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Opposite rotation induced by dopamine agonists in rats with unilateral lesions of the globus pallidus or substantia nigra
Behavioural Brain Research 92 (1998) 77 – 83
Research report
Opposite rotation induced by dopamine agonists in rats with unilateral lesions of the globus pallidus or substantia nigra Spyridon Konitsiotis a,*, Evangelos Kafetzopoulos a, Dimitrios Anastasopoulos b, Pierre J. Blanchet c a
Department of Pharmacology, Uni6ersity of Ioannina Medical School, Ioannina, Greece b Department of Neurology, Uni6ersity of Ioannina Medical School, Ioannina, Greece c Experimental Therapeutics Branch, NINDS, National Institutes of Health, Bethesda, MD 20892 -1406, USA Received 9 June 1997; received in revised form 25 August 1997; accepted 25 August 1997
Abstract Normal rats with a unilateral ibotenic acid lesion of substantia nigra pars reticulata (SNR, n =12) or globus pallidus (GP, n= 12) were challenged systemically with the mixed dopaminergic agonist apomorphine (0.5 and 1.5 mg/kg) and the indirect acting d-amphetamine (1.5 mg/kg). The low dose of apomorphine produced a weak contralateral rotation only in the SNR-lesioned group, which showed an intense ipsilateral rotation following the administration of the higher dose. GP-lesioned rats also showed ipsilateral rotation after the high dose of apomorphine. d-Amphetamine produced ipsilateral rotation in GP-lesioned rats, contrasting with a vigorous contralateral rotation in SNR-lesioned rats. The unexpected opposite rotation after apomorphine and d-amphetamine, observed only in SNR-lesioned animals, indicates that the role of SNR in basal ganglia functions is less clear and more complex than what is expected from our current model of basal ganglia circuitry and functions. On the other hand, the GP lesion resulted in a consistent and predictable ipsilateral rotation after both apomorphine and d-amphetamine, indicating a more determinant effect on the output of the basal ganglia than heretofore believed. Our results may contribute to the recently expressed views challenging the established model of basal ganglia organisation. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Substantia nigra; Globus pallidus; Apomorphine; Amphetamine; Rotational behavior; Dopamine
1. Introduction Since Anden et al. [2] first described that rodents with a functional imbalance of the dopaminergic systems between the two hemispheres of the brain produced a circling behavior in response to dopaminergic agonists, other structures have been described to be involved in this behavior following surgical and/or pharmacological
* Corresponding author. Present address: Experimental Therapeutics Branch, NINDS, National Institutes of Health, Bldg. 10, Room 5C103, Bethesda, MD 20892-1406, USA. Tel: +1 301 4967993; fax: +1 301 4966609; e-mail: [email protected] 0166-4328/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S 0 1 6 6 - 4 3 2 8 ( 9 7 ) 0 0 1 2 7 - 7
manipulations of various brain areas. However, the system that attracted most attention is the nigrostriatal dopaminergic pathway originating from substantia nigra pars compacta (SNC) and projecting to corpus striatum. Intrastriatal dopaminergic activity is in turn mediated through the GABAergic neostriatal efferents projecting mainly to substantia nigra pars reticulata (SNR)/entopeduncular nucleus (EP) and globus pallidus (GP). The GP receives projections mainly from the sensorimotor-afferented parts of the striatum and from the subthalamic nucleus (STN), while SNR receives a more massive input from the associative and limbic-affer-
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ented striatal territories, and from STN and pedunculopontine nucleus (PPN) [31,32]. The GP projects to STN and the ventral-anterior (VA) and ventro-lateral (VL) thalamic nuclei which in turn project to motor and premotor cortex, thus participating in a ‘motor’ loop [14,21]. The SNR which is considered (along with EP) the final output station of basal ganglia projects to the ventro-medial (VM) and parafascicular (PF) thalamic nuclei [11,13], tectum, raphe nuclei, locus coeruleus, PPN, reticular formation as well as to limbic-related structures such as amygdala and septum [21]. Apart from their extrinsic connections these nuclei differ in their internal organisation as well, the DA-containing dendrites of SNC neurons extending into the SNR. These anatomical data may support the concept that the GP and SNR are involved in distinct though equally important aspects of basal ganglia functions, and therefore may differentially modulate motor behaviors and consequently rotational behavior. Results from anatomical and functional studies of the basal ganglia have generated a view of their organisation and a model of circuitry in health and disease, centered around the striatum [1]. The importance of the final basal ganglia output structures (SNR/EP) and the key role of the subthalamic nucleus in this model have been well established by experimental and clinical data, leading to novel therapeutic approaches in the therapy of patients with Parkinson’s disease like pallidotomy and deep brain stimulation [4,18]. In this model [1], the external pallidum (GP in rodents) was until recently viewed almost exclusively as a relay structure, part of the ‘indirect’ pathway transmitting information, directly or through the subthalamic nucleus, to the final output neurons in SNR/EP. According to the model [1], the basal ganglia are organised in such a fashion that nigrostriatal denervation (a cardinal feature of Parkinson’s disease) leads to an hyperactivity of the output stations (SNR/EP). This hyperactivity has been posited to result both from reduced inhibitory output along the direct striatal efferent pathway and overactive inhibitory output to GP neurons along the indirect striatal efferent pathway, thereby disinhibiting STN and increasing SNR/EP activity. The opposite is thought to occur in hyperkinetic movement disorders. However, recent experiments have unexpectedly shown that the GABAergic, metabolic and electrophysiologic activity of GP are not decreased in parkinsonian rats and monkeys [10,17]. In addition, levodopa induced chorea in MPTP-treated monkeys is not relieved after ablating the GP [8]. Thus, the striato-centric model of functional anatomy of the basal ganglia requires re-evaluation [10,12,17] and the relative importance of downstream nuclei should be examined. We conducted the present study to investigate the contribution of GP and SNR in asymmetric motor behaviors following dopaminergic stimulation. A simple approach is to unilaterally lesion
the targets under investigation with ibotenic acid in non dopamine-denervated rats, while sparing fibers of passage. We elected not to use the 6-OHDA-lesioned rat model because of the possibility that additional denervation with resulting supersensitivity of dopamine receptors might complicate the interpretation of the results. In accordance with the traditional hypothesis, we expected the direction of rotation following pharmacological challenge with d-amphetamine and apomorphine to be away from the brain side with higher neuronal activity (presumably the unlesioned side) and therefore ipsilateral to the lesion.
2. Materials and methods Twenty-four male Wistar rats weighing 260–330 g at the beginning of the experiments were divided into two groups (n= 12, for each group) for SNR and GP lesions. Rats were anesthetised with sodium pentobarbital (40 mg/kg) and placed in a David Kopf stereotaxic frame. Ibotenic acid 5 mg (Sigma) in 0.5 ml of saline was then injected unilaterally into either the substantia nigra pars reticulata (AP:− 5.3 mm, L:2.5 mm and V:8.2 mm), or into globus pallidus (AP:− 1.0 mm, L:2.5 mm and V:7.0 mm), according to the stereotaxic atlas of Paxinos and Watson [24], using bregma and skull surface as reference points. All stereotaxic injections were made with a 5-ml Hamilton syringe, over a period of 3 min and the syringe was left in place for 5 min following the injection in order to attenuate leakage of ibotenic acid up the cannula track. Starting three weeks after the operation, rotational behavior was recorded using electronic rotometers connected to a microcomputer. Prior to any drug manipulations the animals were habituated to the test apparatus for 30 min. Thereafter they were briefly removed and injected intraperitoneally with apomorphine hydrochloride (Sigma) 0.5 mg/kg and 1.5 mg/kg, d-amphetamine sulphate (Sigma) 1.5 mg/kg, or saline. All drugs were freshly dissolved in saline, containing 0.2 mg/ml ascorbic acid in the apomorphine solution. Immediately after the injection rats were returned to the rotometer cages where rotational behavior was recorded continuously for 2 h. Non-cumulative 10-min interval recordings of the rotational activity were presented on the system printer. At least five day intervals were allowed between treatments and the order of treatment was randomised. On completion of the experiments, rats were decapitated under deep pentobarbital anaesthesia, brains were removed and a routine histological analysis was performed. Coronal sections of the brain were cut at 30 mm on a cryostat, stained with toluidine blue and examined microscopically in order to verify the site and extent of the lesions.
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Fig. 1. Schematic reconstruction of the localisation and extent of ibotenic acid-induced lesions of the substantia nigra pars reticulata (SNR) or globus pallidus (GP), plotted on the drawings of coronal brain sections according to the stereotaxic atlas of Paxinos and Watson [24]. Numbers indicate distance from bregma in mm. cp, cerebral peduncle; ic, internal capsule; CPu, caudate-putamen, SNC, substantia nigra pars compacta.
Two-way analyses of variance (ANOVA) were performed to analyse total rotation scores expressed as signed differences between ipsilateral and contralateral rotations, with treatment (drug vs. saline) and lesion (SNR vs. GP) as factors. Three separate ANOVAs were performed, two with apomorphine (0.5 mg and 1.5 mg/kg) and one with d-amphetamine data. Student’s t-tests were applied for all comparable groups.
3. Results Ibotenic acid injection into SNR, selectively destroyed the cell bodies of neurons located in the pars reticulata of the substantia nigra, resulting in profound loss of neuronal perikarya and glial response with proliferation of non-neuronal elements (Fig. 1). The area corresponding to the pars compacta was not affected and still showed a high density of its typical large and globular neurons in almost all rats. Ibotenic acid injection into globus pallidus, produced a well shaped lesion with rather constant characteristics from rat to rat (Fig. 1). Intense glial proliferation and a small reduction in the nucleus size were the main findings.
Neurons in the adjacent areas of corpus striatum were not significantly affected. Examination of all the sections stained did not reveal further distant damage. Following the injection of ibotenic acid, some of the rats and especially those injected into SNR, presented aphagia, adipsia and weight loss. One week later, all rats returned to their previous condition and any spontaneous rotational activity had disappeared. The effects of systemic administration of saline, apomorphine and d-amphetamine, in GP- or SNR-lesioned rats are shown in Figs. 2 and 3. Apomorphine 0.5 mg/kg (Fig. 2) in GP-lesioned rats produced a small ipsilateral preference (16.39 3.2, total rotations in 60 min, mean9 SEM) but in SNR-lesioned rats it elicited a weak contralateral rotation (18.29 2.9, PB 0.05, Student’s t-test, ipsilateral vs. contralateral rotations). The ANOVA for the apomorphine 0.5 mg/kg vs. saline treatment revealed a non significant drug effect, a significant lesion effect (P B 0.01) and a significant interaction (PB 0.01), underlying the fact that apomorphine produced a weak rotation only in the SNR-lesioned group. This result is further supported by t-test comparisons within groups which revealed a non significant apomorphine vs. saline difference in the GP-lesioned
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Fig. 2. Rotational behavior expressed as the net difference between total ipsilateral and contralateral rotations in 60 min (mean 9 SEM) in rats with a unilateral ibotenic acid lesion of either the substantia nigra pars reticulata (SNR) or globus pallidus (GP), after treatment with apomorphine (Apo) 0.5 and 1.5 mg/kg or saline (Sal). Positive values indicate rotations ipsilateral to the lesion side and negative values contralateral rotations. *PB0.05, **PB 0.005 vs. saline treatment.
group, but a significant one in the SNR-lesioned group (PB 0.01). Apomorphine 1.5 mg/kg (Fig. 2) elicited a prominent ipsilateral rotation in both groups (88.2 931, total rotations in 60 min, mean9SEM, for the SNR-group and 1329 28 for the GP-group). The ANOVA for the apomorphine 1.5 mg/kg vs. saline treatment revealed a
Fig. 3. Rotational behavior expressed as the net difference between total ipsilateral and contralateral rotations in 120 min (mean 9 SEM) in rats with a unilateral ibotenic acid lesion of either the substantia nigra pars reticulata (SNR) or globus pallidus (GP), after treatment with d-amphetamine (d-amp) 1.5 mg/kg or saline (Sal). Positive values indicate rotations ipsilateral to the lesion side and negative values contralateral rotations. *PB0.01, **PB 0.001 vs. saline treatment.
significant drug effect (PB 0.001), a non significant lesion effect, and a non significant interaction, indicating that apomorphine in the higher dose was equally effective in both groups. This result is also further supported by t-test comparisons between groups, which reveal a significant apomorphine vs. saline difference for both SNR- (PB0.05) and GP- (PB 0.003) lesioned rats. d-Amphetamine 1.5 mg/kg (Fig. 3) evoked a vigorous rotation in both groups, though in an opposite direction: in the SNR-lesioned group it induced an intense contralateral rotation (225.79 25, total rotations in 120 min, mean 9SEM), but in the GP-lesioned group it produced ipsilateral rotation (164.69 35). The ANOVA for d-amphetamine revealed a significant drug effect (PB 0.05), a significant lesion effect (PB0.001), and a significant interaction (PB 0.001), underlying the fact that amphetamine produced rotation towards different directions in the two groups of rats. Subsequent t-test comparisons confirmed a significant amphetamine vs. saline difference in both SNR- and GP-lesioned groups (PB0.001 and PB 0.01, respectively). Neither group showed any spontaneous rotational activity, as shown from the saline scores.
4. Discussion According to the established mechanism for turning behavior, the direction of circling reflects the functional imbalance of the dopaminergic activity between the two sides of the brain, the animal rotating away from the dominant side with higher activity [25]. In the present study, systemic administration of the mixed dopaminergic agonist apomorphine or the indirect-acting d-amphetamine to normal (non-denervated) rats activated the dopaminergic systems of the brain. Unilateral ablation of the GP or SNR cells is interrupting the striatopallidal or striatonigral outflow, respectively, and drug-induced ipsilateral rotation was expected. However, prediction of the direction of circling along the aforementioned model was not always appropriate. While the higher dose of apomorphine elicited ipsilateral rotation in both groups of rats, d-amphetamine and the low dose of apomorphine produced a paradoxical contralateral rotation in SNR-lesioned rats. The opposite rotational behavior induced by low dose apomorphine and by d-amphetamine in SNR-lesioned rats may lie in their respective mechanism of action and receptor affinity, leading to distinct neural events. Since mainly D2 receptors are found in the GP and mainly D1 receptors are present in the SNR [5,7], the deficit in neural transmission responsible for the rotational behavior observed in our study could be attributed to loss of interaction of the drug at these extrastriatal dopamine receptors. Thus, one could argue
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that our findings reflect at least in part the effects of the imbalance between D1 and D2 receptors produced after the SNR or GP lesion. Electrophysiologic studies in intact (non-dopamine denervated) rats reported an inconsistent, highly variable pattern of changes in SNR cells firing after systemic administration of apomorphine where cells exhibited increases, decreases, no changes, or minuteto-minute fluctuations in firing [35]. In contrast, SNR neurones showed a clear, prolonged increase in activity after systemic administration of d-amphetamine [22,26]. This increased activity of SNR neurons on the intact side after d-amphetamine would inhibit the thalamocortical projection, thus leading to the observed contralateral rotation, an effect possibly potentiated by increased DA release in the striatum of the lesioned side, since administration of dopaminergic agonists have been reported to produce a decrease in striatal DA release, possibly via a long-loop feedback through SNR [27]. In our study, the SNR lesion would abolish this negative regulation on striatal DA on the lesioned side. Other transmitter systems may be conceivably involved with SNR ablation possibly inducing compensatory changes in other non-dopaminergic monoamine pathways that may be activated by amphetamine to result in the observed contralateral rotation. A differential rotational response was observed in the SNR-lesioned rats treated with apomorphine since the low dose of apomorphine produced a weak contralateral rotation contrasting with an intense ipsilateral rotation following the administration of the higher dose. A similar profile of response is observed for many behaviors produced by apomorphine [19,33,34], and is attributed to the activation of DA autoreceptors by low doses [19,30,33,34]. For instance, in rats, an i.p. dose of 0.5 mg/kg of apomorphine (as in this study) produced a decrease in spontaneous motor activity while a dose of 2 mg/kg caused a significant increase [19]. The weak contralateral rotation observed after the low dose of apomorphine in the SNR-lesioned rats could be due to differential stimulation of autoreceptors at low doses but postsynaptic receptors at high doses [19,30,33], reverting the direction of rotation into an intense ipsilateral one. Asin and Montana [3] reported ipsilateral rotation after unilateral direct injection of a D2 agonist into SNR, and they suggested that this reflects an effect at D2 autoreceptors present on the dendrites of dopaminergic compacta neurons extending into SNR. Moreover, a reduction of the D2 autoreceptor population by 40% in substantia nigra caused dramatic contralateral rotation after cocaine administration [29]. These observations suggest that the d-amphetamineand low-dose apomorphine-induced contralateral rotation in SNR-lesioned rats in the present study may at least in part be mediated by DA autoreceptors effective only in the intact SNR.
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The impact of our findings on existing concepts of circling behavior as an index of basal ganglia function, more specifically in relation to dopaminergic activity and control of movement, remains speculative. The unexpected contralateral rotation produced after d-amphetamine in SNR-lesioned animals suggests that the traditional view of basal ganglia control is oversimplified and that the direction of turning does not merely reflect greater dopaminergic stimulation on one side. This ‘paradoxical’ rotation produced after d-amphetamine also took place despite interruption of the striatal efferent ‘direct’ pathway, a crucial component of the model proposed by Albin et al. [1]. Electrophysiologic experiments clearly show that dopaminergic drugs do not modulate GABAergic basal ganglia outflow uniformly and that more complex functional changes take place than heretofore believed [6,20,22,26,35], making predictions from the model difficult. The organisation of cellular elements within the substantia nigra, as well as the diverse afferent regulation and extensive and widespread efferent connections to motor and non-motor areas (which may be differentialy affected by dopaminergic stimulation) may contribute to these results. In contrast with all of the above, GP ablation disrupted dopaminergic balance in a more decisive way, since it uniformly produced a consistent ipsilateral rotational behavior after both apomorphine and d-amphetamine as predicted by the model. In electrophysiologic experiments systemic administration of apomorphine produced highly variable changes in the firing rate of SNR neurons in contrast with a consistent and strong excitatory response of GP neurons [6,35]. In view of the fact that the current ‘striatocentric’ basal ganglia model has given much attention to the final output nuclei (SNR/EP), our results extend the model and provide evidence that the GP cannot be considered just a relay station or innocent bystander along the ‘indirect’ striatal efferent pathway. Indeed, an ibotenic acid lesion of the pallidum in rats produced parkinsonian rigidity, not seen following SNR lesion [16] and an excitotoxic lesion of the external pallidum in MPTP parkinsonian monkeys produced also ipsilateral circling after administration of L-DOPA [8]. Clinical observations in humans also suggest an important role for the GP, lesions of the latter structure impairing voluntary movements and producing various hyperkinetic or hypokinetic neurological signs including involuntary movements [9]. Therefore, it seems that the contribution of the indirect pathway is essential at least for the expression of asymmetric motor behaviors and that the GP, with its direct reciprocal connections with STN and recently described projections to GPi/EP, SNR and thalamus [15,23,28], has a crucial position in basal ganglia circuitry and may act as an integrative structure exerting a more widespread control over the final output stations.
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In conclusion, our results raise very conspicuous and important functional differences between the basal ganglia nuclei studied, and underlie the different ways by which SNR and GP modulate striatal dopaminergic function and rotational behavior. Our results also contribute to recently expressed views [10,12,17] reinterpreting the functional position of the GP. The consistent and predictable rotation produced both by apomorphine and d-amphetamine after GP lesion suggests that the external pallidum occupies a central position in basal ganglia functions more than a mere relay structure, mediating crucial physiological and pharmacological events, and may have a more important role in the pathophysiology of Parkinson’s disease and other movement disorders than previously assumed.
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Research report
Opposite rotation induced by dopamine agonists in rats with unilateral lesions of the globus pallidus or substantia nigra Spyridon Konitsiotis a,*, Evangelos Kafetzopoulos a, Dimitrios Anastasopoulos b, Pierre J. Blanchet c a
Department of Pharmacology, Uni6ersity of Ioannina Medical School, Ioannina, Greece b Department of Neurology, Uni6ersity of Ioannina Medical School, Ioannina, Greece c Experimental Therapeutics Branch, NINDS, National Institutes of Health, Bethesda, MD 20892 -1406, USA Received 9 June 1997; received in revised form 25 August 1997; accepted 25 August 1997
Abstract Normal rats with a unilateral ibotenic acid lesion of substantia nigra pars reticulata (SNR, n =12) or globus pallidus (GP, n= 12) were challenged systemically with the mixed dopaminergic agonist apomorphine (0.5 and 1.5 mg/kg) and the indirect acting d-amphetamine (1.5 mg/kg). The low dose of apomorphine produced a weak contralateral rotation only in the SNR-lesioned group, which showed an intense ipsilateral rotation following the administration of the higher dose. GP-lesioned rats also showed ipsilateral rotation after the high dose of apomorphine. d-Amphetamine produced ipsilateral rotation in GP-lesioned rats, contrasting with a vigorous contralateral rotation in SNR-lesioned rats. The unexpected opposite rotation after apomorphine and d-amphetamine, observed only in SNR-lesioned animals, indicates that the role of SNR in basal ganglia functions is less clear and more complex than what is expected from our current model of basal ganglia circuitry and functions. On the other hand, the GP lesion resulted in a consistent and predictable ipsilateral rotation after both apomorphine and d-amphetamine, indicating a more determinant effect on the output of the basal ganglia than heretofore believed. Our results may contribute to the recently expressed views challenging the established model of basal ganglia organisation. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Substantia nigra; Globus pallidus; Apomorphine; Amphetamine; Rotational behavior; Dopamine
1. Introduction Since Anden et al. [2] first described that rodents with a functional imbalance of the dopaminergic systems between the two hemispheres of the brain produced a circling behavior in response to dopaminergic agonists, other structures have been described to be involved in this behavior following surgical and/or pharmacological
* Corresponding author. Present address: Experimental Therapeutics Branch, NINDS, National Institutes of Health, Bldg. 10, Room 5C103, Bethesda, MD 20892-1406, USA. Tel: +1 301 4967993; fax: +1 301 4966609; e-mail: [email protected] 0166-4328/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S 0 1 6 6 - 4 3 2 8 ( 9 7 ) 0 0 1 2 7 - 7
manipulations of various brain areas. However, the system that attracted most attention is the nigrostriatal dopaminergic pathway originating from substantia nigra pars compacta (SNC) and projecting to corpus striatum. Intrastriatal dopaminergic activity is in turn mediated through the GABAergic neostriatal efferents projecting mainly to substantia nigra pars reticulata (SNR)/entopeduncular nucleus (EP) and globus pallidus (GP). The GP receives projections mainly from the sensorimotor-afferented parts of the striatum and from the subthalamic nucleus (STN), while SNR receives a more massive input from the associative and limbic-affer-
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ented striatal territories, and from STN and pedunculopontine nucleus (PPN) [31,32]. The GP projects to STN and the ventral-anterior (VA) and ventro-lateral (VL) thalamic nuclei which in turn project to motor and premotor cortex, thus participating in a ‘motor’ loop [14,21]. The SNR which is considered (along with EP) the final output station of basal ganglia projects to the ventro-medial (VM) and parafascicular (PF) thalamic nuclei [11,13], tectum, raphe nuclei, locus coeruleus, PPN, reticular formation as well as to limbic-related structures such as amygdala and septum [21]. Apart from their extrinsic connections these nuclei differ in their internal organisation as well, the DA-containing dendrites of SNC neurons extending into the SNR. These anatomical data may support the concept that the GP and SNR are involved in distinct though equally important aspects of basal ganglia functions, and therefore may differentially modulate motor behaviors and consequently rotational behavior. Results from anatomical and functional studies of the basal ganglia have generated a view of their organisation and a model of circuitry in health and disease, centered around the striatum [1]. The importance of the final basal ganglia output structures (SNR/EP) and the key role of the subthalamic nucleus in this model have been well established by experimental and clinical data, leading to novel therapeutic approaches in the therapy of patients with Parkinson’s disease like pallidotomy and deep brain stimulation [4,18]. In this model [1], the external pallidum (GP in rodents) was until recently viewed almost exclusively as a relay structure, part of the ‘indirect’ pathway transmitting information, directly or through the subthalamic nucleus, to the final output neurons in SNR/EP. According to the model [1], the basal ganglia are organised in such a fashion that nigrostriatal denervation (a cardinal feature of Parkinson’s disease) leads to an hyperactivity of the output stations (SNR/EP). This hyperactivity has been posited to result both from reduced inhibitory output along the direct striatal efferent pathway and overactive inhibitory output to GP neurons along the indirect striatal efferent pathway, thereby disinhibiting STN and increasing SNR/EP activity. The opposite is thought to occur in hyperkinetic movement disorders. However, recent experiments have unexpectedly shown that the GABAergic, metabolic and electrophysiologic activity of GP are not decreased in parkinsonian rats and monkeys [10,17]. In addition, levodopa induced chorea in MPTP-treated monkeys is not relieved after ablating the GP [8]. Thus, the striato-centric model of functional anatomy of the basal ganglia requires re-evaluation [10,12,17] and the relative importance of downstream nuclei should be examined. We conducted the present study to investigate the contribution of GP and SNR in asymmetric motor behaviors following dopaminergic stimulation. A simple approach is to unilaterally lesion
the targets under investigation with ibotenic acid in non dopamine-denervated rats, while sparing fibers of passage. We elected not to use the 6-OHDA-lesioned rat model because of the possibility that additional denervation with resulting supersensitivity of dopamine receptors might complicate the interpretation of the results. In accordance with the traditional hypothesis, we expected the direction of rotation following pharmacological challenge with d-amphetamine and apomorphine to be away from the brain side with higher neuronal activity (presumably the unlesioned side) and therefore ipsilateral to the lesion.
2. Materials and methods Twenty-four male Wistar rats weighing 260–330 g at the beginning of the experiments were divided into two groups (n= 12, for each group) for SNR and GP lesions. Rats were anesthetised with sodium pentobarbital (40 mg/kg) and placed in a David Kopf stereotaxic frame. Ibotenic acid 5 mg (Sigma) in 0.5 ml of saline was then injected unilaterally into either the substantia nigra pars reticulata (AP:− 5.3 mm, L:2.5 mm and V:8.2 mm), or into globus pallidus (AP:− 1.0 mm, L:2.5 mm and V:7.0 mm), according to the stereotaxic atlas of Paxinos and Watson [24], using bregma and skull surface as reference points. All stereotaxic injections were made with a 5-ml Hamilton syringe, over a period of 3 min and the syringe was left in place for 5 min following the injection in order to attenuate leakage of ibotenic acid up the cannula track. Starting three weeks after the operation, rotational behavior was recorded using electronic rotometers connected to a microcomputer. Prior to any drug manipulations the animals were habituated to the test apparatus for 30 min. Thereafter they were briefly removed and injected intraperitoneally with apomorphine hydrochloride (Sigma) 0.5 mg/kg and 1.5 mg/kg, d-amphetamine sulphate (Sigma) 1.5 mg/kg, or saline. All drugs were freshly dissolved in saline, containing 0.2 mg/ml ascorbic acid in the apomorphine solution. Immediately after the injection rats were returned to the rotometer cages where rotational behavior was recorded continuously for 2 h. Non-cumulative 10-min interval recordings of the rotational activity were presented on the system printer. At least five day intervals were allowed between treatments and the order of treatment was randomised. On completion of the experiments, rats were decapitated under deep pentobarbital anaesthesia, brains were removed and a routine histological analysis was performed. Coronal sections of the brain were cut at 30 mm on a cryostat, stained with toluidine blue and examined microscopically in order to verify the site and extent of the lesions.
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Fig. 1. Schematic reconstruction of the localisation and extent of ibotenic acid-induced lesions of the substantia nigra pars reticulata (SNR) or globus pallidus (GP), plotted on the drawings of coronal brain sections according to the stereotaxic atlas of Paxinos and Watson [24]. Numbers indicate distance from bregma in mm. cp, cerebral peduncle; ic, internal capsule; CPu, caudate-putamen, SNC, substantia nigra pars compacta.
Two-way analyses of variance (ANOVA) were performed to analyse total rotation scores expressed as signed differences between ipsilateral and contralateral rotations, with treatment (drug vs. saline) and lesion (SNR vs. GP) as factors. Three separate ANOVAs were performed, two with apomorphine (0.5 mg and 1.5 mg/kg) and one with d-amphetamine data. Student’s t-tests were applied for all comparable groups.
3. Results Ibotenic acid injection into SNR, selectively destroyed the cell bodies of neurons located in the pars reticulata of the substantia nigra, resulting in profound loss of neuronal perikarya and glial response with proliferation of non-neuronal elements (Fig. 1). The area corresponding to the pars compacta was not affected and still showed a high density of its typical large and globular neurons in almost all rats. Ibotenic acid injection into globus pallidus, produced a well shaped lesion with rather constant characteristics from rat to rat (Fig. 1). Intense glial proliferation and a small reduction in the nucleus size were the main findings.
Neurons in the adjacent areas of corpus striatum were not significantly affected. Examination of all the sections stained did not reveal further distant damage. Following the injection of ibotenic acid, some of the rats and especially those injected into SNR, presented aphagia, adipsia and weight loss. One week later, all rats returned to their previous condition and any spontaneous rotational activity had disappeared. The effects of systemic administration of saline, apomorphine and d-amphetamine, in GP- or SNR-lesioned rats are shown in Figs. 2 and 3. Apomorphine 0.5 mg/kg (Fig. 2) in GP-lesioned rats produced a small ipsilateral preference (16.39 3.2, total rotations in 60 min, mean9 SEM) but in SNR-lesioned rats it elicited a weak contralateral rotation (18.29 2.9, PB 0.05, Student’s t-test, ipsilateral vs. contralateral rotations). The ANOVA for the apomorphine 0.5 mg/kg vs. saline treatment revealed a non significant drug effect, a significant lesion effect (P B 0.01) and a significant interaction (PB 0.01), underlying the fact that apomorphine produced a weak rotation only in the SNR-lesioned group. This result is further supported by t-test comparisons within groups which revealed a non significant apomorphine vs. saline difference in the GP-lesioned
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Fig. 2. Rotational behavior expressed as the net difference between total ipsilateral and contralateral rotations in 60 min (mean 9 SEM) in rats with a unilateral ibotenic acid lesion of either the substantia nigra pars reticulata (SNR) or globus pallidus (GP), after treatment with apomorphine (Apo) 0.5 and 1.5 mg/kg or saline (Sal). Positive values indicate rotations ipsilateral to the lesion side and negative values contralateral rotations. *PB0.05, **PB 0.005 vs. saline treatment.
group, but a significant one in the SNR-lesioned group (PB 0.01). Apomorphine 1.5 mg/kg (Fig. 2) elicited a prominent ipsilateral rotation in both groups (88.2 931, total rotations in 60 min, mean9SEM, for the SNR-group and 1329 28 for the GP-group). The ANOVA for the apomorphine 1.5 mg/kg vs. saline treatment revealed a
Fig. 3. Rotational behavior expressed as the net difference between total ipsilateral and contralateral rotations in 120 min (mean 9 SEM) in rats with a unilateral ibotenic acid lesion of either the substantia nigra pars reticulata (SNR) or globus pallidus (GP), after treatment with d-amphetamine (d-amp) 1.5 mg/kg or saline (Sal). Positive values indicate rotations ipsilateral to the lesion side and negative values contralateral rotations. *PB0.01, **PB 0.001 vs. saline treatment.
significant drug effect (PB 0.001), a non significant lesion effect, and a non significant interaction, indicating that apomorphine in the higher dose was equally effective in both groups. This result is also further supported by t-test comparisons between groups, which reveal a significant apomorphine vs. saline difference for both SNR- (PB0.05) and GP- (PB 0.003) lesioned rats. d-Amphetamine 1.5 mg/kg (Fig. 3) evoked a vigorous rotation in both groups, though in an opposite direction: in the SNR-lesioned group it induced an intense contralateral rotation (225.79 25, total rotations in 120 min, mean 9SEM), but in the GP-lesioned group it produced ipsilateral rotation (164.69 35). The ANOVA for d-amphetamine revealed a significant drug effect (PB 0.05), a significant lesion effect (PB0.001), and a significant interaction (PB 0.001), underlying the fact that amphetamine produced rotation towards different directions in the two groups of rats. Subsequent t-test comparisons confirmed a significant amphetamine vs. saline difference in both SNR- and GP-lesioned groups (PB0.001 and PB 0.01, respectively). Neither group showed any spontaneous rotational activity, as shown from the saline scores.
4. Discussion According to the established mechanism for turning behavior, the direction of circling reflects the functional imbalance of the dopaminergic activity between the two sides of the brain, the animal rotating away from the dominant side with higher activity [25]. In the present study, systemic administration of the mixed dopaminergic agonist apomorphine or the indirect-acting d-amphetamine to normal (non-denervated) rats activated the dopaminergic systems of the brain. Unilateral ablation of the GP or SNR cells is interrupting the striatopallidal or striatonigral outflow, respectively, and drug-induced ipsilateral rotation was expected. However, prediction of the direction of circling along the aforementioned model was not always appropriate. While the higher dose of apomorphine elicited ipsilateral rotation in both groups of rats, d-amphetamine and the low dose of apomorphine produced a paradoxical contralateral rotation in SNR-lesioned rats. The opposite rotational behavior induced by low dose apomorphine and by d-amphetamine in SNR-lesioned rats may lie in their respective mechanism of action and receptor affinity, leading to distinct neural events. Since mainly D2 receptors are found in the GP and mainly D1 receptors are present in the SNR [5,7], the deficit in neural transmission responsible for the rotational behavior observed in our study could be attributed to loss of interaction of the drug at these extrastriatal dopamine receptors. Thus, one could argue
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that our findings reflect at least in part the effects of the imbalance between D1 and D2 receptors produced after the SNR or GP lesion. Electrophysiologic studies in intact (non-dopamine denervated) rats reported an inconsistent, highly variable pattern of changes in SNR cells firing after systemic administration of apomorphine where cells exhibited increases, decreases, no changes, or minuteto-minute fluctuations in firing [35]. In contrast, SNR neurones showed a clear, prolonged increase in activity after systemic administration of d-amphetamine [22,26]. This increased activity of SNR neurons on the intact side after d-amphetamine would inhibit the thalamocortical projection, thus leading to the observed contralateral rotation, an effect possibly potentiated by increased DA release in the striatum of the lesioned side, since administration of dopaminergic agonists have been reported to produce a decrease in striatal DA release, possibly via a long-loop feedback through SNR [27]. In our study, the SNR lesion would abolish this negative regulation on striatal DA on the lesioned side. Other transmitter systems may be conceivably involved with SNR ablation possibly inducing compensatory changes in other non-dopaminergic monoamine pathways that may be activated by amphetamine to result in the observed contralateral rotation. A differential rotational response was observed in the SNR-lesioned rats treated with apomorphine since the low dose of apomorphine produced a weak contralateral rotation contrasting with an intense ipsilateral rotation following the administration of the higher dose. A similar profile of response is observed for many behaviors produced by apomorphine [19,33,34], and is attributed to the activation of DA autoreceptors by low doses [19,30,33,34]. For instance, in rats, an i.p. dose of 0.5 mg/kg of apomorphine (as in this study) produced a decrease in spontaneous motor activity while a dose of 2 mg/kg caused a significant increase [19]. The weak contralateral rotation observed after the low dose of apomorphine in the SNR-lesioned rats could be due to differential stimulation of autoreceptors at low doses but postsynaptic receptors at high doses [19,30,33], reverting the direction of rotation into an intense ipsilateral one. Asin and Montana [3] reported ipsilateral rotation after unilateral direct injection of a D2 agonist into SNR, and they suggested that this reflects an effect at D2 autoreceptors present on the dendrites of dopaminergic compacta neurons extending into SNR. Moreover, a reduction of the D2 autoreceptor population by 40% in substantia nigra caused dramatic contralateral rotation after cocaine administration [29]. These observations suggest that the d-amphetamineand low-dose apomorphine-induced contralateral rotation in SNR-lesioned rats in the present study may at least in part be mediated by DA autoreceptors effective only in the intact SNR.
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The impact of our findings on existing concepts of circling behavior as an index of basal ganglia function, more specifically in relation to dopaminergic activity and control of movement, remains speculative. The unexpected contralateral rotation produced after d-amphetamine in SNR-lesioned animals suggests that the traditional view of basal ganglia control is oversimplified and that the direction of turning does not merely reflect greater dopaminergic stimulation on one side. This ‘paradoxical’ rotation produced after d-amphetamine also took place despite interruption of the striatal efferent ‘direct’ pathway, a crucial component of the model proposed by Albin et al. [1]. Electrophysiologic experiments clearly show that dopaminergic drugs do not modulate GABAergic basal ganglia outflow uniformly and that more complex functional changes take place than heretofore believed [6,20,22,26,35], making predictions from the model difficult. The organisation of cellular elements within the substantia nigra, as well as the diverse afferent regulation and extensive and widespread efferent connections to motor and non-motor areas (which may be differentialy affected by dopaminergic stimulation) may contribute to these results. In contrast with all of the above, GP ablation disrupted dopaminergic balance in a more decisive way, since it uniformly produced a consistent ipsilateral rotational behavior after both apomorphine and d-amphetamine as predicted by the model. In electrophysiologic experiments systemic administration of apomorphine produced highly variable changes in the firing rate of SNR neurons in contrast with a consistent and strong excitatory response of GP neurons [6,35]. In view of the fact that the current ‘striatocentric’ basal ganglia model has given much attention to the final output nuclei (SNR/EP), our results extend the model and provide evidence that the GP cannot be considered just a relay station or innocent bystander along the ‘indirect’ striatal efferent pathway. Indeed, an ibotenic acid lesion of the pallidum in rats produced parkinsonian rigidity, not seen following SNR lesion [16] and an excitotoxic lesion of the external pallidum in MPTP parkinsonian monkeys produced also ipsilateral circling after administration of L-DOPA [8]. Clinical observations in humans also suggest an important role for the GP, lesions of the latter structure impairing voluntary movements and producing various hyperkinetic or hypokinetic neurological signs including involuntary movements [9]. Therefore, it seems that the contribution of the indirect pathway is essential at least for the expression of asymmetric motor behaviors and that the GP, with its direct reciprocal connections with STN and recently described projections to GPi/EP, SNR and thalamus [15,23,28], has a crucial position in basal ganglia circuitry and may act as an integrative structure exerting a more widespread control over the final output stations.
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In conclusion, our results raise very conspicuous and important functional differences between the basal ganglia nuclei studied, and underlie the different ways by which SNR and GP modulate striatal dopaminergic function and rotational behavior. Our results also contribute to recently expressed views [10,12,17] reinterpreting the functional position of the GP. The consistent and predictable rotation produced both by apomorphine and d-amphetamine after GP lesion suggests that the external pallidum occupies a central position in basal ganglia functions more than a mere relay structure, mediating crucial physiological and pharmacological events, and may have a more important role in the pathophysiology of Parkinson’s disease and other movement disorders than previously assumed.
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