Orexin‐A increases the activity of globus pallidus neurons in both normal and parkinsonian rats

Orexin is a member of neuropeptides which was first identified in the hypothalamus. The globus pallidus is a key structure in the basal ganglia, which is involved in both normal motor function and movement disorders. Morphological studies have shown the expression of both OX₁ and OX₂ receptors in the globus pallidus. Employing single unit extracellular recordings and behavioural tests, the direct in vivo electrophysiological and behavioural effects of orexin‐A in the globus pallidus were studied. Micro‐pressure administration of orexin‐A significantly increased the spontaneous firing rate of pallidal neurons. Correlation analysis revealed a negative correlation between orexin‐A induced excitation and the basal firing rate. Furthermore, application of the specific OX₁ receptor antagonist, SB‐334867, decreased the firing rate of pallidal neurons, suggesting that endogenous orexinergic systems modulate the firing activity of pallidal neurons. Orexin‐A increased the excitability of pallidal neurons through both OX₁ and OX₂ receptors. In 6‐hydroxydopamine parkinsonian rats, orexin‐A‐induced increase in firing rate of pallidal neurons was stronger than that in normal rats. Immunostaining revealed positive OX₁ receptor expression in the globus pallidus of both normal and parkinsonian rats. Finally, postural test showed that unilateral microinjection of orexin‐A led to contralateral deflection in the presence of systemic haloperidol administration. Further elevated body swing test revealed that pallidal orexin‐A and SB‐334867 induced contralateral‐biased swing and ipsilateral‐biased swing respectively. Based on the electrophysiological and behavioural findings of orexin‐A in the globus pallidus, the present findings may provide a rationale for the pathogenesis and treatment of Parkinson's disease.     

Down-regulation of metabotropic glutamate receptor 1alpha in globus pallidus and substantia nigra of parkinsonian monkeys

Enhanced glutamatergic neurotransmission via the subthalamopallidal or subthalamonigral projection seems crucial for developing parkinsonian motor signs. In the present study, the possible changes in the expression of metabotropic glutamate receptors (mGluRs) were examined in the basal ganglia of a primate model for Parkinson's disease. When the patterns of immunohistochemical localization of mGluRs in monkeys administered systemically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were analysed in comparison with normal controls, we found that expression of mGluR1alpha, but not of other subtypes, was significantly reduced in the internal and external segments of the globus pallidus and the substantia nigra pars reticulata. To elucidate the functional role of mGluR1 in the control of pallidal neuron activity, extracellular unit recordings combined with intrapallidal microinjections of mGluR1-related agents were then performed in normal and parkinsonian monkeys. In normal awake conditions, the spontaneous firing rates of neurons in the pallidal complex were increased by DHPG, a selective agonist of group I mGluRs, whereas they were decreased by AIDA, a selective antagonist of group I mGluRs, or LY367385, a selective antagonist of mGluR1. These electrophysiological data strongly indicate that the excitatory mechanism of pallidal neurons by glutamate is mediated at least partly through mGluR1. The effects of the mGluR1-related agents on neuronal firing in the internal pallidal segment became rather obscure after MPTP treatment. Our results suggest that the specific down-regulation of pallidal and nigral mGluR1alpha in the parkinsonian state may exert a compensatory action to reverse the overactivity of the subthalamic nucleus-derived glutamatergic input that is generated in the disease.     

Electrophysiological and behavioral effects of neurotensin in rat globus pallidus: an in vivo study

The globus pallidus plays a critical role in movement regulation. Morphological study has indicated that the globus pallidus receives neurotensinergic innervation from the striatum. The present study investigated the effects of activating neurotensin receptor in globus pallidus. In vivo single unit electrophysiological recordings showed that micro-pressure ejection of neurotensin into the globus pallidus increased spontaneous firing of pallidal neurons. The excitatory effect of neurotensin could be mimicked by the C-terminal fragment, neurotensin (8-13), but not by the N-terminal fragment, neurotensin (1-8). Local administration of both the non-selective neurotensin receptor antagonist, SR142948A, and the selective neurotensin type-1 receptor antagonist, SR48692, blocked the excitatory effect induced by neurotensin. In the behaving rats, we observed the postural effects of neurotensin in the globus pallidus. Unilateral microinjection of neurotensin into the globus pallidus induced a SR48692-sensitive contralateral dystonic posturing in the presence of systemic haloperidol administration, which could be accounted for by the electrophysiological effect of neurotensin in increasing the firing rate of pallidal neurons. Our in vivo electrophysiological and behavioral findings suggest that pallidal neurotensin receptor plays a role in the basal ganglia motor circuit by mediating an excitation of spontaneous activity in the globus pallidus.     

Behavioral and electrophysiological effects of 5‐HT in globus pallidus of 6‐hydroxydopamine lesioned rats

Anatomical studies have shown that the globus pallidus receives abundant 5‐hydroxytryptamine (5‐HT) innervations from raphe nuclei. 5‐HT may occupy an important position in the modulation of motor function through its affect on the activity of globus pallidus. In the present study, intrapallidal microinjection of 5‐HT (0.1 mM) alone did not induce any motor behavior or postural asymmetry in the unilateral 6‐hydroxydopamine (6‐OHDA)‐lesioned rats. However, when infused concomitantly with a low dose of 3, 4‐dihydroxyphenylalanine (L‐DOPA, 3 mg/kg i.p.), which itself can induce modest contralateral rotational behavior, 5‐HT significantly potentiated the number of contralateral rotations. To elucidate the cellular mechanism, in vivo extracellular recordings were performed to examine the effects of 5‐HT on globus pallidus neurons. In normal rats, the predominant effect of micropressure ejection of 5‐HT on pallidal neurons was excitation. In 6‐OHDA‐lesioned rats, although 5‐HT increased the firing rate in most pallidal neurons, 5‐HT‐induced inhibitory effects was stronger than that on the unlesioned side as well as normal rats. Furthermore, 5‐HT_1B receptors are mainly involved in 5‐HT‐induced excitation while 5‐HT_1A receptors are involved in 5‐HT‐induced inhibition. The results suggest that 5‐HT may potentiate the antiparkinsonian effect of L‐DOPA through modulating the activity of globus pallidus. © 2009 Wiley‐Liss, Inc.     

Substance P excites globus pallidus neurons in vivo

Substance P is a member of the neurokinin family. Previous studies have reported the existence of substance P and its high-affinity receptor, neurokinin-1 receptor, in globus pallidus. Employing in vivo extracellular recording combined with behavioural tests, the effects of substance P in globus pallidus of rats were studied. Micropressure ejection of the selective neurokinin-1 receptor agonist [Sar9,Met(O2)11] substance P increased the spontaneous firing rate of pallidal neurons in a concentration-dependent manner, with increases of 27.3% at 0.01, 33.4% at 0.03, 45.5% at 0.1, 38.4% at 0.3 and 36.4% at 1.0 mm. The selective neurokinin-1 receptor antagonist SR140333B prevented the excitatory effects induced by [Sar9,Met(O2)11] substance P. In behaving rats, we observed the postural effects of neurokinin-1 receptor activation in the globus pallidus. Consistent with electrophysiological results, unilateral microinjection of [Sar9,Met(O2)11] substance P (0.1 mm) led to a SR140333B-sensitive contralateral deflection in the presence of systemic haloperidol administration. Combining electrophysiological and behavioural findings, we concluded that substance P produces excitatory effects on globus pallidus neurons via neurokinin-1 receptors.     

苍白球神经降压素对氟哌啶醇所致帕金森病僵直症状的影响:行为学和电生理学研究(英文)

目的苍白球在机体运动功能调节中发挥重要作用。形态学研究证实苍白球接受来自纹状体的神经降压素能纤维支配。有研究报道全身给予神经降压素类似物可诱导产生抗帕金森病效应。本研究旨在探讨苍白球神经降压素对氟哌啶醇所致的帕金森病僵直症状的影响。方法用行为学实验检测大鼠的帕金森病僵直症状,用电生理学实验方法记录苍白球神经元的自发放频率。结果双侧苍白球微量注射神经降压素可以缓解氟哌啶醇所致的帕金森病僵直症状。在氟哌啶醇条件下,微量注射神经降压素可以兴奋苍白球神经元。选择性神经降压素1型受体拮抗剂SR48692可以拮抗神经降压素所致的行为学和电生理学效应。结论上述结果提示,神经降压素的抗帕金森病作用可能与苍白球神经降压素受体的激活有关。     

Nigrostriatal lesion alters neurophysiological responses to selective and nonselective D-1 and D-2 dopamine agonists in rat globus pallidus

The effects of the selective D-1 dopamine agonist SKF 38393, the selective D-2 agonist quinpirole, and the nonselective D-1/D-2 agonist apomorphine on spontaneous activity of globus pallidus neurons were compared in normal control rats and rats with unilateral 6-hydroxydopamine induced lesions of the nigrostriatal pathway. In control, unlesioned rats, SKF 38393 (0.4 and 10 mg/kg, i.v.) caused no significant net change in the activity of globus pallidus neurons, although some individual cells showed significant increases or decreases in discharge rates following 10 mg/kg SKF 38393 administration. In animals with unilateral 6-hydroxydopamine induced lesions, SKF 38393 caused greater increases and decreases in the discharge rates of a larger percentage of pallidal cells recorded on the ipsilateral side than in control, unlesioned animals. These rate changes were effectively reversed by the D-1 antagonist SCH 23390, but not by the D-2 antagonist YM-09151-2. Quinpirole (0.3 mg/kg, i.v.) produced modest rate increases in control, unlesioned animals and significantly larger rate increases in nigrostriatal lesioned animals. YM-09151-2, but not SCH 23390, effectively reversed quinpirole's effects in the lesioned animals. As previously reported, the nonselective D-1/D-2 agonist apomorphine (0.3 mg/kg, i.v.) produced large increases in discharge rates of pallidal cells in control, unlesioned rats. In contrast, in nigrostriatal lesioned rats, the discharge rates of some ipsilateral pallidal neurons were markedly increased, others were decreased, and some were unaffected following apomorphine administration. The dopamine antagonist spiroperidol partially to fully reversed these rate changes. In summary, apomorphine's neurophysiological profile appears to be an exaggeration of the D-1 agonist profile in the globus pallidus of these lesioned animals. The degree of change observed after apomorphine administration is consistent with results from other studies that have indicated that a synergistic interaction between effects triggered by stimulation of the two receptor subtypes can occur in these animals, as in control, unlesioned animals. However, these results further show that in rats with unilateral nigrostriatal lesions, the denervated dopamine receptors or the processes they mediate are altered so that they no longer have the requirement seen in controls for concurrent stimulation of the complementary dopamine receptor subtype for expression of the selective agonist effects.     

Hypertrophy of medial globus pallidus and substantia nigra reticulata in 6‐hydroxydopamine‐lesioned rats treated with L‐DOPA: Implication for L‐DOPA‐induced dyskinesia in Parkinson's disease

The medial globus pallidus plays a crucial role in generation of L‐DOPA‐induced dyskinesia in patients with Parkinson's disease. The 6‐hydroxydopamine‐lesioned rat exhibiting behavioral sensitization to L‐DOPA is one useful animal model for examining L‐DOPA‐induced dyskinesia. To determine neuropathological abnormality responsible for behavioral sensitization, the medial globus pallidus and the substantia nigra reticulata in 6‐hydroxydopamine‐lesioned rats treated with L‐DOPA were examined. Intermittent L‐DOPA treatment induced hypertrophy of the lesioned‐side of medial globus pallidus and substantia nigra reticulata of 6‐hydroxydopamine‐lesioned rats with behavioral sensitization to L‐DOPA. Additionally, coadministration of a 5‐HT_1A receptor agonist, 8‐hydroxy‐2(di‐n‐propylamino)tetralin with L‐DOPA, alleviated the hypertrophy with improvement of the behavioral sensitization. These results suggest that hypertrophy of the medial globus pallidus and substantia nigra reticulata is associated with induction of behavioral sensitization to L‐DOPA in 6‐hydroxydopamine‐lesioned rats. Therefore, neuropathological changes corresponding to hypertrophy might underlie L‐DOPA‐induced dyskinesia in patients with Parkinson's disease.     

Subthalamo-pallidal interactions underlying parkinsonian neuronal oscillations in the primate basal ganglia

Parkinson’s disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized oscillations in the basal ganglia contribute to the expression of parkinsonian motor symptoms. However, the mechanism that generates abnormal oscillations in a dopamine‐depleted state remains poorly understood. We addressed this question by examining basal ganglia neuronal activity in two 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐treated parkinsonian monkeys. We found that systemic administration of l ‐3,4‐dihydroxyphenylalanine (l ‐DOPA; dopamine precursor) decreased abnormal neuronal oscillations (8–15 Hz) in the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during the ON state when parkinsonian signs were alleviated and during l ‐DOPA‐induced dyskinesia. GPi oscillations and parkinsonian signs were suppressed by silencing of the STN with infusion of muscimol (GABA_A receptor agonist). Intrapallidal microinjection of a mixture of 3‐(2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid (CPP; N‐methyl‐d ‐aspartate receptor antagonist) and 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzo[f]quinoxaline‐7‐sulfonamide (NBQX; AMPA/kainate receptor antagonist) also decreased the oscillations in the GPi and the external segment of the globus pallidus (GPe). Neuronal oscillations in the STN were suppressed after intrasubthalamic microinjection of CPP/NBQX to block glutamatergic afferents of the STN. The STN oscillations were further reduced by muscimol inactivation of the GPe to block GABAergic inputs from the GPe. These results suggest that, in the dopamine‐depleted state, glutamatergic inputs to the STN and reciprocal GPe–STN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinson’s disease.     

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate firing of globus pallidus neurons in vivo

The globus pallidus plays a significant role in motor control under both health and pathological states. Recent studies have revealed that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels occupy a critical position in globus pallidus pacemaking activity. Morphological studies have shown the expression of HCN channels in the globus pallidus. To investigate the in vivo effects of HCN channels in the globus pallidus, extracellular recordings and behavioral tests were performed in the present study. In normal rats, micro-pressure ejection of 0.05 mM ZD7288, the selective HCN channel blocker, decreased the frequency of spontaneous firing in 21 out of the 40 pallidal neurons. The average decrease was 50.4 ± 5.4%. Interestingly, in another 18 out of the 40 pallidal neurons, ZD7288 increased the firing rate by 137.1 ± 27.6%. Similar bidirectional modulation on the firing rate was observed by a higher concentration of ZD7288 (0.5 mM) as well as another HCN channel blocker, CsCl. Furthermore, activation of HCN channels by 8-Br-cAMP increased the firing rate by 63.0 ± 9.3% in 15 out of the 25 pallidal neurons and decreased the firing rate by 46.9 ± 9.4% in another 8 out of the 25 pallidal neurons. Further experiments revealed that modulation of glutamatergic but not GABAergic transmission may be involved in ZD7288-induced increase in firing rate. Consistent with electrophysiological results, further studies revealed that modulation of HCN channels also had bidirectional effects on behavior. Taken together, the present studies suggest that HCN channels may modulate the activity of pallidal neurons by different pathways in vivo.     

Neuronal responses of the globus pallidus to systemic administration of d-amphetamine: investigation of the involvement of dopamine, norepinephrine, and serotonin

Systemic administration of d-amphetamine (d-AMP) caused significant increases in the unit activity of spontaneously firing neurons in the rat globus pallidus. Intravenous injection of 0.2 mg/kg of d-AMP produced an average increase of 32% while a cumulative dose of 6.4 mg/kg of d-AMP increased cell firing 81% above base line control. The excitatory effects of d-AMP on pallidal cells were effectively blocked and reversed by haloperidol. Increasing intravenous doses of l-amphetamine (l-AMP), totaling 12.8 mg/kg, caused a slight excitation of pallidal neurons. The average maximum increase was 18.3%. Minor rate-elevating effects were also observed after systemic administration of desmethylimipramine and clonidine. The serotonin uptake inhibitor, fluoxetine, produced varied changes in firing frequencies. Pretreatment with reserpine and alpha-methyl-p-tyrosine significantly attenuated the d-AMP-induced increase in pallidal activity. These results suggest that dopamine plays a prominent role in mediating the stimulatory effects of d-AMP on the firing rates of a population of globus pallidus cells in gallamine-paralyzed rats.     

Distribution of cholinergic pallidal neurons in the squirrel monkey (Saimiri sciureus) based upon choline acetyltransferase.

The distribution of cells immunoreactive to choline acetyltransferase (ChAT-IR) in, and around the globus pallidus were studied in the squirrel monkey. Intrinsic pallidal ChAT-IR neurons in the globus pallidus were most numerous in ventrocaudal regions of the lateral pallidal segment (LPS) and in the oral pole of the medial pallidal segment (MPS). Smaller numbers of ChAT-positive cells were seen in portions of the medullary laminae of the pallidum. Computer measurements of somal areas of ChAT-IR cells in the globus pallidus, substantia innominata and putamen were made. Morphological features and somal areas of ChAT-IR cells in the globus pallidus and in the Ch4 group of the substantia innominata were strikingly similar. Cholinergic pallidal neurons appear to be part of the Ch4 cell group and have similar widespread cortical projections. The smaller cholinergic neurons in the striatum are considered to be intrinsic neurons which primarily act upon spiny striatal projection neurons. The possible local interaction of pallidal cholinergic neurons upon GABAergic neurons is unknown.     

Effects of interruption of the nigrostriatal pathway and of dopaminergic agents on the spontaneous activity of globus pallidus neurons in the awake monkey

Interruption of the nigrostriatal pathway has been shown to change parameters of striatal activity. These changes are often difficult to explain because the functional structure of the striatum is not understood sufficiently. The function of the globus pallidus appears to be simpler. It transmits the output of the striatum to the thalamus and to the midbrain. Yet the effects of interruption of the nigrostriatal pathway on the activity of pallidal neurons are unknown. To study these effects the spontaneous activity of globus pallidus neurons was recorded in intact monkeys and in monkeys with lesions of the ventromedial midbrain tegmentum. The two groups of animals were studied with and without administration of dopaminergic agents. In intact monkeys medial pallidal neurons discharge uninterruptedly at high firing rates, while the discharge of most lateral pallidal neurons is interrupted by relatively long periods of silence. Lesions involving the nigrostriatal pathway change the firing patterns but not the mean firing rates of pallidal neurons. In lesioned monkeys pallidal neurons fire in bursts continuously: during movement, rest and sleepiness. Two lines of evidence strongly suggest that the bursting pallidal activities are a consequence of the interruption of the nigrostriatal dopaminergic pathway: (1) the percentage of bursting pallidal neurons is proportional to the amount of degeneration in the pars compacta of the ipsilateral substantia nigra; (2) chronic administration of dopamine antagonists, haloperidol and reserpine, reproduces in intact monkeys the bursting activities observed in lesioned animals. On the other hand, single injections of dopamine agonists, apomorphine and piribedil, silence the medial pallidum and concomittantly abolish the signs of parkinsonism displayed by lesioned monkeys.     

Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism

The mixed (D1 and D2) dopamine agonist apomorphine was injected (10-200 micrograms/kg, s.c.) to cynomolgus monkeys before and after they were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Motor behavior was examined together with corresponding neuronal activity in the external (GPe) and internal (GPi) segments of the globus pallidus, including a small population of neurons localized within the GPe and displaying a characteristic discharge at low frequency with bursts (LFB), and border (Bor) neurons localized at the periphery of the pallidal segments. In the intact animal strong but not weak doses of the drug induced generalized agitation without apparent neuronal effects. In 1 parkinsonian animal that showed some recuperation of normal behavioral and pallidal activity, weak doses induced agitation and partly reduced the signs of parkinsonism, again without apparent neuronal effects. The same results were obtained before day 21 after MPTP in a parkinsonian monkey that did not recuperate. After day 21, however, the drug acted at a shorter latency, completely abolished the signs of parkinsonism, induced dyskinesia, increasing with repetition of injections, and clear neuronal effects. The same results were obtained from the start in another monkey in which recordings were begun 398 days after MPTP. Nearly all GPi neurons decreased their firing rate following apomorphine. The reverse was true of the predominant neuronal population in the GPe. In both cases, the intensity of the changes in firing rate varied much between neurons following the same dose of apomorphine. When the changes in firing rate were moderate or null, abnormal bursting firing patterns were normalized. Both LFB and Bor neurons decreased their firing rate following apomorphine; LFB neurons being extremely sensitive. The selective D2 agonist RU-24213 induced behavioral and neuronal effects identical to those of apomorphine.     

Unilateral lesion of the nigrostriatal pathway decreases the firing rate and alters the firing pattern of globus pallidus neurons in the rat

Activities of spontaneously firing neurons in the globus pallidus of intact rats and rats that survived unilateral lesions of the nigrostriatal pathway for 3 days, 1 week, or 6-11 weeks were compared. No significant differences in neuronal firing rate, firing pattern, and number of cells per pass were observed between chloral hydrate-anesthetized control and lesioned animals. However, in locally anesthetized animals, pallidal cells fired significantly faster than in chloral hydrate-anesthetized animals, and the lesion caused a decrease in the firing rates of pallidal cells 1 week and 6-9 weeks postlesion. In addition, significant differences in the firing pattern of pallidal cells, as determined by the ratio of the mean to median interspike intervals, were seen between locally anesthetized controls and animals surviving 3 days, 1 week, and 6-9 weeks postlesion. This altered firing pattern tended to return to normal with time. The number of cells per pass was not significantly altered by the lesion. Data from this study suggest that, in locally anesthetized animals, the removal of the tonic dopaminergic input to the basal ganglia causes pallidal cells to decrease their firing rates in a time-dependent fashion and causes reversable firing pattern changes. This suggests that tonically active dopamine neurons, probably acting through the striatopallidal pathway, regulate the firing rate and mechanisms controlling the temporal ordering of spontaneous discharges of globus pallidus neurons.     

Neuronal activity in the globus pallidus in primary dystonia and off-period dystonia

Decreased neuronal activity and altered firing patterns in the globus pallidus have been commonly observed in primary dystonia. Intraoperative neuronal recording in a patient with off-period dystonia revealed that the mean firing rates were considerably low in both the internal and external segments of the globus pallidus and that firing was irregular in the internal segment of the globus pallidus when dystonia developed, as compared with firing patterns in off-state parkinsonian patients without dystonia. These altered firing patterns were immediately reversed to those of off-state parkinsonism after relief of dystonia. These results suggest that primary dystonia and off-period dystonia result from the same physiological change in the basal ganglia. Ablation and stimulation of the internal segment of the globus pallidus can abolish both types of dystonia by blocking the abnormal activity of pallidal neurons.

     

Lesion of the subthalamic nucleus or globus pallidus does not cause chaotic firing patterns in basal ganglia neurons in rats

The basal ganglia appears to play an important role in behavioral selection. One model (Berns and Sejnowski’s) of basal ganglia function argues that the subthalamic nucleus plays a critical role in this selection process and predicts that the subthalamic nucleus prevents the basal ganglia and its re-entrant circuits with the thalamus and cerebral cortex from developing chaotic oscillations. We tested this prediction by generating three-dimensional sequential interval state space plots of the spike trains from 684 globus pallidus, substantia nigra pars reticulata and subthalamic neurons recorded in intact, subthalamic lesioned and globus pallidus lesioned rats, neurons which had previously been analyzed with more standard statistical methods. Only 1 neuron (a globus pallidus neuron in a subthalamic lesioned rat) of the 684 showed a chaotic attractor. In no case did subthalamic nucleus lesion induce a chaotic firing pattern elsewhere in the basal ganglia.     

Stimulation of both D1 and D2 dopamine receptors appears necessary for full expression of postsynaptic effects of dopamine agonists: a neurophysiological study

The abilities of 4 dopamine agonists to inhibit the tonic single unit activity of substantia nigra dopamine neurons and stimulate tonic activity of globus pallidus neurons were compared to study the agonists' effects on pre- and postsynaptic dopamine receptors, respectively. The agonists studied were apomorphine and pergolide, which interact with both D₁ and D₂ receptors, and the selective D₂ agonists quinpirole and RU 24926. Drugs were administered systematically. The 4 dopamine agonists were equipotent and equiefficacious at inhibiting the firing rates of dopamine neurons. In contrast, their effects on pallidal cells were not identical; apomorphine and pergolide induced significantly greater increases in pallidal cell activity than did quinpirole and RU 24926. In addition, pretreatment with a small dose of quinpirole did not attenuate the excitatory effect of apomorphine on globus pallidus cell activity, as low doses of apomorphine have previously been shown to do. Possible mechanisms underlying the differences in efficacy between the non-selective and D₂ selective dopamine agonists in the globus pallidus were investigated. Coadministering quinpirole with apomorphine did not significantly attenuate the effect of apomorphine, suggesting that quinpirole is not a partial agonist at postsynaptic dopamine receptors. In addition, prazosin pretreatment did not attenuate the stimulatory effect of pergolide on firing rates of pallidal cells, indicating that the greater efficacy of the non-selective agonists was not due to concurrent stimulation of ₁ adrenergic receptors and dopamine receptors. However, the effect of quinpirole on pallidal cell activity was significantly potentiated by pretreatment with the D₁ agonist RS-SKF 38393 but not its inactive enantiomer S-SKF 38393. These results suggest that concurrent D₁ and D₂ receptor stimulation may be necessary for the full expression of postsynaptic receptor-mediated effects of dopamine and dopamine agonists in the basal ganglia.     

Blockade of excitatory neurotransmission in the globus pallidus induces rigidity and akinesia in the rat: implications for excitatory neurotransmission in pathogenesis of Parkinson's diseases

Bilateral microinjections of the selective N-methyl-D-aspartate (NMDA) antagonist, (-)-2-amino-7-phosphonoheptanoate (AP7), 0.02-0.5 nmol, into the globus pallidus and ventral-posterior portions of the caudate-putamen result in an increase in the muscle tone (rigidity) and catalepsy (akinesia) in rats. NMDA blocked the actions of AP7 on motility in sensitive regions of the globus pallidus and caudate-putamen. Topographical differences in the action of AP7 in the striatum were detected in the dorsal-ventral and rostral-caudal direction. Microinjections of AP7 into the nucleus accumbens induced neither an increase in the muscle tone nor catalepsy in rats, while ventral regions of the caudate-putamen were sensitive to both actions of AP7. Microinjections of AP7 into the dorsal caudate-putamen resulted in a moderate or no increase in the muscle tone. AP7 failed to induce catalepsy from dorsal regions of the caudate-putamen. These data identify the globus pallidus and a defined subregion of the caudate-putamen as crucial sites where excitatory neurotransmission acts to regulate the final set-point of the respective output neurons providing modulation of the passage of motor information through the basal ganglia.     

Striatal NTS1 , dopamine D2 and NMDA receptor regulation of pallidal GABA and glutamate release--a dual-probe microdialysis study in the intranigral 6-hydroxydopamine unilaterally lesioned rat

The current microdialysis study elucidates a functional interaction between the striatal neurotensin NTS(1) receptor and the striatal dopamine D(2) and N-methyl-d-aspartic acid (NMDA) receptors in the regulation of striatopallidal gamma-aminobutyric acid (GABA) and glutamate levels after an ipsilateral intranigral 6-hydroxydopamine-induced lesion of the ascending dopamine pathways to the striatum. Lateral globus pallidus GABA levels were higher in the lesioned group while no change was observed in striatal GABA and glutamate levels. The 6-hydroxydopamine-induced lesion did not alter the ability of intrastriatal NT (10 nm) to counteract the decrease in pallidal GABA and glutamate levels induced by the dopamine D(2) -like receptor agonist quinpirole (10 μm). A more pronounced increase in the intrastriatal NMDA- (10 μm) induced increase in pallidal GABA levels was observed in the lesioned group while it attenuated the increase in striatal glutamate levels and amplified the increase in pallidal glutamate levels compared with that observed in the controls. NT enhanced the NMDA-induced increase in pallidal GABA and glutamate and striatal glutamate levels; these effects were counteracted by the NTS(1) antagonist SR48692 (100 nm) in both groups. These findings demonstrate an inhibitory striatal dopamine D(2) and an excitatory striatal NMDA receptor regulation of striatopallidal GABA transmission in both groups. These actions are modulated by NT via antagonistic NTS(1) /D(2) and facilitatory NTS(1) /NMDA receptor-receptor interactions, leading to enhanced glutamate drive of the striatopallidal GABA neurons associated with motor inhibition, effects which all are counteracted by SR48692. Thus, NTS(1) antagonists in combination with conventional treatments may provide a novel therapeutic strategy in Parkinson's disease.