Brain Research 824 Ž1999. 81–88
Research report
Unilateral dopamine depletion paradoxically enhances amphetamine-induced Fos expression in basal ganglia output structures David Wirtshafter a
a, )
, Karen E. Asin
b
Department of Psychology, M r C 285, The UniÕersity of Illinois at Chicago, 1007 West Harrison St., Chicago, IL 60607-7137, USA b Department of Toxicology, Abbott Laboratories, D468, Building AP13A, Abbott Park, IL 60604, USA Accepted 22 December 1998
Abstract The ability of amphetamine to induce expression of the immediate early gene protein, Fos, was examined by immunocytochemistry in animals with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle. Amphetamine induced Fos expression in the globus pallidus ŽGP. on the intact side of the brain, but this response was greatly attenuated on the dopamine-depleted side. In contrast, amphetamine induced little Fos expression in the entopeduncular nucleus ŽEPN. and the substantia nigra pars reticulata ŽSNpr. on the intact side of the brain, but resulted in pronounced expression in these structures on the lesioned side. These findings demonstrate that unilateral dopamine depletion results in a pathophysiological state in which some responses to amphetamine are attenuated while others are paradoxically potentiated. One explanation of these effects is that amphetamine may indirectly activate excitatory inputs to the SNpr and the EPN on both sides of the brain. On the intact side, these effects would be opposed by the simultaneous activation of inhibitory pathways arising in the striatum and the GP, with the result that little Fos expression would be seen. On the dopamine-depleted side, however, engagement of these inhibitory pathways would be attenuated and the unopposed effects of the excitatory inputs mobilized by amphetamine would result in exaggerated Fos synthesis. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Immediate early gene; c-fos; Striatum; Globus pallidus; Entopeduncular nucleus; Subthalamic nucleus; Substantia nigra; Dopamine; 6-Hydroxydopamine
1. Introduction Many recent workers have proposed that the circuitry of the basal ganglia is organized around a principle of cascaded inhibition w2,3,10,12,24x. The pars reticulata of the substantia nigra ŽSNpr. and the entopeduncular nucleus ŽEPN., or its primate homologue, the internal segment of the globus pallidus ŽGPi., play a critical role in these models, functioning as the principle output structures of the basal ganglia. These nuclei send inhibitory, GABAergic, projections to a number of subcortical sites including the lateral habenular nucleus, the ventromedial thalamic nucleus, the superior colliculus and the pedunculopontine nucleus w12,21,48x. As a result of their high rates of spontaneous activity w14x, cells in the EPN and SNpr appear to exert a tonic inhibitory influence on the struc-
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tures to which they project. The EPN and SNpr, in turn, receive inhibitory, GABAergic, inputs from the striatum and from the external segment of the globus pallidus ŽGP. w7,8x. Several authors have proposed that stimulation of striatal dopamine receptors results in an activation of these inhibitory pathways w2,3,10,24,42x, an effect which should be associated with a disinhibition of cells in nuclei receiving inputs from the EPN and SNpr. In many neurons, excitation of a sufficient magnitude and duration is accompanied by the expression of immediate early genes such as c-fos w17,20,31,60x and a large number of studies have now demonstrated that examination of Fos expression provides a powerful tool for studying the circuitry of the basal ganglia w15,31,53x. The cascaded inhibition model predicts that stimulation of dopamine receptors should disinhibit cells in structures receiving projections from the SNpr and EPN and, consistent with this view, amphetamine and other dopamine agonists induce pronounced Fos-like immunoreactivity ŽFLI. in the habenula, ventromedial thalamus, superior
0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 1 0 9 1 - 4
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colliculus and pedunculopontine nucleus w69,73,74x. Additionally, we have found that unilateral 6-hydroxydopamine Ž6-OHDA. lesions greatly attenuate the ability of amphetamine to induce Fos expression in all of these structures on the lesioned side w69,73x, suggesting that the gene expression results specifically from an engagement of basal ganglia circuitry. Since the model outlined above assumes that dopamine agonists such as amphetamine inhibit cells in the SNpr and EPN, it would not predict that this drug would induce Fos expression within these regions. Indeed, in the intact animal, only scattered labeling is present in these nuclei following treatment with a variety of dopamine agonists wunpublished observationsx. During the course of our studies on the effects of unilateral 6-OHDA lesions, however, we observed, unexpectedly, that amphetamine induces clear Fos expression within the SNpr and EPN on the dopamine-depleted side. Since these observations could not have been anticipated based on contemporary models of basal ganglia organization, and since they may have important implications for our understanding of these
structures, we present them here, together with some speculations on their significance. We also present data on the effects of unilateral 6-OHDA lesions on amphetamine-induced Fos expression in the GP and the subthalamic nucleus ŽSTN.. A preliminary version of the current report was presented at the 1994 meeting of the Society for Neuroscience w69x.
2. Methods 2.1. Subjects and surgery Subjects were male Sprague–Dawley rats obtained from Charles River ŽPortage, MI. weighing about 300 g at the time of surgery. Unilateral injections of 6-OHDA ŽSigma, St. Louis, MO, 8 mg free base in 4 ml of 0.1% ascorbic
Fig. 1. Photomicrographs displaying amphetamine-induced Fos-like immunoreactivity in the globus pallidus ipsilateral and contralateral to a unilateral 6-OHDA lesion. The upper part of the figure shows the locations of the photographed fields on a camera lucida drawing of the section.
D. Wirtshafter, K.E. Asin r Brain Research 824 (1999) 81–88 Table 1 Amphetamine-induced Fos expression on the intact and dopaminedepleted side in animals with unilateral 6-OHDA lesions Structure
N
Intact side a
Lesioned side a
p
Globus pallidus Subthalamic nucleus Entopeduncular nucleus Substantia nigra
8 7 4 11
164"42 979"173 46"9 98"22
66"15 770"229 255"44 252"33
- 0.03 - 0.25 - 0.025 - 0.001
a
Numbers represent mean cellsrmm2 "S.E.M.
acid. were made into the lateral hypothalamus of desipramine Ž20 mgrkg.-pretreated rats under sodium pentobarbital anesthesia Ž40 mgrkg.. Two weeks following surgery, rats were injected with apomorphine Ž0.3 mgrkg, s.c.. and placed in automated rotometer bowls for 60 min; animals showing fewer than 300 contralateral rotations across this period were not studied further. 2.2. Drug treatment and perfusion At least 2 months following surgery, animals were injected with either D-amphetamine sulfate Ž5 mgrkg, i.p., Sigma. Ž N s 11. or saline Ž N s 5.. Three hours later, rats were deeply anesthetized with sodium pentobarbital and perfused transcardially with about 100 ml of normal saline followed by about 500 ml of a 10% solution of formalin prepared in phosphate buffer. The brains were then removed from the skulls, post-fixed in the same fixative for 2 h at 48C and then cryoprotected overnight in a 30%
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solution of sucrose prepared in phosphate-buffered saline ŽPBS.. 2.3. Immunohistochemical processing and analysis Cryostat sections were prepared through selected levels of the brain at a thickness of 30 mm. The sections were thoroughly rinsed in PBS and then processed for Fos-like immunoreactivity ŽFLI. using methods we have described elsewhere in detail w73x. The primary antibody was a sheep anti-Fos serum which has been widely used in studies of Fos expression w5,18,51,73x ŽCambridge Research Biochemicals, Wilmington, DE, OA-11-823.. Detection was accomplished using Vectastain Elite ABC kit ŽVector Labs, Burlingame, CA . employing nickel-intensified diaminobenzadine as the chromogen. In control sections in which the primary antibody was omitted, no specific nuclear staining could be identified. Counts of the numbers of labeled cells in the GP, EPN, STN and SNpr ipsilateral and contralateral to the 6-OHDA lesions were made using a Leica Quantamet 500 image analysis system. Cells were detected based on their staining intensity, size and aspect ratio. Detection parameters were determined after extensive preliminary study and were adjusted so that even lightly labeled cells were counted. Cell were counted in the entire cross-sectional area of the STN and EPN, within fields measuring 0.41 mm2 within in the GP and within a region of the SNpr extending laterally 0.64 mm from its medial border. In some subjects, sections were not collected at appropriate
Fig. 2. Photomicrographs displaying amphetamine-induced Fos-like immunoreactivity in the substantia nigra ipsilateral and contralateral to a unilateral 6-OHDA lesion.
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levels through all of the structures and as a result, the number of sections analyzed differs for various nuclei. Numbers of cells on the intact and lesioned sides of the brain were analyzed statistically using paired t-tests.
were obtained in the EPN; a small to moderate number of lightly stained neurons was observed on the intact side of the brain, while a significantly larger number of more darkly stained neurons could be seen on the lesioned side ŽFig. 3; Table 1..
3. Results In control subjects sacrificed following vehicle injections, the GP, STN, EPN and SNpr were almost devoid of labeled cells on both the intact and lesioned sides. In all animals treated with amphetamine, cells displaying FLI could be identified bilaterally in the GP ŽFig. 1., but the number of these cells was significantly smaller on the lesioned side than the intact side ŽTable 1.. Amphetamine also induced clear staining in the subthalamic nucleus; labeling again tended to be slightly more pronounced on the intact than the lesioned side, but this difference fell short of the usual criterion of statistical significance ŽTable 1.. Amphetamine injections induced FLI in a only a small number of cells in the SNpr on the intact side of the brain and labeling in individual cells tended to be quite light. In marked contrast, a much larger number of more darkly stained neurons could be identified in the SNpr on the lesioned side of the brain ŽFig. 2.. This pattern was present in every animal examined and quantitative analysis indicated a significant potentiation of amphetamine-induced Fos expression in the dopamine-depleted substantia nigra as compared to the intact side ŽTable 1.. Similar results
4. Discussion The present experiments indicate that unilateral injections of 6-OHDA are able to drastically modify the pattern of basal ganglia Fos expression induced by administration of the indirect dopamine agonist, amphetamine. In some structures, such as the GP, the 6-OHDA lesions attenuated amphetamine-induced Fos expression on the lesioned side. In the EPN and SNpr, in contrast, unilateral dopamine depletion markedly potentiated the effects of amphetamine on the lesioned side. These findings indicate that chronic dopamine depletion produces a more complex pattern of alterations in the activity of the basal ganglia than might have been anticipated from current models of the organization of these nuclei. Our current observation that amphetamine induces Fos expression in the GP is consistent with previous studies which have utilized both direct and indirect dopamine receptor agonists w38,40,50,58,65,71x. It is likely that this effect at least partly reflects a disinhibition of pallidal cells resulting from a dopamine-mediated suppression of striatopallidal neurons w24,30,34,40,47,52x. The finding that
Fig. 3. Photomicrographs displaying amphetamine-induced Fos-like immunoreactivity in the entopeduncular nucleus ipsilateral and contralateral to a unilateral 6-OHDA lesion.
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6-OHDA lesions attenuate pallidal Fos expression is consistent with this view, as are observations that pallidal immediate early gene expression can be induced by direct manipulations of the striatum w29x. The current study is the first, to our knowledge, to observe Fos expression in the STN following injections of amphetamine, but similar results have been reported following systemic administration of direct dopamine receptor agonists w57,58x. These observations are consistent with electrophysiological studies which have demonstrated that systemic administration of dopaminergic drugs increases the firing rate of subthalamic cells w19,37,54x, but are difficult to reconcile with simplified models of basal ganglia organization which predict an inhibition of STN cells due to increased activity within the GP. Excitatory effects of dopamine agonists might be mediated through stimulation of dopamine receptors located within the STN itself w27,35,37x, but it is possible that less direct routes, such as activation of corticosubthalamic projections w36,56x, might also be involved. It is interesting that unit activity within the STN can be increased not only by dopamine agonists, but also by blockade of dopamine transmission w28,43,66x, an effect which is likely to be mediated through striatopallidosubthalamic pathways. Unlike dopamine agonists, however, dopamine antagonists do not induce Fos expression within the STN w13,49,72x; the reason for these divergent effects is not currently clear, but differences in the patterning of neuronal activity seen after these two types of treatments may play a role. In previous studies, we have found that unilateral 6OHDA lesions attenuate amphetamine-induced Fos expression on the lesioned side in the striatum and in a number of structures which receive projections from the basal ganglia, including the lateral habenula, the reticular and ventromedial thalamic nuclei and the pedunculopontine nucleus w69,73x, as well as in a number of cortical regions wunpublished observationsx. These results, like those observed here in the GP, are not surprising as they represent a suppressant effect of dopamine depletion on responses mediated through dopamine release. In contrast, we observed in the current study that unilateral 6-OHDA lesions markedly potentiate the otherwise very modest Fos response produced by amphetamine in the EPN and SNpr. This effect would appear to represent a type of ‘release phenomenon’ and demonstrates that 6-OHDA lesions do not simply produce a unilateral blockade of dopaminemediated Fos expression, but, additionally, result in a paradoxical potentiation of certain responses. It should be noted that whereas Fos expression can be induced in the SN and EPN of intact animals by administration of dopamine antagonists w49,70,72x, amphetamine induces only a small and inconsistent response in these subjects wunpublished observationsx. A number of explanations for the paradoxical induction of FLI by amphetamine could be formulated; the most likely possibility is that it results from a unilateral increase
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in the excitability of cells in the SNpr and EPN occurring as a consequence of dopamine depletion. In monkeys, for example, dopamine depletion greatly increases the proportion of GPi neurons which can be excited by sensory stimuli or by passive movement of the limbs w23,32,43x. Additionally, Feger et al. w19x and Robledo and Feger w54x have shown that dopamine depletion markedly enhances the ability of STN stimulation to activate cells in the SNpr. Dopamine depletion has also been reported to increase the basal firing rate of cells in the SNpr in rats w11x and in the GPi in monkeys w22,43x, and similar abnormalities may be present in Parkinsonian patients w9,62x. These effects can be explained by current models of basal ganglia organization since dopamine depletion is presumed to reduce the activity of inhibitory, GABAergic, projections to the EPN and SNpr arising in the striatum and GP w2,3,10,24x. Consistent with this proposal, chronic interference with dopamine transmission has been shown to reduce glutamic acid decarboxylase levels in the SNpr and the EPN w26,33x and analogous results have been reported in post-mortem studies of human Parkinsonian patients w39x. Dopamine depletion might also reduce the ability of cortical inputs to engage inhibitory striatonigral and striatoentopeduncular pathways w59x and thus, potentiate the net excitatory impact of cortical activation. In the intact animal, these models predict that amphetamine would further increase activity in inhibitory GABAergic pathways, an effect which should also be blunted following 6-OHDA lesions. The previous discussion suggests that ‘tone’ of inhibitory projections to the SNpr and EPN is lower in on the side of the 6-OHDA lesion that it is on the intact side. Clearly, this effect is not sufficient, by itself, to induce Fos expression, since no such response is seen in subjects treated with saline. If, however, injections of amphetamine were to activate excitatory inputs to the SNpr and EPN, cells on the lesioned side might be expected to show a larger response than those on the intact side and might, as a result, display exaggerated Fos expression. Although recent models have emphasized the ability of dopamine to activate inhibitory projections to the SNpr, direct studies in intact subjects have shown that systemically administered dopamine agonists do, in fact, excite a substantial proportion of nigral cells w46,68x. These effects can be accounted for within the framework of contemporary models if one takes into account the long feedback loops which are characteristic of basal ganglia circuitry. For example, many authors have suggested that stimulation of dopamine receptors ultimately results in a disinhibition of cells in motor and premotor regions of the cortex w2,3x. Since, however, these cortical regions exert a powerful excitatory influence on the SNpr and EPN, mediated both directly and through corticosubthalamic pathways w1,19,25,36,41,44x, it is clear that dopamine agonists would be expected to engage excitatory, as well as inhibitory inputs to basal ganglia output structures and either one or the other of these effects might predominate in a given neuron. It is possible that subtotal
D. Wirtshafter, K.E. Asin r Brain Research 824 (1999) 81–88
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dopamine depletion might shift the net balance of these effects in the direction of excitation. Another possibility is suggested by the fact that excitatory influences of the cortex on the basal ganglia appear to be exerted bilaterally; e.g., unilateral stimulation of the frontal cortex has been found to induce Fos expression in the STN and SNpr on both sides of the brain w61,67x and analogous results have been observed in electrophysiological experiments w56x. Several reports have additionally shown that unilateral manipulations of the cortex or thalamus can induce bilateral changes in transmitter release within the basal ganglia w6,45,55x and, in all of these cases, contralateral effects could be prevented by lesions of the corpus callosum. Applied to the current study, these findings suggest that neuronal activity induced by amphetamine on the intact side of the brain may have provided a source of excitation to cells in the SNpr and EPN on the dopaminedepleted side. It is interesting in this context that dopamine depletion in primates results in a dramatic increase in the proportion of GPi cells which can be excited by movements of the ipsilateral limbs; in intact animals, these movements influence neuronal activity almost exclusively in the opposite hemisphere w23x. It has usually been assumed that the behavioral asymmetries produced by amphetamine in animals with unilateral 6-OHDA lesions result from drug-induced effects on the intact side of the brain, unmatched by the occurrence of similar changes on the lesioned side. Our current results suggest, however, that events occurring in the lesioned hemisphere may also play an active role. For example, intracranial injection studies have shown that direct excitation of cells in the SNpr results in rotation towards the stimulated side w4,16,64x. If amphetamine-induced Fos expression in the SNpr of the dopamine-depleted hemisphere reflects an abnormal excitation of cells in these areas, it is possible that such excitation could contribute to the ipsilateral rotation or postural asymmetry seen under these conditions. It is interesting, in this regard, that section of the corpus callosum has been found to reduce certain behavioral asymmetries in rats with unilateral 6-OHDA lesions w63x; it would be of interest to determine whether these sections would also attenuate the paradoxical Fos expression induced by amphetamine.
5. Note added in proof While this manuscript was in press, we became aware of a paper by Ishida et al. wBrain Res. 809 Ž1998. 107–114x which described results in the substantia nigra consistent with those reported here.
Acknowledgements DW was supported by NS33992.
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