts implanted along the nigrostriatal pathway in 6-hydroxydopamine lesioned adult rats.

Dissociated ventral mesencephalon of 6 to 8-week-old human embryos were implanted by stereotaxic injection at different sites along the nigrostriatal pathway in adult rats, previously subjected to a 6-hydroxydopamine lesion of the intrinsic mesotelencephalic dopamine pathways. The recipients were immunosuppressed by daily injections of cyclosporin A to prevent rejection. At 13-20 weeks after transplantation, the implanted human neurons and their associated fiber outgrowths were visualized with a species-specific antibody recognizing human, but not rat, intermediary neurofilaments (HNF). From implants placed in the host rostral mesencephalic region, HNF-positive axonal projections were seen to extend in large numbers rostrally along the medial forebrain bundle and the internal capsule, and ramify within the caudate putamen, the ventral striatum and the amygdaloid nuclei (a distance of about 5-6 mm), and more sparsely in the frontal cortex and the olfactory bulb (a distance of about 10 mm). From implants placed in the internal capsule, abundant HNF-positive axons extended in the rostral, but not caudal, direction along the myelinated fiber bundles into the caudate putamen and the ventral striatum. Tyrosine hydroxylase (TH) immunohistochemistry revealed that the vast majority of the rostrally projecting HNF-positive axons were also TH-positive, and that the graft-derived axons gave rise to dense TH-positive terminal networks, above all in large areas of the previously denervated caudate putamen. From control implants of cortical neuroblasts, axonal projections were seen along the medial forebrain bundle and the internal capsule, but the axons were TH-negative and showed only sparse projections to the striatal areas. Instead, dense projections were seen, e.g., in the frontal cortex. The results demonstrate a remarkable ability of human mesencephalic neuroblasts to extend axons along the trajectories of the nigrostriatal and mesolimbocortical pathways to reach and innervate the principal striatal and limbic target areas in the forebrain. This shows that the basic requirements for the formation of long axonal pathways may be present in the adult mammalian central nervous system (CNS) at least for certain types of projection neurons. Furthermore, it implies that the developing human neuroblasts can escape the inhibitory features known to be present along myelinated growth trajectories in the adult mammalian brain. In addition, the present approach may offer new possibilities for functional neural grafting in the rat Parkinson model, since transplanted nigral neurons placed in their natural position within the rostral mesencephalon could provide an anatomically and functionally more integrated system than the standard model with ectopically placed intrastriatal nigral grafts.

Animals↗

PubMed2025

Chemoproteomic Profiling of Reactive Cysteines in Response to Oxidative Stress Induced by 6-Hydroxydopamine.

Although oxidative stress is a well-established driver of neurodegeneration, it remains poorly understood as to how the global cysteine (Cys) proteome is remodeled under oxidative stress conditions. Proteins with aberrantly modified cysteines in response to oxidative stress can induce and exacerbate neurodegeneration, contributing to disorders like Alzheimer's, Parkinson's, frontotemporal dementia, and amyotrophic lateral sclerosis. In this study, we induced oxidative stress in SH-SY5Y neuronal cells by subjecting them to the neurotoxin 6-hydroxydopamine (6-OHDA). To identify proteins with altered cysteine oxidation or PTM status, we used a desthiobiotin iodoacetamide (DBIA) probe, which selectively labels cysteines with unmodified and preserved thiols. Using these unbiased chemoproteomic strategies, we identified proteins with reduced Cys reactivity to DBIA in response to 6-OHDA-induced oxidative stress. Many of these proteins are critically involved in biological processes linked to cell stress responses (e.g., mitochondrial oxidative stress and apoptosis). Furthermore, we found that two key Cys on UCHL1 (a deubiquitinase critically involved in neurodegeneration) exhibited enhanced reactivity under oxidative stress conditions. Our study defines the remodeling of the Cys proteome under 6-OHDA-induced oxidative stress conditions. Furthermore, these findings suggest potential cysteine-mediated regulatory mechanisms in response to oxidative stress, providing a valuable resource for further exploration of cysteine modifications in the context of neurodegenerative signaling.

Oxidopamine↗

PubMed1992

Neonatal 6-OHDA lesions differentially affect striatal D1 and D2 receptors.

Lesions to the dopamine (DA) system in early postnatal development have different behavioral consequences compared to lesions made in adulthood. Intrastriatal injections of the neurotoxin 6-hydroxydopamine (6-OHDA) on the day of birth (PO) or postnatal day 1 (P1) produce a selective supersensitivity to D1 receptor agonists and a subsensitivity to D1 antagonists (Neal and Joyce, 1991a). In this paper, we describe the long-term effects of early DA loss on DA receptor regulation. Pups received bilateral intrastriatal injections of the neurotoxin 6-OHDA (4 micrograms per striatum) on PO or P1. Adult rats were killed at 90 days of age and the brains were processed for quantitative autoradiography (QAR) or tyrosine hydroxylase (TH) immunocytochemistry. Cohorts were tested for the behavioral responses to the selective D1 receptor agonist SKF38393 (10 mg/kg). Neonatally lesioned rats exhibited increases in abnormal perioral movements in response to D1 receptor stimulation. There was a heterogenous and patchy loss (40-50%) of [3H]mazindol binding to high-affinity DA uptake sites (a marker of DA terminal density) and a similar loss of TH-like immunoreactivity within the striata of the neonatally lesioned rats. There was also a reduction in the number of mu-opioid receptor patches (labelled with [3H]naloxone), a marker for the striatal patch compartment, and a similar patchy loss of D1 binding sites (labeled with [3H]SCH23390). The binding of [3H]spiroperidol to D2 sites was not altered. This is in contrast to the changes observed following adult 6-OHDA lesions, wherein there is a significant increase in the number of D2 binding sites (Joyce, 1991a,b). The results are discussed with respect to the behavioral consequences of neonatal lesions and the differences between neonatal and adult lesions.

Animals↗

PubMed1992

Dopamine supersensitivity and D1/D2 synergism are unrelated to changes in striatal receptor density.

Experiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D1/D2 synergism (i.e., the requirement of concomitant stimulation of D1 and D2 receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D1/D2 synergism was found to be independent of striatal D1 or D2 receptor density in rats as: (1) increasing striatal D1 and/or D2 receptor density (as confirmed by quantitative receptor autoradiography) by chronic treatment with SCH 23390 (0.5 mg/kg/day for 21 days) and/or haloperidol (0.5 mg/kg/day for 21 days) did not alter the normal pattern of D1/D2 synergism as determined by behavioral responsiveness to agonist stimulation of D1 or D2 receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D1 or D2 receptor density, induced a breakdown in D1/D2 synergism (i.e., behavior was elicited by independent stimulation of D1 or D2 receptors). In addition, the density of striatal D2 binding sites was not indicative of behavioral sensitivity to D2 agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D2 agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6-hydroxy-dopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D2 density. This enhanced sensitivity to quinpirole was no greater than that observed in neurologically intact rats treated concomitantly with a maximally stimulating dose of SKF 38393. Furthermore, rats with unilateral 6-hydroxydopamine lesions that were treated chronically with eticlopride continued to rotate contralateral to the lesion in response to quinpirole despite having hemispheric symmetry of striatal D2 receptor binding. By contrast, when rats with unilateral 6-hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity. The results support the hypothesis that two distinct types of dopamine supersensitivity exist: a modest one associated with increased D2 density, and a more profound one associated with a breakdown in D1/D2 synergism and independent of D2 density.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

The effect of intrastriatal application of directly and indirectly acting dopamine agonists and antagonists on the in vivo release of acetylcholine measured by brain microdialysis. The importance of the post-surgery interval.

The effect of intrastriatal application of D-1, D-2 and indirect dopaminergic drugs on the release of striatal acetylcholine as a function of the post-implantation intervals was studied using in vivo microdialysis. The dopamine D-2 agonists LY 171555 and (-)N0437 inhibited the release of striatal acetylcholine to 40% of control values 16-24 h after implantation of the dialysis cannula. When LY 171555 was infused 40-48 h after implantation of the dialysis cannula, the response was attenuated to 20% of control values. Meanwhile, the effectiveness of infusions of the antagonists (-)sulpiride and haloperidol was augmented from a non significant effect at 16-24 h to a 150% increase 40-48 h after implantation of the cannula. Infusions of the dopamine releasing agent amphetamine or the dopamine uptake inhibitor nomifensine resulted in a dose-dependent increase in the overflow of dopamine. Not until a sevenfold increase in the level of dopamine was seen, the release of acetylcholine was significantly affected. This hyporesponsiveness of the striatal cholinergic interneurons to endogenous dopamine could not be attributed to dopamine D-1 receptor activation, since no effects on striatal acetylcholine release were found by intrastriatal infusions of the selective D-1 agonist CY 208-243 or the selective D-1 antagonist SCH 23390. The results indicate that dopamine D-2 receptors are involved in the regulation of striatal acetylcholine release and that these receptors are tonically occupied by endogenous dopamine under the present experimental conditions 40-48 h after probe implantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1992

Cryopreservation, survival and function of intrastriatal fetal mesencephalic grafts in a rat model of Parkinson's disease.

In the present study we quantitatively assessed to what extent freeze-storage at liquid nitrogen temperature influences the survival and function of fetal mesencephalic grafts in the dopamine-depleted rat striatum. Ventral mesencephalic (VM) tissue was dissected from rat fetuses and stored overnight in a preservative medium at 4 degrees C (hibernation). It was grafted intrastriatally either as a fresh cell suspension or was frozen as tissue fragments or as a cell suspension after stepwise incubation in ascending concentrations of dimethyl-sulphoxide. Following a cryopreservation interval of 80 days in liquid nitrogen, the frozen samples were rapidly thawed, rinsed, and grafted. Cellular viabilities of graft cell suspensions, as assessed by ethidium bromide/acridine orange staining, were decreased from 90% in fresh tissue to 38-35% in frozen and thawed tissue. Amphetamine-induced turning behavior at 6 weeks post-grafting was significantly attenuated in hosts that had received fresh grafts or grafts that were frozen as tissue fragments. Tyrosine hydroxylase-(TH-) immunocytochemistry of recipient brains revealed significant decreases in TH-positive graft cell numbers in rats grafted with cryopreserved tissue (38-42% of fresh tissue). Moreover, the dye exclusion viability of thawed VM tissue was found to accurately predict the subsequent graft survival. There was no difference with respect to graft cell numbers between the two freezing methods employed, though block storage seems to be more simple from a practical point of view.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗

PubMed1992

Alpha-adrenoceptor function before and after chemical sympathectomy in human and feline detrusor muscles.

Isolated bladder segments from man and cat were treated with 6-hydroxydopamine (6-OHDA) in vitro. Chemical sympathectomy was evaluated with fluorescence microscopy and found to be very similar to the effect of 6-OHDA administered in vivo to cats. Isometric smooth muscle contractile responses were induced by field stimulation (FS). The amplitude of the responses increased after denervation. The effects of alpha-adrenoceptor agonists and antagonists on the FS-induced contractile responses were compared before and after treatment with 6-OHDA. The reduction in the contractile responses after the addition of noradrenaline to the feline bladder strips was more pronounced after treatment. Phentolamine induced an increase in contractile responses before treatment, an effect not seen afterwards in human bladder strips but which persisted in feline bladder strips. Selective alpha-adrenoceptor agonists did not alter the contractile responses in denervated strips. It is suggested that the function of the alpha-adrenoceptors in the detrusor is to inhibit neuronally mediated contractile responses of smooth muscle.

Adrenergic alpha-Agonists↗

PubMed1992

Autoradiographic localization of gamma-aminobutyric acidA receptors within the ventral tegmental area.

Destruction of intrinsic neurons in the ventral tegmental area (VTA) with the excitotoxin, quinolinic acid produced a significant decrease (80%) in [3H]muscimol binding to GABAA receptors within the parabrachial pigmented and paranigral nuclei of the VTA. Selective destruction of the dopaminergic neurons with 6-hydroxydopamine (6-OHDA) did not reduce [3H]muscimol binding within the VTA. However, the destruction of dopaminergic neurons did produce an increase (20%) in [3H]muscimol binding contralateral to the lesion, suggesting a reduction in the GABAergic innervation to this region. Additionally, destruction of the VTA afferents with quinolinic acid injections in the medial accumbens failed to produce alterations in [3H]muscimol binding within the VTA. These results are consistent with the predominant localization of GABAA receptors to non-dopaminergic neurons intrinsic to the VTA.

Animals↗

PubMed1992

Effects of alpha 2- and beta-adrenoceptor agonists on growth hormone secretion following lesion of the noradrenergic system of the rat.

The aim of the present investigation was to lesion the noradrenergic system and to measure the effect on growth hormone (GH) secretion following peripheral administration of alpha 2- and beta-adrenoceptor agonists. Direct injection of these agonists into the paraventricular nucleus of the hypothalamus (PVN) and its effect on GH secretion were also investigated. Systemic administration of N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4, 60 mg/kg, injected i.p. 10 days prior to experimentation) significantly decreased the noradrenaline (NA) content of the hippocampus, frontal cortex and hypothalamus but had no effect on the dopamine (DA) or serotonin (5-HT) content of these areas. Bilateral injection of 6-hydroxydopamine (6-OHDA, 10 micrograms/microliters, 14 days prior to experimentation) into the medial forebrain bundle (MFB) caused a greater reduction of NA and also decreased the DA and 5-HT content of the hypothalamus. Analysis of the PVN of the hypothalami of rats following 6-OHDA lesion of the MFB showed significantly decreased NA and 5-HT content. Neither DSP4 treatment nor 6-OHDA lesion of the MFB affected the clonidine (250 micrograms/kg, i.p.) induced stimulation of GH secretion. Injection of isoproterenol (1 mg/kg, i.p.) had varying effects on GH secretion. It stimulated GH release in control rats but not in DSP4 or MFB lesioned rats. Direct injection of clonidine (0.1 microgram/microliters) into the PVN significantly stimulated GH secretion, whereas injection of isoproterenol (2.5 micrograms/microliters) into the PVN did not affect GH levels when compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Dopamine fiber growth induction by implantation of synthetic dopamine-containing microspheres in rats with experimental hemi-parkinsonism.

Injectable local drug delivery formulations-so-called microspheres have recently been developed, in which drugs are microencapsulated within biocompatible and biodegradable copolymer excipients like poly[DL-lactide-co-glycolide]. In view of its potential therapeutical usefulness, we have studied the microsphere methodology as a means to substitute for experimentally induced subnormal levels of endogenous dopamine (DA). Administration of 6-hydroxydopamine (6-OH-DA) unilaterally in the medial forebrain bundle of rats results in an up-regulation of postsynaptic receptors in the denervated striatum, functionally manifested as contralateral rotational behavior after apomorphine. DA microspheres were implanted in the denervated striatum. The majority of the rats displayed an attenuation of the contralateral rotational behavior induced by apomorphine up to 8 wk postimplantation. Immunocytochemical observations unexpectedly demonstrated growth of DA and tyrosine hydroxylase immunoreactive fibers in the denervated striatum. Interestingly, there was an apparent correlation between functional recovery and the degree of growth of DA fibers. The present results suggest that implantation of DA microspheres may promote DA fiber growth and extended recovery of surviving DA neurons, and, therefore, could be of therapeutic usefulness in Parkinson's disease.

Animals↗

PubMed1992

Dissociation of the striatal D-2 dopamine receptor from adenylyl cyclase following 6-hydroxydopamine-induced denervation.

Intracellular cyclic AMP accumulation following exposure to dopamine (DA) agonists and and antagonists was measured in striatal slices from rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway and which showed contralateral circling to apomorphine. Both DA (10-320 microM) and the D-1 agonist SKF 38393 (0.1-32 microM) increased cyclic AMP accumulation in striatal slices from the lesioned and intact hemispheres. The EC50 for DA to increase cyclic AMP accumulation in slices was greater in the 6-OHDA-lesioned striata compared to the intact striatum, but the EC50 for SKF 38393 was not affected. The D-1 antagonist SCH 23390 (10 microM) completely inhibited the ability of DA and SKF 38393 to increase cyclic AMP accumulation in striatal slices from both denervated and intact sides of the brain. In slices from the intact hemisphere the increase in DA-induced cyclic AMP accumulation was enhanced by the D-2 antagonist (+/-)-sulpiride (50 microM) but (+/-)-sulpiride had no effect on the DA response in slices from the lesioned side. Similarly, the ability of SKF 38393 to enhance cyclic AMP accumulation was blocked by the D-2 agonist quinpirole (10 microM) in striatal slices from the intact hemisphere but not in tissue from the lesioned side. The density of striatal D-1 and D-2 receptors assessed by [3H]SCH 23390 and [3H]spiperone binding did not differ between the hemispheres although there was an increase in the affinity of D-1 receptors for [3H]SCH 23390 in the lesioned striatum. After striatal deafferentiation there appears to be an uncoupling of the "inhibitory" D-2 receptor from the D-1 receptor-associated adenylyl cyclase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Dopaminergic modulation of striatal neuropeptides: differential effects of D1 and D2 receptor stimulation on somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin.

Dopaminergic modulation of neuropeptides in rat striatum was investigated by examining the effects of prolonged D1 or D2 receptor stimulation on levels of somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway were treated for 7 days with either the D1 agonist SKF 38393 (12.5 mg/kg/day) or the D2 agonist quinpirole (1 mg/kg/day). Two regimens of agonist treatment were compared: continuous infusion via osmotic pump implanted i.p. and intermittent (once daily) i.p. injection. Rats were sacrificed 3 h after the last injection and peptide levels measured in the striatum bilaterally by radioimmunoassay; alterations in peptide content were observed primarily in the denervated striatum. In comparison to values from lesioned, vehicle-treated controls, intermittent administration of SKF 38393 reduced somatostatin and neuropeptide Y (down 61% and 57%, respectively), increased neurotensin (up 105%) and dynorphin (up 184%) and had no effect on enkephalin; continuous SKF 38393 decreased neuropeptide Y by 39% but did not alter levels of the other peptides. Continuous quinpirole elevated somatostatin and neuropeptide Y levels (up 43% and 33%, respectively), but reduced the lesion-induced increases in both neurotensin (down 51%) and enkephalin (down 24%) content. Conversely, intermittent quinpirole decreased somatostatin (down 35%) and neuropeptide Y (down 27%), increased neurotensin content by 79% and had no effect on enkephalin. Dynorphin levels were not altered by either continuous or intermittent quinpirole. These findings reveal the complexity of dopaminergic influences on striatal neuropeptides.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Excitotoxic lesions of the pedunculopontine tegmental nucleus of the rat. II. Examination of eating and drinking, rotation, and reaching and grasping following unilateral ibotenate or quinolinate lesions.

The pedunculopontine tegmental nucleus (PPTg) contains a population of cholinergic neurons thought to be part of the ascending reticular activating system, and non-cholinergic neurons. In the previous study it was shown that various excitotoxins made effective lesions of cholinergic neurons in the PPTg but that quinolinate made smaller lesions in the non-cholinergic population, making it more selective than any other excitotoxin. The purpose of the present experiment was, first, to make lesions of cholinergic neurons throughout the length of the PPTg by infusing toxin at two different sites within it; and second, to examine simple motor activities in rats bearing either quinolinate or ibotenate lesions of the PPTg, and contrast these with the deficits seen after 6-hydroxydopamine (6-OHDA) induced lesions of mesostriatal dopamine (DA)-containing neurons. Post-mortem examination was carried out using choline acetyltransferase (ChAT) and tyrosine hydroxylase (TOH) immunohistochemistry, and routine Nissl staining. Both quinolinate and ibotenate destroyed approximately 75% of ChAT-positive neurons in the PPTg, but damage to non-cholinergic neurons (assessed by Nissl staining) was twice as great following ibotenate as quinolinate. 6-OHDA induced almost complete lesions of mesostriatal DA neurons, assessed by TOH immunohistochemistry. DA depleted rats showed deficits in drinking and spilled more food in the first 2 weeks after surgery, and were unable to reach or grasp food pellets in the staircase test. They also showed strong ipsilateral turning in response to amphetamine and contralateral turning to apomorphine. Quinolinate lesioned rats had no eating or drinking impairment in the home cage but showed a reaching (though not grasping) disability in the staircase test. They had a mild ipsilateral bias following amphetamine. Ibotenate lesioned rats, despite having larger lesions than the quinolinate, showed no deficits in eating or drinking in the home cage, or reaching or grasping disabilities in the staircase test. They did have a mild contralateral bias in response to amphetamine. This dissociation of the effects of quinolinate and ibotenate lesions of the PPTg is consistent with the suggestion that the PPTg has two functionally distinct components, and is attributed to the differential lesion of non-cholinergic neurons by the two excitotoxins.

Animals↗

PubMed1992

Differential effect of subthalamic nucleus ablation on dopamine D1 and D2 agonist-induced rotation in 6-hydroxydopamine-lesioned rats.

The effect of unilateral subthalamic nucleus ablation on rotation in response to dopamine D1 and D2 agonists was examined in rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway. Four to five weeks following subthalamic nucleus lesion, D2 agonist-induced rotation was reduced in subthalamic nucleus-lesioned rats relative to sham controls, although no such reduction in D1 agonist-induced circling occurred. However, 1-2 weeks following subthalamic nucleus lesion marked reductions occurred in both D1 and D2 agonist-induced rotation in subthalamic nucleus lesioned rats compared to sham controls. These results suggest that the subthalamic nucleus contributes primarily to the expression of D2-mediated motor behaviors, although ablation of the subthalamic nucleus may induce certain time-dependent compensatory mechanisms in other basal ganglia structures which affect D1-mediated actions.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Transplantation of embryonic mesencephalic and medullary raphe neurons to the neostriatum of rats with unilateral 6-hydroxydopamine lesions.

The implantation of dopamine-rich mesencephalic grafts into the 6-hydroxydopamine (6-OHDA)-lesioned neostriatum of rats was accompanied by marked hyperinnervation by serotonin (5-HT) fibers. The purpose of this study was to examine the possibility that the graft-derived 5-HT hyperinnervation is governed by target-related effects present in the host neostriatum and the question of whether grafts rich in 5-HT cells can ameliorate the drug-induced motor asymmetry resulting from unilateral 6-OHDA lesions. Rats were allocated to one of two groups: lesion plus mesencephalic raphe grafts (group R5-HT/L); and lesion plus medullary raphe grafts (group C5-HT/L). A third group, sham-lesion plus mesencephalic raphe grafts (group R5-HT/S) was included. Complete recovery of (+)-amphetamine-induced rotation was observed only in rats which received 5-HT grafts derived from medullary raphe neurons. There was no marked recovery of apomorphine-induced rotation in either of the R5-HT/L and C5-HT/L groups. Immunohistochemistry showed that the R5-HT/L and C5-HT/L groups had 5-HT hyperinnervation in the neostriatum of the lesioned side. There was no target-related effect of the 6-OHDA-lesioned neostriatum specific for the different types of 5-HT tissue. It seems likely that the 5-HT tissue derived from the medullary raphe may contain additional neurotransmitters which contribute to the behavioral recovery.

Amphetamine↗

PubMed1992

Lesions of the mesotelencephalic dopamine system enhance the effects of selective dopamine D1 and D2 receptor agonists on striatal acetylcholine release.

In vivo microdialysis was used to determine the effects of 6-hydroxydopamine (6-OHDA) lesions of the mesotelencephalic dopamine system on dopamine receptor agonist induced changes in extracellular acetylcholine (ACh) concentrations in the striatum. Such lesions increased the inhibitory effect of a low dose of the D2 receptor agonist quinpirole (0.05 mg/kg s.c.) on striatal ACh release. In addition, 6-OHDA lesions enhanced the facilitatory effect of the selective D1 receptor agonist CY 208-243 on striatal ACh release, enabling a subthreshold (0.2 mg/kg s.c.) dose to increase striatal dialysate concentrations of ACh by over 60%. These results indicate that denervation supersensitivity potentiates both the facilitatory effects of D1 receptor agonists and the inhibitory effects of D2 receptor agonists on striatal cholinergic activity. It was also found that the 6-OHDA lesions reduced basal interstitial ACh concentrations by 75% in the ipsilateral striatum. The later results are consistent with the hypothesis that the prepotent action of dopamine in the forebrain is to enhance striatal ACh release via a D1 receptor mechanism.

Acetylcholine↗

PubMed1992

A-77636: a potent and selective dopamine D1 receptor agonist with antiparkinsonian activity in marmosets.

A-77636, ((1R,3S) 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benz opyran hydrochloride), is a selective dopamine D1 receptor agonist. In a battery of receptor binding assays, A-77636 shows the highest affinity (pKi = 7.40 +/- 0.09; Ki = 39.8 nM) for the dopamine D1 receptor. A-77636 is an agonist at the dopamine D1 receptors in the fish retina (pEC50 = 8.13; EC50 = 1.1 nM; intrinsic activity = 102% of dopamine) and the rat caudate-putamen (pEC50 = 8.97; intrinsic activity = 134% of dopamine). The compound is functionally inactive at dopamine D2 receptors (EC50 > 10 microM). In rats with unilateral 6-OHDA (6-hydroxydopamine) lesions of the nigro-striatal dopaminergic pathway, A-77636 elicits prolonged (> 20 h) contralateral turning that is blocked by SCH 23390, a D1 receptor antagonist, but not by haloperidol at doses selective for the dopamine D2 receptor. Higher doses of A-77636 produce forelimb clonus in rats and mice. When tested in marmosets treated with MPTP to induce a parkinsonian-like state, A-77636 increases locomotor activity and decreases the severity of the parkinsonian-like symptoms: the compound is active after either subcutaneous or oral administration. A-77641, the optical antipode of A-77636, has a lower affinity towards the dopamine D1 receptor (pKi = 5.14, Ki = 7200 nM), is less potent as a dopamine D1 receptor agonist (pEC50 = 5.65; EC50 = 2200 nM), fails to elicit turning in the 6-OHDA-lesioned rat, and lacks antiparkinsonian efficacy in the MPTP-treated marmoset.(ABSTRACT TRUNCATED AT 250 WORDS)

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