Short and long term plasticity after lesioning of the cell body or terminal field area of the dopaminergic mesocorticolimbic system in the rat (original) (raw)
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Regulation of striatal acetylcholine release by dopamine after nigrostriatal bundle injury
Lesions of the dopaminergic component of the nigrostriatal bundle (NSB) are associated with marked neurological deficits. These deficits are due in part to the disruption of the normal presynaptic inhibition of cholinergic activity in striatum by dopamine (DA). Thus, the deficits can be alleviated by pharmacological treatments that either increase dopaminergic activity (e.g., L-DOPA) or block cholinergic activity (e.g., atropine). Most cases of Parkinson's disease arc associated with progressive NSB degeneration and accompanying neurological dysfunctions. However, under conditions in which the degeneration is not progressive. both patients and experimental animals may show a recovery of function (for review see Reference 1). We have previously observed that such recovery is associated with an increase in the capacity of D,4 to inhibit acetylcholine (ACh) release as measured in vitro.-The purpose of the prcscnt study was to investigate the mechanism of that recovery of function.
Timecourse of striatal re-innervation following lesions of dopaminergic SNpc neurons of the rat
European Journal of Neuroscience, 2003
Previously we described the extent of sprouting that axons of the rat substantia nigra pars compacta (SNpc) undergo to grow new synapses and re-innervate the dorsal striatum 16 weeks after partial lesions. Here we provide insights into the timing of events related to the re-innervation of the dorsal striatum by regenerating dopaminergic nigrostriatal axons over a 104-week period after partial SNpc lesioning. Density of dopamine transporter and tyrosine hydroxylase immunoreactive axonal varicosities (terminals) decreased up to 80% 4 weeks after lesioning but returned to normal by 16 weeks, unless SNpc lesions were greater than 75%. Neuronal tracer injections into the SNpc revealed a 119% increase in axon ®bres (4 mm rostral to the SNpc) along the medial forebrain bundle 4 weeks after lesioning. SNpc cells underwent phenotypic changes. Four weeks after lesioning the proportion of SNpc neurons that expressed tyrosine hydroxylase fell from 90% to 38% but returned to 78% by 32 weeks. We discuss these phenotype changes in the context of neurogenesis. Signi®cant reductions in dopamine levels in rats with medium (30±75%) lesions returned to normal by 16 weeks whereas recovery was not observed if lesions were larger than 75%. Finally, rotational behaviour of animals in response to amphetamine was examined. The clear rightward turning bias observed after 2 weeks recovered by 16 weeks in animals with medium (30±75%) lesions but was still present when lesions were larger. These studies provide insights into the processes that regulate sprouting responses in the central nervous system following injury.
The effect of unilateral 6-hydroxydopamiae lesions of the dopamin-ergic nigrostriatal pathway on glutamic acid decarboxylase (GAD) and choline acetyltranaferase (CAT) was examined in various nuclei of the basal ganglia of the rat. GAD was significantly increased in the accumbens, head and tail of the striatum, and globus palli-dus on the lesioned compared to the contralateral aide. CAT was significantly increased in the head of the striatum, while the activity in the tail was decreased. During the past decade the nigro-striatal dopaminergic projection (NSP) has been the subject of extensive anatomical, physiological, pharmacological and behavioural studies. In spite of the considerable knowledge vrhich has been gained as a result of these investigations, there is presently little information available regarding the possible long term effects of NSP lesions on biochemical parameters in the etriat~. There is evidence for denervation super-sensitivity is this structure after NSP lesions (1) but the biochemical data bearing oa this point are controversial (2). We (J .I. Nagy, T. Lee, P. Seeuran and H.C. Fibiger, submitted) and others (3) have found these lesions to cause an increase in the binding of the DA-receptor antagonist 3H-haloperidol to stri-atal membrane preparations. More recently we (4) reported the activity of stri-atal glutamic acid decarboxylase (GAD) increased 25 days postoperatively following the production of specific lesions of the NSP with 6-hydroxydopamine (6-OHDA). Changes in the activity of these post-synaptic systems may contribute to the overall alterations in striatal function observed after NSP lesion. The NSP lesion has been suggested as a model of Parkinson's disease and aimilar-itiea exist is the behavioural deficits seen is lesioned animals and in Parkin-sonian patients (5,6,7). Thus a comparison of biochemical parameters in Parkin-sonian brains with those of NSP lesioned animals may provide some insight into the etiology of this disease. In our previous study we examined the effects of NSP lesions on "striatal" samples which included the nûcleus accumbene, caudate-putamen and globus pallidus (4). We now report that 6-OHDA lesions of the dopaminergic NSP have distinct effects upon the activities of GAD and CAT in discrete nuclei of the extrapyra-midal system. Methode Animals weighing about 300 g were placed under Nembutal anaesthesia sad given unilateral atereotaxic injections into the nigro-striatal projection. These injections consisted of 2 .0 ul of a physiological saline solution containing 4
Brain, 2007
We have examined dopaminergic cell survival after alteration of the subthalamic nucleus (STN) in methyl-4 -phenyl-1,2,3,6 -tetrahydropyridine (MPTP)-treated monkeys. The STN was lesioned with kainic acid (B series) or underwent deep brain stimulation (DBS) at high frequency (C series). In another series, MPTPtreated and non-MPTP-treated monkeys had no STN alteration (intact animals; A series). Animals were treated with MPTP either after (B1, C1) or before (B2, C2) STN alteration. We also explored the long-term ($7 months) effect of DBS in non-MPTP-treated monkeys (D series). Brains were aldehyde-fixed and processed for routine Nissl staining and tyrosine hydroxylase immunocytochemistry. Our results showed that there were significantly more (20^24%) dopaminergic cells in the substantia nigra pars compacta (SNc) of the MPTPtreated monkeys that had STN alteration, either with kainic acid lesion or DBS, compared to the non-MPTPtreated monkeys (intact animals). We suggest that this saving or neuroprotection was due to a reduction in glutamate excitotoxicity, as a result of the loss or reduction of the STN input to the SNc. Our results also showed that SNc cell number in the B1 and C1 series were very similar to those in the B2 and C2 series. In the cases that had long-term DBS of the STN (D series), there was no adverse impact on SNc cell number. In summary, these results indicated that STN alteration offered neuroprotection to dopaminergic cells that would normally die as part of the disease process.
Brain Research, 1996
Rat models of Parkinson's disease typically employ a rapid nigral injection of 6-hydroxydopamine (6-OHDA) to produce a near-complete loss of nigrostriatal dopamine neurons, and thus model end stage disease. The present report describes the use of a continuous, low dose infusion of 6-OHDA into the striatum which produces a terminal axotomy of nigrostriatal dopamine neurons and protracted behavioral response. A solution of 6-OHDA in 0.4% ascorbate, delivered at 37°C from osmotic minipumps, was stable for 8 days as determined by its retained toxicity to a dopaminergic neuroblastoma cell line. The continuous infusion of 0.2 /~g 6-OHDA per h did not affect the striatal uptake of [3H]GABA, [3H]choline, or [3H]glutamate but reduced [3H]dopamine uptake by 55% within 1.5 days after the start of the infusion. The striatal infusion of 6-OHDA produced a dose-dependent reduction of striatal dopamine and DOPAC levels but did not alter HVA, 5-HT, or 5-HIAA. An increase in amphetamine-induced ipsiversive rotations occurred within 1.5 days after the acute striatal injection of 20 /xg or 30 /zg of 6-OHDA but required 4 days to develop with the continuous 6-OHDA infusion. The topography of the lesion mapped by [3H]mazindol binding showed that, begining by 1.5 days, a diffuse depletion of terminals encompassed much of the striatum in the 30 /xg acute injection group, whereas in the continuously infused rats, the lesion was apparent only by 4 days and was restricted to a smaller and more completely lesioned area. Unlike acutely lesioned animals, continuously infused rats revealed no obvious loss of dopamine neurons in the pars compacta by 5 weeks after 6-OHDA. The continuous striatal infusion of 6-OHDA can produce a topographically limited terminal axotomy of dopamine neurons and a protracted behavioral impairment.
Brain Research, 1974
Thierry et al. 16 described dopamine (DA) stores in the cortex cerebri and were the first to suggest the existence of cortical DA nerve terminals. Subsequent pharmaco-histochemical studies using recent sensitive modifications of the Falck-Hillarp technique2,6,13 together with DA-fi-hydroxylase inhibitors 15 and L-DOPA combined with peripheral decarboxylase inhibitors after reserpine pretreatment have confirmed and extended this study to show that cortical DA nerve terminals probably exist but mainly in the limbic cortex and in the deep layers of the frontal cortex 7,s,11,12. In order to obtain information as to the origin of these cortical DA nerve terminals, lesions have been made in the ventromedial tegmental area of the midbrain, rich in DA nerve cell bodies (group A9-A10 according to DahlstrSm and Fuxe 4) and in the hypothalamic catecholamine (CA) cell group A13 a,5 localized in the dorsal hypothalamus. Male Sprague-Dawley rats (body wt. 150-250 g) have been used. Most of the electrolytic lesions (0.5 mA DC, 30 sec, unipolar) were performed in the area between the A9 and A10 group (Fig. 1). The coordinates were according to K6nig and KlippeP as follows: A (anterior) = +2.0 mm; L (lateral) = + 1.0 mm; V (vertical) ~-2.8 mm. Unilateral intracerebral injections with 6-hydroxydopamine (6-OH-DA, 16 #g/8 /~1) were also performed (A-+ 2.5; L = + 1.2; V =-2.4). Two rats received electrolytic lesions in the midline (L = 0) at the same level and depth as above in order to destroy mainly the A10 group. Also a lateral lesion with the same electrical parameters as above was made in one rat in order to avoid lesioning the A10 group (A = +1.95; L = +1.8; V =-2.8). The A13 group was lesioned in two rats using the following coordinates: A = +4.9 mm; L = +0.6 m m ; V =-1.8 mm. In this case the DC current was 1 mA. All the lesions were unilateral and the non-lesioned side served as a control. The degree of anterograde degeneration of the DA systems to the forebrain was studied 2-3 weeks following the lesion. The DA nerve terminals were distinguished from the noradrenaline (NA) and 5-hydroxytryptamine (5-HT) nerve terminals by using the recent discovery that in the forebrain reserpine-resistant accumulations of CA seem to occur exclusively in the DA nerve terminals 7,11. Some rats were therefore pretreated with reserpine (5-10 mg/kg, i.p.) 18-24 h before killing.
European Journal of Neuroscience, 2003
Recently it was demonstrated that sprouting of dopaminergic neurons and a microglial and astrocyte response follows both partial lesions of the substantia nigra pars compacta and blockade of the D 2 dopamine receptor. We therefore studied the effects of the combination of these two treatments (lesioning and D 2 dopamine receptor blockade). Haloperidol administration caused a 57% increase in dopaminergic terminal tree size (measured as terminal density per substantia nigra pars compacta neuron) and an increase of glia in the striatum. Following small to medium nigral lesions (less than 60%), terminal tree size increased by 51% on average and returned density of dopaminergic terminals to normal. In contrast, administration of haloperidol for 16 weeks following lesioning resulted in reduced dopaminergic terminal density and terminal tree size (13%), consistent with absent or impaired sprouting. Glial cell numbers increased but were less than with lesions alone. When haloperidol was administered after the striatum had been reinnervated through sprouting (16±32 weeks after lesioning), terminal tree size increased up to 150%, similar to the effect of haloperidol in normal animals. By examining the effect of administering haloperidol at varying times following a lesion, we concluded that a switch in the effect of D 2 dopamine receptor blockade occurred after dopaminergic synapses began to form in the striatum. We postulate that when synapses are present, D 2 dopamine receptor blockade results in increased terminal density, whereas prior to synapse formation D 2 dopamine receptor blockade causes attenuation of a sprouting response. We speculate that D 2 dopamine receptors located on growth cones`push' neurites toward their targets, and blockade of these receptors could lead to attenuation of sprouting.