The role of the globus pallidus D2 subfamily of dopamine receptors in pallidal immediate early gene expression.

The globus pallidus plays an important role in basal ganglia circuitry, representing the first relay nucleus of the 'indirect pathway' of striatal efferents. In contrast to the well-characterized actions of dopamine on striatal neurons, the functional role of the dopamine innervation of globus pallidus is less well understood. Previous research showed that systemic administration of either a dopamine D2 receptor antagonist or combined dopamine D1 and D2 receptor agonists induces Fos, the protein product of the immediate early gene c-fos, in neurons of globus pallidus [Ruskin and Marshall (1997) Neuroscience 81, 79-92]. To determine whether the ability of the D2 receptor antagonist, sulpiride, to induce Fos in rat pallidal neurons is mediated by D2-like receptors in striatum or globus pallidus, intrastriatal or intrapallidal sulpiride infusions were conducted. The diffusion of intrastriatal sulpiride was estimated by measuring this antagonist's competition for N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-induced D2 receptor inactivation. The phenotype of the striatal neurons expressing Fos after intrastriatal infusion was assessed by combining Fos immunocytochemistry with D2 receptor mRNA in situ hybridization. Intrastriatal infusions of (-)-sulpiride (10-200 ng) dose-dependently increased the number of striatal cells expressing Fos; and the Fos-immunoreactive striatal cells were D2 receptor mRNA-expressing, the same population in which systemic D2 receptor antagonists induce Fos. Intrastriatal infusions of high (5 microg), but not low (10-200 ng), (-)-sulpiride doses also induced Fos in globus pallidus cells but the sulpiride appeared to spread to the globus pallidus. Direct intrapallidal infusions of (-)-sulpiride (50-100 ng) dose-dependently induced Fos in globus pallidus with minimal influence on striatum or other basal ganglia structures. Using sensitive in situ hybridization conditions, prominent labeling of D2 receptor mRNA was evident in globus pallidus. D2 receptor mRNA was densest in a lateral 200 microm wide band that follows the curvature of the pallidal/striatal boundary. Cellular analysis revealed silver clusters associated with D2 receptor mRNA labeling over globus pallidus neurons that were immunoreactive for neuron-specific nuclear protein. These results strongly suggest that the dopaminergic innervation of globus pallidus, acting through D2-like receptors internal to this structure, can control gene expression in pallidal neurons.     

D1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons.

The expression of Fos, the product of the proto-oncogene c-fos, is thought to be a marker of neuronal activity. D1, but not D2, dopamine receptor agonists have previously been shown to increase Fos immunoreactivity in striatonigral neurons ipsilateral to a 6-hydroxydopamine lesion of the nigrostriatal pathway. In the present study, it was demonstrated that the D1 receptor agonist SKF 38393 rarely increased Fos in striatopallidal neurons of the 6-hydroxydopamine denervated striatum. Conversely, in the intact striatum, the D2 receptor antagonist haloperidol enhanced Fos expression predominantly in striatopallidal neurons labelled retrogradely from the globus pallidus or with an oligonucleotide probe complementary to mRNA encoding enkephalin. These results are consistent with studies suggesting that D1 receptors are located predominantly on striatonigral neurons and that D2 receptors reside principally on enkephalin-containing striatopallidal neurons. They also provide a neuroanatomical basis for neurochemical and neurophysiological observations indicating that dopamine facilitates the activity of striatonigral neurons but inhibits striatopallidal neurons. In another experiment the selective D2 receptor agonist quinpirole was found to increase Fos immunoreactivity in the globus pallidus ipsilateral to a 6-hydroxydopamine lesion. It is proposed that this may have been due to a D2 receptor-mediated inhibition of enkephalin and GABA release from striatopallidal terminals that in turn disinhibited the pallidal neurons. In a final series of experiments, brain microdialysis was used to determine the location of dopamine receptors regulating striatal Fos expression. Local application of the selective D1 receptor agonist CY 208-243 in the 6-hydroxydopamine-denervated striatum, or of haloperidol in the intact striatum via the dialysis probe increased Fos immunoreactivity in the immediate vicinity of the probe. Hence, the inductive effects of these systematically administered compounds on Fos expression in the striatum are mediated at least partly by local dopamine receptors in the striatum. Taken together, these results suggest that the differential regulation of striatonigral and striatopallidal activity by dopamine is mediated by the largely separate location of D1 and D2 receptors on these outputs.     

Dopaminergic transplants normalize amphetamine- and apomorphine-induced Fos expression in the 6-hydroxydopamine-lesioned striatum.

Dopamine receptor-mediated Fos protein expression in the striatum has been used to monitor dopamine receptor activation at the cellular level after dopaminergic denervation and reinnervation by fetal nigral transplants. The pattern of striatal Fos expression after systemic administration of either the dopamine receptor agonist, apomorphine, or the dopamine-releasing agent, amphetamine, was studied in rats which had received cell suspension grafts of fetal ventral mesencephalic neurons into the striatum after a complete 6-hydroxydopamine lesion of mesostriatal dopaminergic projection. Grafted animals, and normal and lesioned controls were killed 2 h after administration of either D-amphetamine (5 mg/kg, i.p.) or apomorphine (0.25 mg/kg, s.c.). Fos protein was detected immunohistochemically, and the density of Fos-immunoreactive cell nuclei was measured in 12 selected areas of caudate-putamen, nucleus accumbens and globus pallidus by computerized image analysis. Consistent with previous studies, amphetamine induced high Fos expression in the medial and dorsal parts of the intact caudate-putamen and significantly lower expression in the denervated caudate-putamen. A significant difference between lesioned and intact striata was present also in globus pallidus, but not in nucleus accumbens. In grafted rats, amphetamine-induced Fos activation was restored to normal or supranormal levels in the anterior and central caudate-putamen (i.e. close to the graft deposits), whereas in the tail of caudate-putamen Fos expression was significantly lower than normal. The side-to-side difference in globus pallidus seen in lesioned rats was no longer present in the grafted animals. Apomorphine led to high Fos activation throughout the dopamine-depleted caudate-putamen, whereas only very few immunopositive cells were observed in the intact caudate-putamen. Also in globus pallidus and nucleus accumbens, a significantly higher number of Fos-immunoreactive cells was detected on the denervated side. In the grafted rats, apomorphine-induced Fos activation was similar to normal in all striatal areas sampled, as well as in the globus pallidus. The graft-induced effect extended over a considerably larger area than that covered by the graft-derived tyrosine hydroxylase-immunoreactive innervation. These findings indicate that fetal ventral mesencephalic transplants normalize dopamine receptor-mediated function in the 6-hydroxydopamine-lesioned caudate-putamen and nucleus accumbens, as well as in a primary target of the striatal output neurons, the globus pallidus. The results support the idea that dopamine released from the grafted neurons, both under baseline conditions and after amphetamine administration, exerts functional effects over a larger volume of the striatum than that reached by the graft-derived fibers.     

Association of dopamine D1 and D2 receptors with specific cellular elements in the basal ganglia of the cat: the uneven topography of dopamine receptors in the striatum is determined by intrinsic striatal cells, not nigrostriatal axons

To ascertain the cellular associations of the D1 and D2 dopamine receptor subtypes in components of the basal ganglia, cats were prepared with unilateral, axon-sparing, ibotenic acid lesions of the striatum (n = 6) or lesions of the nigrostriatal dopamine system by intranigral infusion of 6-hydroxydopamine (n = 8). After 42 days survival, tissue sections from the brains were processed for quantitative, in vitro receptor autoradiography with [3H]SCH23390 (D1 radioligand) or [3H]spiroperidol (D2 radioligand). Lesion-induced changes in basal ganglia nuclei were assessed by comparing them to the corresponding nuclei on the intact side and in naive brains. Ibotenate lesions cause a decline in specific D1 and D2 receptor-binding in the area of the striatal lesion of 94% and 85%, respectively, and completely eliminate the uneven patterns of high- and low-density binding that are characteristic of the cat's caudate nucleus. The globus pallidus, entopeduncular nucleus and pars reticulata of the substantia nigra also show marked reductions in binding after striatal ibotenate lesions. Thus, after caudate nucleus lesions, D2 binding in the two pallidal segments declines by approximately 50%, but remains unchanged in the substantia nigra. Binding of the D1 radioligand (which is not measurable in the globus pallidus) declines by about 75% in the affected regions of the entopeduncular nucleus and pars reticulata, and by about 30% in the pars compacta. Lesions of the nigral dopamine neurons reduce D2 receptor-binding by 95% in the pars compacta and 40% in the pars reticulata, but have no effect on the concentration of D1 or D2 radioligand-binding in the striatum or pallidum. Moreover, such lesions failed to alter the uneven patterns of binding in the striatum. These data suggest that most, if not all, D1 receptors in the basal ganglia are associated with cells of the striatum and their axons in the entopeduncular nucleus and substantia nigra, and likewise, a large majority of D2 receptors are associated with striatal cells and their axons in pallidal structures. Nearly all D2 receptors in the substantia nigra are associated with dopamine neurons (autoreceptors). Finally, the heterogeneous patterns of D1 and D2 receptors in the striatum are a consequence of intrinsic neuronal distributions.     

Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons.

In the infant and adult human basal ganglia, the finding of mRNA exclusively in the striatal medium-sized neurons together with the detection of [3H]CP55,940 binding sites in the caudate-putamen, accumbens, substantia nigra pars reticulata and globus pallidus suggests cannabinoid receptor localization on the striatal intrinsic enkephalinergic and substance P-projecting neurons and on their nigral and pallidal terminals. However, the consistent finding of higher binding in the substantia nigra pars reticulata and medial part of the globus pallidus over its lateral segment suggests cannabinoid receptor enrichment on the striatal substance P neurons which express selectively the dopamine D1 receptor.     

6-Hydroxydopamine lesions of the nigrostriatal pathway alter the expression of glutamate decarboxylase messenger RNA in rat globus pallidus projection neurons.

In situ hybridization was used to study the effect of 6-hydroxydopamine-induced damage to the midbrain dopaminergic neurons on the level of glutamate decarboxylase mRNA in globus pallidus neurons in the rat. Some animals received an injection of Fluoro-gold in the entopeduncular nucleus or the substantia nigra prior to the 6-hydroxydopamine lesion in order to identify glutamic acid decarboxylase mRNA levels in pallidal neurons that project to one of these targets. Analysis was carried out on a sample of all pallidal neurons as well as neurons that were identified as projection neurons in control and lesioned groups. The loss of the dopamine-containing neurons in the substantia nigra resulted in significant increases in the percentage of globus pallidus neurons that expressed glutamate decarboxylase mRNA and in the amount of glutamate decarboxylase mRNA per globus pallidus neuron. These increases were noted in a sample of all pallidal neurons, as well as pallidal neurons that were identified as projecting to either the entopeduncular nucleus or the substantia nigra. In control animals, glutamate decarboxylase mRNA was clearly identified in globus pallidus neurons projecting to the entopeduncular nucleus, indicating that this recently reported projection is at least partially GABAergic. The results of this study indicate that substantia nigra dopaminergic neurons regulate globus pallidus neurons in the rat, and that removal of the dopaminergic input to the corpus striatum results in a significant increase in the amount of glutamate decarboxylase mRNA in pallidal neurons. The decreased firing rate of pallidal neurons that is seen following the loss of dopamine input appears to be accompanied by an increase in the level of glutamate decarboxylase mRNA in these neurons.     

Dopamine-opiate interaction in the regulation of neostriatal and pallidal neuronal activity as assessed by opioid precursor peptides and glutamate decarboxylase messenger RNA expression.

Neostriatal GABAergic neurons projecting to the globus pallidus synthesize the opioid peptide enkephalin, while those innervating the substantia nigra pars reticulata and the entopeduncular nucleus synthesize dynorphin. The differential control exerted by dopamine on the activity of these two efferent projections concerns also the biosynthesis of these opioid peptides. Using in situ hybridization histochemistry, we investigated the role of opioid co-transmission in the regulation of neostriatal and pallidal activity. The expression of the messenger RNAs encoding glutamate decarboxylase-the biosynthetic enzyme of GABA-and the precursor peptides of enkephalin (preproenkephalin) and dynorphin (preprodynorphin) were measured in rats after a sustained blockade of opioid receptors by naloxone (s.c. implanted osmotic minipump, eight days, 3 mg/kg per h), and/or a subchronic blockade of D2 dopamine receptors by haloperidol (one week, 1.25 mg/kg s.c. twice a day). The density of mu opioid receptors in the neostriatum and globus pallidus was determined by autoradiography. Naloxone treatment resulted in a strong up-regulation of neostriatal and pallidal mu opioid receptors that was not affected by the concurrent administration of haloperidol. Haloperidol alone produced a moderate down-regulation of neostriatal and pallidal micro opioid receptors. Haloperidol strongly stimulated the expression of neostriatal preproenkephalin and preprodynorphin messenger RNAs. This effect was partially attenuated by naloxone, which alone produced moderate increases in preproenkephalin and preprodynorphin messenger RNA levels. In the neostriatum, naloxone did not affect either basal or haloperidol-stimulated glutamate decarboxylase messenger RNA expression. A strong reduction of glutamate decarboxylase messenger RNA expression was detected over pallidal neurons following either naloxone or haloperidol treatment, but concurrent administration of the two antagonists did not result in a further decrease. The amplitude of the variations of mu opioid receptor density and of preproenkephalin and preprodynorphin messenger RNA levels suggests that the regulation of neostriatal and pallidal micro opioid receptors is more susceptible to a direct opioid antagonism, while the biosynthesis of opioid peptides in the neostriatum is more dependent on the dopaminergic transmission. The down-regulation of mu opioid receptors following haloperidol represents probably an adaptive change to increased enkephalin biosynthesis and release. The haloperidol-induced increase in neostriatal preprodynorphin messenger RNA expression might result from an indirect, intermittent stimulation of neostriatal D1 receptors. The haloperidol-induced decrease of pallidal glutamate decarboxylase messenger RNA expression suggests, in keeping with the current functional model of the basal ganglia, that the activation of the striatopallidal projection produced by the interruption of neostriatal dopaminergic transmission reduces the GABAergic output of the globus pallidus. The reduction of pallidal glutamate decarboxylase messenger RNA expression following opioid receptor blockade indicates an indirect, excitatory influence of enkephalin upon globus pallidus neurons and, consequently, a functional antagonism between the two neuroactive substances (GABA and enkephalin) of the striatopallidal projection in the control of globus pallidus output. Through this antagonism enkephalin could partly attenuate the GABA-mediated effects of a dopaminergic denervation on pallidal neuronal activity.     

Neonatal dopamine depletion reveals a synergistic mechanism of mRNA regulation that is mediated by dopamine(D1) and serotonin(2) receptors and is targeted to tachykinin neurons of the dorsomedial striatum

It has been hypothesized that dopamine(D1) and serotonin(2) receptors become sensitized to agonist-mediated regulation of gene expression following loss of dopaminergic innervation to the striatum. We have previously demonstrated that the combined administration of dopamine(D1) and serotonin(2) receptor agonists to dopamine-depleted adult rats induced preprotachykinin mRNA expression within the periventricular rostral striatum to levels which were significantly different than what could be elicited by either agonist alone. In the present study, we have determined that this phenomenon is revealed only after dopamine depletion. In addition, it is targeted primarily to tachykinin producing neurons of the dorsomedial striatum and is dependent on both dopamine(D1) and serotonin(2) receptor activation. Preprotachykinin mRNA levels in the intact striatum were unaltered 4 h following an i.p. injection of either SKF-38393 (1 mg/kg, dopamine(D1) partial agonist) or (+/-)-1-(4-Iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI 1 mg/kg, serotonin(2) agonist). However, the combined application of both agonists increased (+44%) preprotachykinin message levels, but these changes were restricted to the dorsomedial striatum. In adult animals depleted of dopamine as neonates, striatal preprotachykinin mRNA expression was reduced by approximately 50%. From this lowered level of basal expression, DOI or SKF-38393 raised preprotachykinin mRNA levels within the dorsomedial, but not the dorsolateral striatum. Furthermore, co-stimulation of dopamine(D1) and serotonin(2) receptors produced a nearly four-fold induction of preprotachykinin message levels in the dorsomedial striatum that was significantly greater than either agonist alone. Application of both agonists also elevated preprotachykinin mRNA expression within the dorsolateral striatum, but to a lesser extent. All increases in preprotachykinin mRNA resulting from co-application of SKF-38393 and DOI were prevented by pretreatment with either SCH-23390 (1 mg/kg, dopamine(D1) antagonist) or ritanserin (1 mg/kg, serotonin(2) antagonist). Alternately, preproenkephalin mRNA expression was unaffected by dopamine(D1) receptor stimulation, but was slightly elevated by DOI or both agonists together (42-58%) in intact animals. However, neither agonist treatment in this experiment significantly altered preproenkephalin mRNA expression in the dopamine-depleted striatum which was elevated in response to dopamine lesion alone.Dopamine depletion appears to promote a synergistic interaction between dopamine(D1) and serotonin(2) receptors that leads to enhanced expression of striatal preprotachykinin mRNA levels. The localization of this phenomenon to tachykinin neurons of the direct striatonigral pathway specifically within the dorsomedial regions of the rostral striatum may be relevant to the problem of dyskinetic behaviors which arise during the pharmacological treatment of movement disorders.     

Dopamine inhibits GABA transmission from the globus pallidus to the thalamic reticular nucleus via presynaptic D4 receptors

The globus pallidus sends a significant GABAergic projection to the thalamic reticular nucleus. Because pallidal neurons express D4-dopamine receptors, we have explored their presence on pallidoreticular terminals by studying the effect of dopamine and D4-receptor agonists on the GABAergic transmission in the thalamic reticular nucleus. We made whole-cell recordings of inhibitory postsynaptic currents (IPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in the thalamic reticular neurons. Dopamine consistently reduced the IPSCs. The effect of dopamine was associated with paired-pulse facilitation, indicating a presynaptic location of the receptors. The effect of dopamine was also measured on the mIPSCs, reducing their frequency but not affecting their amplitude, which also suggests a presynaptic site of action. The selective D4-receptor agonist PD 168,077 also reduced the IPSCs, which was also associated with paired-pulse facilitation. In addition, this agonist reduced the frequency of the mIPSCs with no effect on their amplitude. The D4-receptor antagonist l-745,870 totally blocked the effect of the D4-receptor agonist, indicating the specificity of its effect. To verify the location of the receptors on the pallidal terminals, these were eliminated by injecting kainic acid into the globus pallidus. Kainic acid produced a drastic (80%) fall in the globus pallidus neuronal population. In this condition, the effect of the activation of D4 receptors both on the IPSCs and mIPSCs was prevented, thus indicating that the location of the receptors was on the pallidal terminals. Our results demonstrate that dopamine controls the activity of the thalamic reticular neurons by regulating the inhibitory input from the globus pallidus.     

Embryonic striatal grafts restore neuronal activity of the globus pallidus in a rodent model of Huntington's disease

It has been demonstrated in rats that embryonic striatal grafts placed in the excitotoxically lesioned striatum establish neuronal connections with the host globus pallidus. In order to determine whether the morphologically verified connections between the grafts and host are functional, the present study investigated the effects of embryonic striatal grafts on changes in the neuronal activity of the globus pallidus in rats with quinolinic acid-induced striatal lesions. The activity of pallidal neurons was determined by use of quantitative cytochrome oxidase histochemistry and an electrophysiological technique. Striatal lesions induced an increase in both the cytochrome oxidase activity and the spontaneous firing rate of the globus pallidus ipsilateral to the lesions. Grafts derived from the lateral ganglionic eminence, but not the medial ganglionic eminence, reversed the lesion-induced increase in the cytochrome oxidase activity of the globus pallidus with concomitant reduction of apomorphine-induced rotational asymmetry. The lateral ganglionic eminence grafts also attenuate the increase in the firing rate of pallidal neurons in rats with striatal lesions. The present results provide evidence that striatal lesions lead to the loss of a tonic inhibitory input to the globus pallidus with consequent increase in the activity of pallidal neurons, and that intrastriatal striatal grafts reverse the altered activity of pallidal neurons. The findings strongly suggest that embryonic striatal grafts functionally repair the damaged striatopallidal pathway.     

Baclofen attenuates harmaline induced tremors in rats

Because activation of D2 dopamine receptors inhibits gamma-aminobutyric acid (GABA) release from intrapallidal nerve terminals, we measured the effects of modifiers of dopamine D2 receptors on the firing rate of single neurons in the globus pallidus (GP) of the anesthetized rat. The predominant effect of intrapallidal administration of the selective D2 agonist quinpirole was an increase in the rate of spontaneous firing while the D2 blocker sulpiride caused a decrease. The spontaneous firing of GP neurons is inhibited by stimulation of the GABAergic striatopallidal projection. We therefore measured the effects of modifiers of D2 receptors on striatal inhibition of GP neurons and found that intrapallidal quinpirole blocked the inhibitory effects of striatal stimulation while sulpiride enhanced them. These experiments show that both the spontaneous rate of firing of pallidal neurons and its modification by striatopallidal inputs is controlled by intrapallidal dopamine D2 receptors. In addition, taken together with other findings in the literature, our results suggest that activation of dopamine D2 receptors within the globus pallidus leads to inhibition of GABA release from presynaptic terminals.     

Enkephalin regulates acute D2 dopamine receptor antagonist-induced immediate-early gene expression in striatal neurons.

Projection neurons of the striatum release opioid peptides in addition to GABA. Our previous studies showed that the opioid peptide dynorphin regulates that subtype of projection neurons which sends axons to the substantia nigra/entopeduncular nucleus, as indicated by an inhibitory action of dynorphin/agonists on D1 dopamine receptor-mediated immediate-early gene induction in these neurons. The other subtype of striatal projection neurons projects to the globus pallidus and contains the opioid peptide enkephalin. Here, we investigated whether enkephalin regulates the function of striatopallidal neurons, by analysing opioid effects on immediate-early gene induction by D2 dopamine receptor blockade that occurs in these neurons. Thus, the effects of systemic and intrastriatal administration of various opioid receptor agonists and antagonists on immediate-early gene expression (c-fos, zif 268) induced by the D2 receptor antagonist eticlopride were examined with in situ hybridization histochemistry. Intrastriatal infusion of enkephalin (delta and mu), but not dynorphin (kappa), receptor agonists suppressed immediate-early gene induction by eticlopride in a dose-dependent manner. This suppression was blocked by the opioid receptor antagonist naloxone, confirming the involvement of opioid receptors. Repeated treatment with D2 receptor antagonists produces increased enkephalin expression and diminished immediate-early gene inducibility in striatopallidal neurons, as well as behavioral effects that are attenuated compared to those of acute treatment (e.g., reduced akinesia). Naloxone reversed such behavioral recovery (i.e. reinstated akinesia), but did not significantly affect suppressed immediate-early gene induction. Our results indicate that enkephalin acts, via mu and delta receptors in the striatum, to inhibit acute effects of D2 receptor blockade in striatopallidal neurons. Moreover, the present findings suggest that increased enkephalin expression after repeated D2 receptor antagonist treatment is an adaptive response that counteracts functional consequences of D2 receptor blockade, but is not involved in suppressed immediate-early gene induction. Together with our earlier findings of the role of dynorphin, these results indicate that opioid peptides in the striatum serve as negative feedback systems to regulate the striatal output pathways in which they are expressed.     

Effects of repeated methyl levodopa administration on apomorphine sensitivity of rotational behavior and striatal Fos expression of rats with unilateral 6-OHDA lesions

This study was designed to elucidate the mechanism to develop levodopa-induced dyskinesia in patients with Parkinson's disease. For this purpose, we administered methyl levodopa repeatedly to a rat model of Parkinson's disease with unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine pathway. After a washout period, we measured apomorphine sensitivity of contralateral rotation and made parallel determination of Fos expression in the caudate-putamen and globus pallidus of the same animal. Once daily, i.p. injection of methyl levodopa plus benserazide for 10 days increased the number of rotations over time. A challenge dose of apomorphine showed enhanced rotational response in rats pretreated with methyl levodopa. Repeated administration of methyl levodopa resulted in diminished apomorphine sensitivity of Fos expression in the dopamine depleted caudate-putamen and in enhanced sensitivity in the globus pallidus of the same side. Present results may add evidence to the idea that repeated administration of levodopa develops dopaminergic sensitization mediated by augmented activation of pallidal neurons involved in D2-responsive pallidal output pathway.     

Different effects of dopamine D1 receptor on the firing of globus pallidus neurons in rats

The globus pallidus in rodents, equivalent to the external globus pallidus in primates, plays an important role in movement regulation. Morphological studies have indicated that the globus pallidus receives dopamine innervation from the collaterals of nigrostriatal fibers. To investigate the direct electrophysiological effects of dopamine D(1) receptors in the globus pallidus, in vivo extracellular recordings were performed in the present study. In 25 out of 58 globus pallidus neurons, micro-pressure ejection of 5mM SKF38393 increased the spontaneous firing rate from 9.8 ± 1.9 Hz to 14.3 ± 2.5 Hz. The average increase was 61.5 ± 8.3% (P<0.001). In another 12 out of the 58 globus pallidus neurons, micro-pressure ejection of SKF38393 decreased the spontaneous firing rate from 4.7 ± 1.2 Hz to 2.1 ± 0.6 Hz. The average decrease was 52.1 ± 6.7% (P<0.05). Micro-pressure ejection of SKF38393 did not alter the firing rate significantly in the left 21 globus pallidus neurons. The present findings may provide a rational for further investigations into the potential of pallidal dopamine D(1) receptor in the treatment of Parkinson's disease.     

The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease

In order to investigate the sequence and pattern of neurodegeneration in Huntington's disease, the distribution and density of cannabinoid CB(1), dopamine D(1) and D(2), adenosine A(2a) and GABA(A) receptor changes were studied in the basal ganglia in early (grade 0), intermediate (grades 1, 2) and advanced (grade 3) neuropathological grades of Huntington's disease. The results showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the very early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB(1), dopamine D(2) and adenosine A(2a) receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABA(A) receptor binding in the globus pallidus externus. Second, intermediate neuropathological grades (grades 1, 2) showed a further marked decrease of CB(1) receptor binding in the caudate nucleus and putamen; this was associated with a loss of D(1) receptors in the caudate nucleus and putamen and a loss of both CB(1) and D(1) receptors in the substantia nigra. Finally, advanced grades of Huntington's disease showed an almost total loss of CB(1) receptors and the further depletion of D(1) receptors in the caudate nucleus, putamen and globus pallidus internus, and an increase in GABA(A) receptor binding in the globus pallidus internus.These findings suggest that there is a sequential but overlapping pattern of neurodegeneration of GABAergic striatal efferent projection neurons in increasing neuropathological grades of Huntington's disease. First, GABA/enkephalin striatopallidal neurons projecting to the globus pallidus externus are affected in the very early grades of the disease. Second, GABA/substance P striatonigral neurons projecting to the substantia nigra are involved at intermediate neuropathological grades. Finally, GABA/substance P striatopallidal neurons projecting to the globus pallidus internus are affected in the late grades of the disease. In addition, the finding that cannabinoid receptors are dramatically reduced in all regions of the basal ganglia in advance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington's disease.     

Single pallidal neurons project both to the striatum and thalamus in the rat

Collateral projections of single small pallidal neurons to the striatum and paraventricular nucleus of the thalamus were observed in the rat using a fluorescent retrograde double labeling technique. This population of pallidal cells was almost separate from the more predominant pallidal cell group projecting to the subthalamic nucleus. We propose that the globus pallidus proper might have the same two functionally distinct populations (limbic and motor), that have been well documented in the striatum and entopeduncular nucleus.     

The role of the human globus pallidus in Huntington's disease

Huntington's disease (HD) is characterized by pronounced pathology of the basal ganglia, with numerous studies documenting the pattern of striatal neurodegeneration in the human brain. However, a principle target of striatal outflow, the globus pallidus (GP), has received limited attention in comparison, despite being a core component of the basal ganglia. The external segment (GPe) is a major output of the dorsal striatum, connecting widely to other basal ganglia nuclei via the indirect motor pathway. The internal segment (GPi) is a final output station of both the direct and indirect motor pathways of the basal ganglia. The ventral pallidum (VP), in contrast, is a primary output of the limbic ventral striatum. Currently, there is a lack of consensus in the literature regarding the extent of GPe and GPi neurodegeneration in HD, with a conflict between pallidal neurons being preserved, and pallidal neurons being lost. In addition, no current evidence considers the fate of the VP in HD, despite it being a key structure involved in reward and motivation. Understanding the involvement of these structures in HD will help to determine their involvement in basal ganglia pathway dysfunction in the disease. A clear understanding of the impact of striatal projection loss on the main neurons that receive striatal input, the pallidal neurons, will aid in the understanding of disease pathogenesis. In addition, a clearer picture of pallidal involvement in HD may contribute to providing a morphological basis to the considerable variability in the types of motor, behavioral, and cognitive symptoms in HD. This review aims to highlight the importance of the globus pallidus, a critical component of the cortical‐basal ganglia circuits, and its role in the pathogenesis of HD. This review also summarizes the current literature relating to human studies of the globus pallidus in HD.     

Cortical stimulation induces fos expression in striatal neurons.

Electrical stimulation of a broad area of the frontoparietal cortex in the rat brain induces immunocytochemically detectable Fos in striatal neurons normally devoid of the protein. The vividness of labeling within striatal neurons was maximal at 0.5 h after the cessation of a 15-min-long stimulation period and became weaker by 3 h. Although Fos-reactive neurons were widely distributed in the striata of both hemispheres in an uneven pattern, those on the stimulated side were more numerous and more darkly stained. At no time-point were labeled neurons found in the globus pallidus, entopeduncular nucleus or substantia nigra. Destruction of the nigrostriatal dopamine projection with 6-hydroxydopamine did not induce Fos production and failed to prevent the induction of Fos by cortical stimulation. That many of the Fos-positive neurons project to the substantia nigra was confirmed by retrograde labeling with Fluoro-Gold. The data suggest that corticostriatal excitatory transmission may directly influence the genomic activity of striatal neurons by way of Fos.