D1-dopamine receptor agonists selectively activate striatal c-fos independent of rotational behaviour

L-Dopa and dopaminergic agonists selective for the D1- or D2-dopamine receptor subtype induce contraversive rotation in rats which have been unilaterally lesioned with injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra. D-Amphetamine, which releases dopamine from neurones on the unlesioned side of the animal, causes ipsiversive rotation. These increases in rotational behaviour are mediated, at least in part, by dopamine receptors in the striatum. In unilaterally lesioned animals, L-dopa and the D1-selective agonists SKF 38393 and CY 208-243 produce contralateral rotation and induction of the nuclear proto-oncogene c-fos in the lesioned striatum. D-Amphetamine induces both ipsilateral rotation and c-fos activation in the intact striatum. Three lines of evidence, however, dissociate fos induction and rotation. First, LY 171555, a selective D2-dopamine receptor agonist, also induces contraversive rotation but this rotation is not accompanied by c-fos activation in striatum. Second, D1-dopamine agonists produce activation of striatal c-fos even if rotation is prevented by an anaesthetic. Third, rotation induced by injection of SKF 38393 into substantia nigra is not accompanied by c-fos induction. These results suggest a mechanism by which D1-dopamine receptor mechanisms may regulate long-term changes in dopaminergic systems.     

5-HT1D receptors in the guinea pig brain: pre- and postsynaptic localizations in the striatonigral pathway

The caudate-putamen, globus pallidus and substantia nigra pars reticulata of the guinea pig contain high densities of the 5-HT1D receptor subtype. The cellular localization of these sites in the striatonigral pathway was investigated using receptor autoradiography and selective neurotoxin lesions. In guinea pigs with unilateral 6-hydroxydopamine lesions of the nigral dopaminergic cells, no significant decrease was observed in any of the components of the striatonigral pathway. In contrast, when quinolinic acid was injected in the caudate-putamen, marked reductions in [3H]5-HT binding were seen in the caudate-putamen, the globus pallidus and the substantia nigra pars reticulata, on the side ipsilateral to the lesion. These data, which are comparable to previous results in human pathologies where similar cell populations are known to degenerate (Parkinson disease and Huntington's chorea), indicate a presynaptic localization of 5-HT1D receptors on the terminals of the striatal neurons projecting to the pars reticulata of the substantia nigra. In addition, these receptors could be located on the cell bodies or dendrites of these neurons in the striatum, postsynaptically to serotoninergic fibers.     

Changes in [3H]muscimol binding in substantia nigra, entopeduncular nucleus, globus pallidus, and thalamus after striatal lesions as demonstrated by quantitative receptor autoradiography

A quantitative autoradiographic technique for measuring the binding of [3H]muscimol to central nervous system GABA receptors is described using tritium-sensitive film. [3H]Muscimol binding was studied in primary and secondary striatal projection areas of rat brain following kainic acid lesions of the striatum. Seven days after the lesion, binding affinities in the striatum and its projection areas were not altered significantly. There was a loss of [3H]muscimol receptors in the striatum. Receptors increased in numbers in the ipsilateral globus pallidus (19%), entopeduncular nucleus (22%), and substantia nigra pars reticulata (38%). [3H]Muscimol binding was decreased in the ipsilateral anteroventrolateral and ventromedial (8%) thalamic nuclei. [3H]Muscimol binding in other brain areas (layer IV of the cerebral cortex, central gray, superior colliculus, and stratum moleculare of hippocampus) was not affected. The findings suggest that a loss of striatal innervation resulted in increased numbers of GABA receptors in striatal projection sites. It is further suggested that loss of inhibitory striatal inputs to neurons in the entopeduncular nucleus and substantia nigra pars reticulata may activate GABAergic projections to thalamus and thus result in decreased numbers of thalamic GABA receptors.     

Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors.

The effect of administration of subtype selective dopamine (DA) agonists on the 6-hydroxydopamine (6-OHDA) lesion-induced increase of striatal preproenkephalin (PPE) mRNA was examined by dot-blot hybridization. Eight days following a unilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc), PPE mRNA levels in the ipsilateral striatum were increased approximately two-fold. Administration of the D2 DA agonist, quinpirole, dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. The effect of quinpirole was blocked by coadministration of the D2 DA antagonist eticlopride. In contrast, administration of the D1 DA agonist, SKF 38393, either dose-dependently augmented or had no effect on the 6-OHDA lesion-induced increase in striatal PPE mRNA. In the contralateral striatum, administration of quinpirole decreased PPE mRNA, while administration of SKF 38393 increased PPE mRNA compared to sham lesioned control levels. These data suggest the action of DA at D1 and D2 DA receptors differentially regulates striatal PPE mRNA levels and the apparent inhibition of ENK biosynthesis by DA is mediated via an interaction with D2 DA receptors.     

Endogenous brain-derived neurotrophic factor protects dopaminergic nigral neurons against transneuronal degeneration induced by striatal excitotoxic injury

Injury to the central nervous system causes atrophy or death of connecting neurons and can modify the expression of neurotrophic factors. We observed transneuronal upregulation of brain-derived neurotrophic factor (BDNF) expression in the rat ipsilateral substantia nigra pars compacta after a striatal lesion induced by kainate. This effect is developmentally regulated because the enhancement of nigral BDNF expression was only observed when striatal lesion was performed on postnatal day (P) 15 and in adulthood, but not at P7. Interestingly, the lack of regulation of BDNF was coincident with the transynaptic degeneration of nigral neurons after striatal excitotoxic injury. Hence, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta decreased when the lesion was performed at P7, but not at P15 or at P30. The analysis of the functional significance of this BDNF upregulation was done using trkB-IgG fusion proteins. After striatal injury, blockade of endogenous BDNF by trkB fusion proteins induced an atrophy of the dopaminergic neurons of the pars compacta. The injection of trkB-IgG fusion proteins did not modify the effects of kainate in the substantia nigra pars reticulata. Thus, our results show that BDNF exerts an autocrine/paracrine protective effect selectively on dopaminergic neurons against the loss of trophic support from the target striatum.     

Prolonged and selective induction of Fos-related antigen(s) in striatal neurons after 6-hydroxydopamine lesions of the rat substantia nigra pars compacta.

Unilateral 6-hydroxydopamine (6-OHDA) lesions of the rat substantia nigra lead to a large widespread and long-lasting (greater than 3 months) increased expression of Fos-related antigen(s) (FRAs) in striatal neurons ipsilateral to the side of the lesion. However, Fos and Jun expression were only very slightly increased in a few scattered neurons in the dopamine-denervated striatum. These results demonstrate that FRAs are induced long-term in striatal neurons following dopamine-depletion. This increased production of FRAs may be related to neuropeptide and/or D2 dopamine receptor upregulation that also occurs in the dopamine-denervated striatum.     

Dopaminergic grafts in the striatum reduce D1 but not D2 receptor-mediated rotation in 6-OHDA-lesioned rats.

Rats received fetal dopaminergic neuronal grafts in the striatum and/or substantia nigra ipsilateral to a 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). Dopaminergic grafts in the striatum substantially and significantly reduced turning elicited by the selective D1 agonist SKF 38393, but did not reduce turning elicited by the selective D2 agonist LY 171555. Thus, reduced turning in such grafted animals in response to non-selective dopaminergic agonists may be the result of diminished D1 supersensitivity. Fetal dopaminergic grafts in the ipsilateral substantia nigra (SN) did not augment the decreases in turning produced by concomitant ipsilateral dopaminergic grafts in the striatum in response to SKF 38393. LY 171555, D-amphetamine or L-DOPA. Dopaminergic grafts in the SN increased, while dopaminergic grafts in the striatum or in striatum and SN decreased, the facilitatory effect of D-amphetamine on rotation elicited by subsequent injection of dopamine agonists.     

Convergent Synaptic Input From the Neostriatum and the Subthalamus Onto Identified Nigrothalamic Neurons in the Rat

The two major afferents of the substantia nigra pars reticulata are the subthalamic nucleus and the striatum. Stimulation of these afferents has opposing physiological effects on the output neurons of the substantia nigra pars reticulata. In order to better understand the role of these afferents in the flow of information through the basal ganglia and to better understand the ways in which they might interact, experiments have been performed to test the possibility that single-output neurons of the substantia nigra pars reticulata receive convergent synaptic input from the subthalamic nucleus and the neostriatum. To address this, rats received iontophoretic deposits of the anterograde tracer Phaseolus vulgaris leucoagglutinin in the subthalamic nucleus, injections of the anterograde tracer biocytin in the neostriatum and injections of the retrograde tracer horseradish peroxidase conjugated to wheat-germ agglutinin in the ventral medial nucleus of the thalamus. Following appropriate survival times the animals were perfusion-fixed and sections of the substantia nigra were processed to reveal the transported tracers and prepared for electron microscopy. Light microscopic examination revealed that the substantia nigra contained rich plexuses of anterogradely labelled subthalamic and striatal terminals, as well as many retrogradely labelled nigrothalamic neurons. The anterogradely labelled terminals were often seen apposed to the retrogradely labelled neurons. In the electron microscope the subthalamic terminals were seen to form asymmetrical synaptic contacts (subthalamic type 1) with the identified nigrothalamic neurons as well as unlabelled perikarya and both proximal and distal dendrites. In confirmation of previous findings, the striatal terminals made symmetrical synaptic contact with the nigrothalamic neurons as well as unlabelled neurons. In areas of overlap between the two classes of terminals, identified nigrothalamic neurons and unlabelled nigral neurons were found to receive convergent synaptic input from the subthalamic nucleus and the neostriatum. In addition to the anterogradely labelled subthalamic terminals that formed asymmetrical synaptic specializations, a second, much rarer class was also observed (subthalamic type 2). These terminals were much larger and formed symmetrical synapses; several lines of evidence suggest that they originated not in the subthalamic nucleus but in the globus pallidus. These terminals were found to make synaptic contacts with identified nigrothalamic neurons and non-labelled neurons and to form convergent synaptic contacts with subthalamic type 1 terminals and striatal terminals. It is concluded that the topographical and synaptic organization of the so-called direct (striatum to substantia nigra pars reticulata) and indirect pathways (i.e. pathways involving the subthalamic nucleus andlor the globus pallidus) of information flow through the basal ganglia underlies the inhibition and excitation of the output neurons of the substantia nigra pars reticulata that occur following stimulation of the striatum.     

Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system.

The neurotoxic specificity of injections of 6-hydroxydopamine (6-OHDA) into areas containing either dopamine (DA) cell bodies (substantia nigra) or DA axon terminals (striatum) was studied. This selective effect was compared to the unspecific effects of copper sulfate (CuSO4) injection and electrocoagulation. One to two days after unilateral nigral injection of 2 mug of either 6-OHDA or CuSO4 into the nigra the volume of the unspecific lesions around the tip of the cannula was very similar. Only the 6-OHDA-induced lesions were associated with elective degeneration of the nigral DA neurons. Ten days after the administration of the same compounds the gliosis in the substantia nigra was much more extensive in CuSO4-than in 6-OHDA-treated rats; however, the reduction of DA concentrations in the ipsilateral striatum was only noticeable after 6-OHDA (-62%). A somewhat similar decrease of striatal DA levels (-52%) was observed after large electrocoagulation of the substantia nigra. Ten days after 6-OHDA (8mug) or electrolytic lesion of the striatum the Km for DA, serotonin and choline uptakes were similar in the striata of both sides, suggesting that the uptake process in the non-damaged neurons of the lesioned side was functionally normal. Following electrolytic lesion of the striatum, serotonin and choline Vmax values were decreased to about the same extent as the striatal reduction in weight and DA levels. When directly administered into the striatum 6-OHDA also produced a decline in DA concentration and Vmax but in contrast did not affect serotonin and choline uptake (Vmax), suggesting that the drug specifically destroyed dopaminergic neurons. The present data confirm that selective DA denervation can be achieved when appropriate amounts of the drug are injected into brain tissue in order to limit the unspecific lesion.     

Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions

The relative roles of D1 and D2 dopamine receptor stimulation in mediating the antiparkinsonian effects of dopaminergic drugs remain unclear. To determine the functional metabolic consequences of selective dopamine receptor stimulation, we used 2-deoxyglucose (2-DG) autoradiography to examine the effects of the D1 agonist SKF-38393 and the D2 agonist LY-171555 on regional cerebral glucose utilization (RCGU) in rats with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions. SKF-38393 (0.5-25.0 mg/kg) and LY-171555 (0.01-5.0 mg/kg) produced indistinguishable behavioral responses, including vigorous contralateral rotation. Treatment with each drug similarly increased glucose utilization, dose-dependently, in the parafascicular thalamus, subthalamic nucleus, deep layers of the superior colliculus, and lateral midbrain reticular formation ipsilateral to the nigral lesion; glucose utilization was decreased in the ipsilateral lateral habenula. By contrast, the D1 and D2 agonists differentially altered glucose utilization in the entopeduncular nucleus (EP) and the substantia nigra pars reticulata (SNr). SKF-38393, 5.0 and 25.0 mg/kg, increased glucose utilization 127 and 275%, respectively, in the pars reticulata ipsilateral to the lesion. LY-171555, 1.0 and 5.0 mg/kg, caused maximal contralateral turning, yet did not alter glucose utilization in the ipsilateral SNr. The glucose utilization response of the ipsilateral EP paralleled that of the SNr demonstrating large increases following administration of SKF-38393 and minimal change following the use of LY-171555. The results demonstrate that the selective D1 agonist reproduces the marked glucose utilization increases (2-3-fold above control values) in the EP and SNr that were previously observed using L-DOPA and apomorphine in this model, whereas the selective D2 agonist does not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Subthalamic Nucleus Lesion in Rats Prevents Dopaminergic Nigral Neuron Degeneration After Striatal 6-OHDA Injection: Behavioural and Immunohistochemical Studies

Several studies have shown that antagonists of N -methyl-D-aspartate receptors provide protection of the dopaminergic nigrostriatal pathway in animal models of Parkinson's disease. Since the substantia nigra compacta receives a moderate glutamatergic innervation from the subthalamic nucleus, we tried to determine whether subthalamic nucleus lesion could prevent the toxicity of the selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). Experiments were carried out on four groups of rats. Group 1 ( n = 10) received a unilateral injection of 6-hydroxydopamine in the striatum and group 2 ( n = 10) received kainic acid in the subthalamic nucleus. Group 3 ( n = 10) received an injection of kainic acid in the subthalamic nucleus and 1 week later an injection of 6-OHDA in the striatum. Group 4 ( n = 5) received the same treatment but kainic acid was replaced by saline. Apomorphine induced an ipsilateral rotation in rats of groups 2 and 3 and a contralateral rotation in rats of groups 1 and 4. The number of tyrosine hydroxylase-immunoreactive cells in the pars compacta of the substantia nigra was not significantly different between injected and non-injected sides in rats of groups 2 and 3, but was significantly decreased on the side ipsilateral to 6-OHDA striatal injection in rats of groups 1 and 4. These results show that subthalamic nucleus lesion provides neuroprotection of the dopaminergic nigrostriatal pathway against 6-OHDA toxicity and opens a new way for slowing or stopping the progression of Parkinson's disease.     

Prolonged blockade of NMDA or mGluR5 glutamate receptors reduces nigrostriatal degeneration while inducing selective metabolic changes in the basal ganglia circuitry in a rodent model of Parkinson's disease

We compared the neuroprotective and metabolic effects of chronic treatment with ionotropic or metabotropic glutamate receptor antagonists, in rats bearing a unilateral nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). The ionotropic, N-methyl-D-aspartate receptor antagonist MK-801 increased cell survival in the substantia nigra pars compacta (SNc) and corrected the metabolic hyperactivity (increased cytochrome oxidase activity) of the ipsilateral substantia nigra pars reticulata (SNr) associated with the lesion, but showed no effects on the 6-OHDA-induced hyperactivity of the subthalamic nucleus (STN). Significant-although less pronounced-protection of SNc neurons was also observed following treatment with the metabotropic glutamate receptor (mGluR5) antagonist 2-methyl-6-(phenylehtynyl)-pyridine (MPEP). As opposed to MK-801, MPEP abolished the STN metabolic hyperactivity associated with the nigrostriatal lesion, without affecting SNr activity. Specific modulation of STN hyperactivity obtained with mGluR5 blockade may, therefore, open interesting perspectives for the use of this class of compounds in the treatment of Parkinson's disease.     

Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms

Parkinson's disease results from the death of the dopamine-containing neurons in the substantia nigra pars compacta (SNC). This is accompanied by a loss of dopamine in brain regions, such as the corpus striatum, which receives input from dopaminergic neurons in the substantia nigra (SN). Since the corpus striatum is the primary target for these dopaminergic neurons, it has long been thought that the corpus striatum is the principal region affected. It was, therefore, natural to assume that replenishing dopamine in the striatum might be an effective treatment for Parkinson's disease. In fact, the dopamine precursor L-dihydroxyphenylalanine (L-dopa), the current drug of choice for treatment of Parkinson's disease, is believed to exert its therapeutic effect by replenishing dopamine levels in the corpus striatum via enzymatic decarboxylation within the synaptic terminals of surviving nigrostriatal neurons (Hornykiewicz, 1974). However, dopamine is also synthesized, stored, and released from the dendrites of SNC neurons that arborize in the substantia nigra pars reticulata (SNR) (Cheramy et al., 1981). Using a classic animal model for Parkinson's disease (rats with a unilateral 6-hydroxydopamine lesion of the SN), we show that L-dopa is also converted to dopamine in significant amounts within the 6-OHDA-lesioned SN. Furthermore, in contrast to the situation in the striatum where dopamine levels are only elevated for a short time, dopamine levels in the SN remain elevated until the behavioral effects of L-dopa have subsided. This elevation of nigral dopamine levels produces rotation that can be blocked by injecting a selective D1 dopamine receptor antagonist (SCH 23390, 2 micrograms in 1 microliter) directly into the SN pars reticulata. Infusion of SCH 23390 into the ipsilateral striatum produced only a modest reduction in L-dopa-induced circling behavior. These results suggest that D1 dopamine receptors in the SN may be at least as important as D1 dopamine receptors in the striatum as a site for the effects of L-dopa. This may have important implications for the therapy of Parkinson's disease.     

Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia

In the human brain, receptor binding sites for angiotensin are found in the striatum and in the substantia nigra pars compacta overlying dopamine-containing cell bodies. In contrast, angiotensin-converting enzyme occurs in the substantia nigra pars reticulata and is enriched in the striosomes of the striatum. In this study, using quantitative in vitro autoradiography, we demonstrate decreased angiotensin receptor binding in the substantia nigra and striatum of postmortem brains from patients with Parkinson's disease. In the same brains the density of binding to angiotensin-converting enzyme shows no consistent change. We propose, from these results, that angiotensin receptors in the striatum are located presynaptically on dopaminergic terminals projecting from the substantia nigra. In contrast, the results support previous studies in rats demonstrating that angiotensin-converting enzyme is associated with striatal neurons projecting to the substantia nigra pars reticulata. These findings raise the possibility that newly emerging drugs that interact with the angiotensin system, particularly converting enzyme inhibitors and new nonpeptide angiotensin receptor blockers, may modulate the brain dopamine system.     

Glial bFGF and S100 immunoreactivities increase in ascending dopamine pathways following striatal 6-OHDA-induced partial lesion of the nigrostriatal system: a sterological analysis

S100, a calcium-binding protein, and basic fibroblast growth factor (bFGF, FGF-2) are found predominantly in astrocytes in the central nervous system. Those molecules show trophic properties to neurons and are upregulated after brain lesions. The present study investigated the changes in the S100beta and bFGF immunoreactivities after a partial lesion of the rat midbrain ascending dopamine pathways induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). Stereological method revealed increases in the estimated total number and density of bFGF immunoreactive astroglial profiles in the ipsilateral pars compacta of the substantia nigra (SNc) and ventral tegmental area (VTA). Increases in the counts of astroglial S100beta immunoreactive profiles were found in the striatum, SNc, and VTA mainly ipsilateral but also in the contralateral nuclei. These results open up the possibility that interactions between astroglial S100beta and bFGF may be relevant to paracrine events related to repair and maintenance of remaining dopamine neurons following striatal 6-OHDA induced partial lesion of ascending midbrain dopamine pathway.     

Convulsive and postural effects of lesioning the mid-substantia nigra pars reticulata in naïve and 6-hydroxydopamine lesioned rats

The subthalamic nucleus is targeted for the treatment of Parkinson's disease. Unilateral lesions improve some aspects of parkinsonism but produce postural abnormalities in animal models but the exact pathways producing these effects remain to be defined. Using a battery of tests we evaluated the effects of lesioning one of the two major subthalamic targets, the substantia nigra pars reticulata in na?ve and 6-OHDA lesioned rats. Lesions targeting the mid-substantia nigra pars reticulata resulted in acute tonic-clonic seizures and intense contralateral rotational asymmetry. During the first month after substantia nigra pars reticulata lesions there was normalisation of the ipsilateral head position bias induced by unilateral 6-OHDA lesions, significant contralateral body axis bias but no significant alteration of apomorphine induced rotation and sensorimotor neglect in 6-OHDA lesioned rats. Combined with our previous data, this suggests that subthalamic projections via the substantia nigra pars reticulata are important in seizures and postural behaviours. Therefore unilateral subthalamotomy probably induces postural deficits in hemiparkinsonian animals via projections involving the substantia nigra pars reticulata. This has implications for patients undergoing subthalamotomy for treatment of Parkinson's disease.     

Expression of D4 dopamine receptors in striatonigral and striatopallidal neurons in the rat striatum

Recent studies have reported the regional distribution of D(4) dopamine receptors in the rat striatum at the cellular and subcellular levels. However, the precise identity of the striatal neurons that express these receptors remains unknown. We have studied the expression of D(4) receptors in the striatal interneurons as well as in the output regions of the striatum using immunohistochemistry. Furthermore, we have evaluated the contribution of the striatum to D(4) receptor immunoreactivity in these areas by means of ibotenic acid lesion of the striatum. D(4) receptors were observed in the substantia nigra pars reticulata (SNr), the entopeduncular nucleus (EP) and the globus pallidus (GP), and they were found, using electron microscopy, to be located presynaptically. D(4) immunoreactivity in the striatal output nuclei was observed to dramatically decrease following lesion of the striatum with ibotenic acid. Striatal interneurons were not found to express D(4) receptors. These results demonstrate that D(4) receptors are located almost exclusively in striatal projection neurons, in both striatonigral and striatopallidal neurons.     

Transient and widespread astroglial activation in the brain after a striatal 6-OHDA-induced partial lesion of the nigrostriatal system

The authors have previously described astroglial activation in the ipsilateral nigrostriatal system and ventral tegmental area following small doses of 6-hydroxydopamine (6-OHDA) injected unilaterally in the striatum. This article further evaluated astroglial reactivity in several brain regions after striatal 6-OHDA-induced punctate lesion in the nigrostriatal pathway. Adult male Wistar rats received a unilateral stereotaxical injection of the 6-OHDA (8 microg/4 microl) in the neostriatum and sacrificed 1 or 3 weeks later. Control animals received only solvent. Immunohistochemistry was employed for visualization of the tyrosine hydroxylase (TH), marker for dopamine cells, and glial fibrillary acidic protein (GFAP), marker for astrocytes. TH immunoreactive terminals disappeared in the striatum close to the injection site and a disappearance of a small number of a defined population of dopamine cell bodies was observed in the ipsilateral pars compacta of the substantia nigra (SNc). No dopamine lesion was detected in the contralateral nigrostriatal pathway. Astroglial reaction was seen close to the lesion in the neostriatum and in the ipsilateral SNc of the 1 week 6-OHDA lesioned rats. Specific stereological tools employing point intercepts and rotator, revealed an increased presence of reactive astrocytes in many forebrain regions like frontal, parietal and piriform cortex, septum, neostriatum and SNc, bilaterally, and also corpus callosum after 1 week of 6-OHDA injection. The astroglial activation was characterized by increases in the size of the cell body and/or processes. Astrocytic reaction was found only in the ipsilateral nigrostriatal pathway by 3 weeks of 6-OHDA, a slight activation also remaining in the ipsilateral septum and piriform cortex. Astrocytic reaction was seen in the solvent-injected rats only in the neostriatum close to the needle track. The transient widespread astroglial reaction observed in many brain regions following a striatal injection of 6-OHDA may represent a global paracrine trophic response in the brain.     

Neuronal localization of cannabinoid receptors in the basal ganglia of the rat

Cannabinoid receptors have recently been characterized and localized using a high-affinity radiolabeled cannabinoid analog in section binding assays. In rat brain, the highest receptor densities are in the globus pallidus and substantia nigra pars reticulata. Receptors are also dense in the caudate-putamen. In order to determine the neuronal localization of these receptors, selective lesions of key striatal afferent and efferent systems were made. Striatal neurons and efferent projections were selectively destroyed by unilateral infusion of ibotenic acid into the caudate-putamen. The nigrostriatal pathway was selectively destroyed in another set of animals by infusion of 6-hydroxydopamine into the medial forebrain bundle. After 2- or 4-week survivals, slide-mounted brain sections were incubated with ligands selective for cannabinoid ([3H]CP 55,940), dopamine D1 3H]SCH-23390) and D2 ([3H]raclopride) receptors, and dopamine uptake sites ([3H]GBR-12935). Slides were exposed to 3H-sensitive film. The resulting autoradiography showed ibotenate-induced losses of cannabinoid, D1 and D2 receptors in the caudate-putamen and topographic losses of cannabinoid and D1 receptors in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata at both survivals. Four weeks after medial forebrain bundle lesions (which resulted in amphetamine-induced rotations), there was loss of dopamine uptake sites in the striatum and substantia nigra pars compacta but no change in cannabinoid receptor binding. The data show that cannabinoid receptors in the basal ganglia are neuronally located on striatal projection neurons, including their axons and terminals. Cannabinoid receptors may be co-localized with D1 receptors on striatonigral neurons. Cannabinoid receptors are not localized on dopaminergic nigrostriatal cell bodies or terminals.