Striatal Substance Research Articles

Striatal glutamate release evoked in vivo by NMDA is dependent upon ongoing neuronal activity in the substantia nigra, endogenous striatal substance P and dopamine

The aim of the present microdialysis study was to investigate whether the increase in striatal glutamate levels induced by intrastriatal perfusion with NMDA was dependent on the activation of extrastriatal loops and/or endogenous striatal substance P and dopamine. The NMDA-evoked striatal glutamate release was mediated by selective activation of the NMDA receptor-channel complex and action potential propagation, as it was prevented by local perfusion with dizocilpine and tetrodotoxin, respectively. Tetrodotoxin and bicuculline, perfused distally in the substantia nigra reticulata, prevented the NMDA-evoked striatal glutamate release, suggesting its dependence on ongoing neuronal activity and GABA(A) receptor activation, respectively, in the substantia nigra. The NMDA-evoked glutamate release was also dependent on striatal substance P and dopamine, as it was antagonized by intrastriatal perfusion with selective NK(1) (SR140333), D(1)-like (SCH23390) and D(2)-like (raclopride) receptor antagonists, as well as by striatal dopamine depletion. Furthermore, impairment of dopaminergic transmission unmasked a glutamatergic stimulation by submicromolar NMDA concentrations. We conclude that in vivo the NMDA-evoked striatal glutamate release is mediated by activation of striatofugal GABAergic neurons and requires activation of striatal NK(1) and dopamine receptors. Endogenous striatal dopamine inhibits or potentiates the NMDA action depending on the strength of the excitatory stimulus (i.e. the NMDA concentration).

Methylphenidate (Ritalin) induces Homer 1a and zif 268 expression in specific corticostriatal circuits

Corticostriatal circuits participate in limbic, attentional, motor and other networks, and are implicated in psychostimulant addiction. The psychostimulant methylphenidate is used in the treatment of attention-deficit hyperactivity disorder and for recreational purposes. Recent studies indicate that methylphenidate alters gene expression in striatal neurons. We investigated whether methylphenidate affects gene regulation in specific corticostriatal circuits, by comparing drug-induced molecular changes in different functional domains of the striatum with changes in their cortical input regions. In order to assess the potential functional significance of methylphenidate-induced molecular changes, we examined members of two different classes of plasticity-related molecules, the transcription factor zif 268 and the synaptic plasticity factor Homer 1a. Acute methylphenidate administration in adult rats increased the expression of Homer 1a and zif 268 in both cortex and striatum in a dose-dependent and regionally selective manner. These changes in gene expression occurred after doses of 2 mg/kg (i.p.) and higher, and were highly correlated between cortical regions and their striatal targets. In the cortex, increases were maximal in the medial agranular (premotor) and cingulate cortex, followed by motor and somatosensory cortex, and were minimal in the insular cortex. Correspondingly, in the striatum, increases were most robust in sensorimotor sectors that receive medial agranular input, and were weaker or absent in ventral sectors. The methylphenidate-induced increases in cortical Homer 1a and zif 268 expression were also correlated with increases in striatal substance P and dynorphin expression (direct pathway). Overall, the regional distribution of methylphenidate-induced molecular changes in the striatum was similar to that of changes induced by psychostimulants such as cocaine. These findings demonstrate that methylphenidate affects transcription and synaptic plasticity regulatory proteins in specific corticostriatal circuits, including those implicated in attentional functions and psychostimulant addiction. Such methylphenidate-induced gene regulation may contribute to the therapeutic effects and/or abuse liability of this psychostimulant.

The immunocytochemical localization of substance P in the human striatum: A postmortem ultrastructural study

The striatum is a basal ganglia structure that is involved in motor, cognitive, and behavioral functions. In the striatum, the neuroactive peptide, substance P, is colocalized with GABA in the subset of medium spiny neurons that projects to the substantia nigra. Normal human striata (n = 5) obtained from the Maryland Brain Collection were processed for substance P immunoreactivity, prepared for electron microscopy, and analyzed using both stereology and simple profile counts. Most substance P-labeled neurons had a nonindented nucleus and a moderate amount of cytoplasm, typical of medium spiny projection neurons in other species. A small percentage (8%) of labeled neurons had indented nuclei, but otherwise had similar morphology. Synapses formed on labeled cell bodies were rare. Synapses formed by substance P-labeled axon terminals constituted 4.4% of the total synapses in the neuropil. Labeled terminals (1) formed synapses with both spines and dendrites with approximately equal frequency, (2) formed mostly symmetric synapses (76-85%), and (3) formed synapses predominantly with unlabeled (78%) profiles. Substance P-labeled spines varied in shape and comprised 37-42% of all spines forming synapses. In the caudate, the proportion of synapses with perforated postsynaptic densities was 55% on unlabeled vs. 45% on labeled spines, but in the putamen, this type of synapse was much more frequently present on unlabeled (73%) vs. labeled (27%) spines. These data describe substance P in the normal human striatum, which serve as comparative data to that of other species as well as normative data for further studies of brain disease that may involve striatal substance P neurons.

Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation‐induced cellular defects in the rat striatum and globus pallidus

This study examined the effects of prolonged (4 days) high frequency stimulation (HFS) of the subthalamic nucleus (STN), in comparison with those of STN lesion, on the dopamine denervation-mediated cellular changes in the basal ganglia in a Wistar rat model of Parkinson's disease. STN HFS counteracted the dopamine lesion-induced increase in GAD67 mRNA expression in the output structures of the basal ganglia, as shown previously after STN lesion, providing cellular support for the similar antiparkinsonian benefits produced by the two surgical procedures. The dopamine denervation-induced increase in GAD67 mRNA levels in the globus pallidus was partially antagonized after HFS and totally reversed after ibotenate-induced STN lesion. The overexpression of striatal enkephalin mRNA tended to be further increased by HFS but was antagonized by STN lesion. The decrease in striatal substance P mRNA levels was affected neither by STN HFS nor lesion. As STN HFS for two hours was previously found not to interfere with the effects of dopamine lesion in the globus pallidus and striatum, the present data provide strong evidence that the effects of STN surgery in these structures involve long-term adaptive processes and that the rearrangements mediated by HFS and lesion are, at least in part, different.

Regulation of dopamine receptor and neuropeptide expression in the basal ganglia of monkeys treated with MPTP

In Parkinson's disease (PD), striatal dopamine deficiency has been associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. In this study, we simultaneously analyzed the regulation of D 1 and D 2 dopamine receptors and levels of the neuropeptides, substance P, and enkephalin (ENK) in various basal ganglia nuclei following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic denervation of striatum in nonhuman primates. Both unilateral and bilateral lesioned animals were used for this study. Striatal dopamine deficiency resulted in distinct alterations in D 1, D 2, substance P, and enkephalin levels and distribution: (1) Both D 1 and D 2 protein levels were significantly up-regulated in striatum. (2) There was an overall up-regulation of striatal substance P expression following dopamine denervation. (3) Substance P distribution was ‘reversed’ in dopamine depleted striatum: striosomes, which normally express higher levels of substance P, showed decreased expression, whereas substance P expression was up-regulated in the matrix. (4) Substance P expression was up-regulated in the internal segment of the globus pallidus (GPi), but remained unchanged in substantia nigra (SN). (5) Enkephalin levels were increased in striatum and the external segment of the globus pallidus (GPe), but not in substantia nigra. All the changes were more pronounced in the bilateral lesioned monkeys, though the data represent a pooled statistical evaluation of unilateral and bilateral lesioned monkeys. Our studies indicate that D 1 and D 2 dopamine receptors and substance P and enkephalin undergo regulatory changes in response to nigrostriatal dopamine denervation. Simultaneous study of the alterations in these various components of the ‘direct’ and ‘indirect’ pathways in the same animals will enable better understanding of the pathophysiology of PD and its therapeutic targets.

Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain.

Methamphetamine (METH) is an addictive substance that also causes extensive neural degeneration in the central nervous system. Because METH augments striatal substance P (SP) levels, we hypothesized that this neuropeptide plays a role in methamphetamine-induced toxicity and neural damage in the striatum. In this study we present evidence demonstrating that signaling through the neurokinin-1 (NK-1) receptor by SP plays an important role in methamphetamine-induced toxicity in the striatum. We tested the effects of the selective NK-1 receptor antagonists WIN-51,708 and L-733,060 on several markers of dopaminergic terminal toxicity in the mouse striatum. Administration of NK-1 receptor antagonist prevented the loss of dopamine transporters assessed by autoradiography and western blotting, the loss of tissue dopamine assessed by high-pressure liquid chromatography, and the loss of tyrosine hydroxylase, as well as the induction of glial fibrillary acidic protein determined by western blotting. Pre-treatment with NK-1 receptor antagonist had no effect on METH-induced hyperthermia. Pre-exposure of mice to either of the NK-1 receptor antagonists alone was without effect on all of these neurochemical markers. These results provide the first evidence that tachykinins, particularly SP, acting through NK-1 receptors, play a crucial role in the pathogenesis of nigrostriatal dopaminergic terminal degeneration induced by METH. This finding could lead to novel therapeutic strategies to offset drug addictions as well as in the treatment of a number of disorders including Parkinson's and Huntington's diseases.

Differential regional effects of long-term l-DOPA treatment on preproenkephalin and preprotachykinin gene expression in the striatum of 6-hydroxydopamine-lesioned rat

The present study examined the effects of prolonged l-DOPA treatment (6 months) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the mesostriatal dopaminergic pathway on substance P and enkephalin mRNA expression in the rat neostriatum. This was done by means of quantitative in situ hybridization histochemistry. As reported previously, the unilateral dopaminergic lesion induced a significant and homogeneous decrease in striatal substance P mRNA expression and a marked increase in enkephalin mRNA expression in the ipsilateral neostriatum which was more pronounced in the dorsolateral than ventromedial part of the structure. Long-term l-DOPA treatment alone had no significant effects on the two striatal peptide mRNA levels. The chronic l-DOPA treatment in 6-hydroxydopamine-lesioned rats was found to partially reverse the lesion-induced down-regulation of substance P mRNA expression, without significantly affect the up-regulation of enkephalin when considering the neostriatum as a whole. Topographical analysis revealed that long-term l-DOPA treatment reversed, in fact, both post-lesional enkephalin and substance P responses to 6-hydroxydopamine lesion, in the ventromedial neostriatum, without significantly modified these peptide responses in the dorsolateral neostriatum. These findings provide new evidence that prolonged l-DOPA treatment differentially affects the post-lesional peptide responses in the ventromedial and dorsolateral parts of the neostriatum, suggesting regional cellular mechanisms in the neostriatum underlying the benefit and/or side-effects of l-DOPA treatment in parkinsonian patients.

Chronic dizocilpine maleate (MK-801) treatment suppresses the effects of nigrostriatal dopamine deafferentation on enkephalin but not on substance P expression in the rat striatum.

The present study examined the effects of chronic treatment with dizocilpine maleate (0.2 mg/kg i.p., twice a day for 8 days) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic neurons on substance P and enkephalin expression in the rat striatum. This was done by means of quantitative in situ hybridization histochemistry and immunocytochemistry. As reported previously, the unilateral dopaminergic lesion resulted in marked decreases in substance P mRNA expression and immunoreactivity in the ipsilateral striatum while enkephalin mRNA expression and Met-enkephalin immunoreactivity were considerably increased in this structure. Blockade of NMDA receptors by chronic dizocilpine maleate treatment alone resulted in decreased levels of striatal substance P mRNA without significant change in substance P immunoreactivity versus controls. Enkephalin mRNA levels were also decreased in the striatum, matched by parallel reductions in Met-enkephalin immunoreactivity. These observations indicate that NMDA receptor activity may exert tonic excitatory effects on substance P and enkephalin expression in the striatum. The same chronic treatment with dizocilpine maleate started 12 days after the 6-hydroxydopamine injection suppressed the lesion-induced up-regulation of enkephalin expression without significantly affecting the down-regulation of substance P expression. These data provide evidence that NMDA receptor-mediated mechanisms contribute to the alteration of striatal enkephalin expression associated with dopaminergic depletion in hemiparkinsonian rat models.

Partial striatal dopamine depletion differentially affects striatal substance P and enkephalin messenger RNA expression.

Near total striatal dopamine denervation results in a decrease in substance P and an increase in enkephalin messenger RNA expression in the striatum. It is unknown whether partial depletions of striatal dopamine content produce similar changes in these peptide messenger RNAs. To test whether compensations in dopamine synthesis and release following partial dopamine denervation prevent the lesion-induced alterations in substance P and enkephalin messenger RNAs, varying concentrations of 6-hydroxydopamine were injected unilaterally into the substantia nigra. Seven days after injection of 6-hydroxydopamine (2-16 micrograms) or vehicle, in situ hybridization histochemistry was used to examine tyrosine hydroxylase messenger RNA in the substantia nigra and substance P and enkephalin messenger RNAs in the striatum. The extent of the dopamine depletion was determined by measuring striatal dopamine tissue content. The decrease in tyrosine hydroxylase messenger RNA paralleled the change in striatal tissue dopamine content. Substance P messenger RNA was decreased in all lesioned rats. In contrast, a significant increase in enkephalin messenger RNA was not detected until striatal dopamine was reduced to 10% of control levels. These results suggest that compensations within the residual dopamine system are not sufficient to maintain normal striatal substance P messenger RNA levels in partially denervated animals, but are sufficient to maintain normal striatal enkephalin messenger RNA expression.

1625 MPTP Neurotoxicity to striatal substance p-containing neurons and its prevention by dopaminergic input ablation in the rat

1625 MPTP Neurotoxicity to striatal substance p-containing neurons and its prevention by dopaminergic input ablation in the rat

Acute and subchronic effects of dopamine agonists on neuropeptide gene expression in the rat striatum

Acute and subchronic (7 days) effects of subcutaneous administration of the D-1 agonist (SKF 38393; 5.0 mg/kg), the D-2 agonist (quinpirole; 5.0 mg/kg), the mixed D-1/D-2 agonist (apomorphine; 5.0 mg/kg) or pergolide (0.5 mg/kg) on enkephalin and substance P gene expression in the striatum were studied in rats using in situ hybridization. Striatal enkephalin mRNA levels were unaffected by acute dopamine agonist treatment despite animals exhibiting altered motor behaviour. Only acute apomorphine treatment increased substance P mRNA (25%, p <0.01). Following subchronic administration of pergolide, enkephalin mRNA expression was decreased by 23% (p < 0.05) while other drugs were without effect. The abundance of striatal substance P mRNA was increased only following subchronic pergolide treatment (35%, p < 0.05). These data suggest that peptide gene expression in the intact striatum is relatively resistent to intermittent dopamine agonist stimulation in contrast to the pronounced alterations previously observed in 6-hydroxydopamine lesioned rats or following blockade of dopamine receptors.

Neurokinin receptor gene expression in substantia nigra: localization, regulation, and potential physiological significance.

Neurokinin receptor gene expression within the rat and human substantia nigra was examined in detail. In the rat, the relative abundances of nigral neurokinin receptor mRNAs were neurokinin 3 > neurokinin 1 >> neurokinin 2. High levels of neurokinin 3 mRNA were localized to dopamine neurons, as determined by dopamine cell lesions and colocalization with tyrosine hydroxylase mRNA. Stimulation of nigral neurokinin 3 receptors activated dopamine cells, as evidence by increases in striatal dopamine metabolism and in a postsynaptic measure of dopamine neurotransmission (i.e., striatal substance P encoding mRNA). These and other anatomical and physiological data suggest that in the rat, substance P (released from striatonigral neurons) may act on nigral nondopamine cells through neurokinin 1 receptors, while the substance P cotransmitter neurokinin A may act preferentially on nigral dopamine neurons through neurokinin 3 receptors. Interestingly, high levels of neurokinin 1 (but not neurokinin 3) receptor mRNA are seen within human substantia nigra dopamine cells. Thus drugs interacting with neurokinin receptors may prove to be of value in the treatment of various neuropsychiatric disorders.

Dopaminergic and muscarinic regulation of striatal enkephalin and substance P messenger RNAs following striatal dopamine denervation: Effects of systemic and central administration of quinpirole and scopolamine

Striatal dopamine depletion produces an increase in enkephalin and a decrease in substance P messenger RNAs. Subsequent systemic administration of either the D 2 dopamine agonist, quinpirole, or the muscarinic antagonist, scopolamine, results in the reduction of the lesion-induced elevation in striatal enkephalin messenger RNA. These changes in enkephalin messenger RNA levels may be mediated solely within the striatum or through trans-synaptic circuits involving the striatum. To dissociate these possibilities, we have compared the effects of systemic and central administration of quinpirole and scopolamine on striatal enkephalin and substance P messenger RNAs using in situ hybridization histochemistry. Systemic administration of both quinpirole and scopolamine blocked the elevation of striatal enkephalin messenger RNA normally observed in 6-hydroxydopamine-lesioned rats. In addition, high doses of systemic scopolamine (25 and 50 mg/kg per day) prevented the lesion-induced decrease in striatal substance P messenger RNA levels. In order to determine whether the effects of these drugs are mediated directly within the striatum, central administration of quinpirole and scopolamine were compared. In contrast to systemic administration, intraventricular and intrastriatal infusion of quinpirole but not scopolamine prevented the lesion-induced change in striatal enkephalin messenger RNA. However, neither quinpirole nor scopolamine administered centrally affected the level of substance P messenger RNA in the striatum of 6-hydroxydopamine-induced lesioned animals. Together, these data suggest that changes in D 2 receptor activation directly in the striatum are responsible for the effects of quinpirole on enkephalin messenger RNA. In contrast, the effect of systemic scopolamine on striatal enkephalin and substance P messenger RNAs may not be mediated within the striatum.

Differential Effects of Suicide Transport Lesions of the Striatonigral or Striatopallidal Pathways on Subsets of Striatal Neurons

In the basal ganglia, centrally active suicide transport agents produce apparently selective lesions of the striatopallidal and striatonigral pathways based on receptor binding and neuropeptide mRNA studies. In the present study we sought to determine the selectivity of suicide transport lesions for specific subsets of striatal neurons. Using immunohistochemical methods, the neostriata of adult rats were examined 10 days after an injection of volkensin into the substantia nigra or an injection of OX7-saporin into the globus pallidus, Ricin, a suicide transport agent active in the peripheral but not the central nervous system, was injected into each target as a control. Adjacent sections were processed for (1) Nissl stain to assess neuronal density, both overall and for large interneurons. (2) NADPH-diaphorase (NADPH-d) histochemistry, to mark medium-sized aspiny interneurons, (3) eukephalin immunocytochemistry, to label striatopallidal neurons, or (4) substance P immunocythochemistry, to label striatonigral neurons. Ricin injections produced no change in the densities of these subsets of striatal cells. In animals receiving volkensin or OX7-saporin injections, analyses of Nissl material revealed that the striata ipsilateral to the toxin injections appeared normal and did not exhibit shrinkage or gliosis; however, a quantitation analysis revealed a moderate decrease in cell density (12-16% loss, P < 0.01). The densities of both large and NADPH-d-containing striatal interneurons were unchanged after lesions in either target. Following nigral injections with volkensin, the density of striatal substance P-labeled cells decreased (26% loss, P < 0.01), while the density of enkephalin-labeled cells did not decrease significantly (11% decrease, P > 0.1). After pallidal injections with OX7-saporin, the density of striatal enkephalin-labeled cells decreased (20% loss, P < 0.01), while that of substance P-labeled cells remained unchanged. These data show that nigral volkensin and pallidal OX7-saporin injections differentially lesion striatonigral and striatopallidal projection neurons and spare striatal interneurons. This study provides further evidence for the selectivity, specificity, and utility of suicide transport agents to study brain structure and function.

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 D 1 receptor.

Methamphetamine投与による脳内substance P系, TRH系の変化におよぼす選択的D-1, D-2遮断薬の効果

The effects of pretreatment with either SCH 23390, a selective D-1 antagonist or YM-09151-2, a selective D-2 antagonist, on methamphetamine (MAP)-induced changes in the substance P and TRH system were investigated. A single dose of 4 mg/kg of MAP reduced the striatal level of substance P 30 min after injection. This reduction was reversed by pretreatment with YM-09151-2 but not with SCH 23390. Repeated administration of 4 mg/kg of MAP for 14 days reduced specific substance P and TRH binding in the striatum at 1 h, but not at 48 h, after the last injection. The reduction of striatal substance P receptor binding was prevented by pretreatment YM-09151-2 but not SCH 23390 prior to each MAP administration. The reduction of striatal TRH receptor binding was prevented by pretreatment with either antagonist. These results indicate that changes in striatal substance P level and substance P receptor binding induced by subchronic MAP treatment are mediated via activation of D-2 but not D-1 receptors by MAP-released dopamine, while changes in striatal TRH receptor binding are mediated via both D-1 and D-2 receptors.

Effects of excitotoxic striatal lesions on single unit activity in globus pallidus and entopeduncular nucleus of the cat

Striatal projections to the globus pallidus and entopeduncular nucleus are thought to be GABAergic and inhibitory. Thus, striatal lesions might be expected to increase the spontaneous discharge rate of neurons in these nuclei. To test this prediction, we recorded spontaneous single unit activity from awake cats sitting quietly before and 7–160 days after striatal lesions. Striatal lesions were produced by injecting ibotenic acid into the caudate nucleus and putamen. Median, standard deviation, mean, and coefficient of variation of the interspike intervals were calculated for each unit. In globus pallidus the striatal lesion resulted in a significant decrease in median interval length, i.e. an increase in the discharge rate. The prelesion median of 36 ms (S.E.M.= 2.3) decreased 11% to a postlesion value of 32 ms (S.E.M.= 2.1.). The lesion also resulted in a significant decrease in the variability of interspike intervals. The coefficient of variation, 1.31 (S.E.M.= 0.08) before the lesion, decreased 25% to 0.97 (S.E.M.= 0.06) after the lesion. In entopeduncular nucleus, the lesion had no statistically significant effect on the rate of activity, but a significant decrease in the variability of activity occurred. The median interval was 33 ms (S.E.M.= 3.3) before the lesion and decreased 2% to 32 ms (S.E.M.= 2.4). The coefficient of variation decreased 48% from 1.44 (S.E.M.= 0.1) to 0.73 (S.E.M.= 0.03). These observations support the hypothesis that loss of GABAergic inputs to the globus pallidus results in disinhibition. The discharge rate in entopeduncular nucleus was not affected by the striatal lesion, suggesting that striatal substance P or subthalamic excitatory inputs may have a role in regulating discharge rate in the entopeduncular nucleus.

Increase of substance P and met-enkephalin in a severely atrophied striatum without clinical expression of chorea

In a severely demented patient, with a family history of dementia, a severe striatal atrophy was observed. Neither this patient, nor his relatives, had choreoathetosis but he displayed rigidity and bradykinesia. A selective increase of the number of detectable striatal substance P and met-enkephalin neurones was found. These neurones also exhibited a striking increase of the intensity of these peptides' immunoreactivities. Simultaneously, the dense networks of substance P and met-enkephalin nerve fibres were well preserved in the globus pallidus and the substantia nigra. The absence of choreoathetosis, despite severe striatal atrophy, is described in several basal ganglia diseases. Our results are in contrast with the well established reductions of substance P and enkephalins in the atrophied striatum as well as in the globus pallidus and the substantia nigra reported in classical cases of Huntington's disease expressing choreoathetosis.

Substance P-dopamine relationship in the rat substantia nigra: a light and electron microscopy study of double immunocytochemically labeled materials

The synaptic relationships between substance P-containing terminals and dopaminergic neurons (immunoreactive for tyrosine hyodroxylase) in the substantia nigra were studied at both light and electron microscopic levels using a pre-embedding double-labeling immunocytochemical method. Many substance P-containing terminals were found to form synapses directly with dendrites and somata of nigral dopaminergic neurons. Since most of the substance P-containing axon terminals arise from the striatum, this result suggests that striatal substance P neurons can have monosynaptic influence on nigral dopaminergic neurons.

A detailed examination of substance P in pathologically graded cases of Huntington's disease

Substance P concentrations have been found to be reduced in the basal ganglia in Huntington's disease (HD). In order to further examine this finding in the present study we measured substance P-like immunoreactivity (SPLI) in cases of HD which had been graded as to the severity of pathological changes in the striatum. Marked significant reductions of SPLI were found in all striatal nuclei which were significantly correlated with the percentage of neuronal loss in the varying pathologic grades. Similar changes were found in the projection sites of striatal substance P neurons, the globus pallidus interna and the substantia nigra. These changes are consistent with a loss of striatal substance P containing projection neurons in HD. Significant reductions in SPLI were also found in the external pallidum, bed nucleus of the stria terminalis and the subthalamic nucleus. Small significant increases in SPLI (20–30%) were found in 3 frontal cortical regions (Brodmann areas 6, 8 and 9). The finding of neurochemical changes in the subthalamic nucleus is of particular interest since lesions in this nucleus are known to result in chorea and therefore might contribute to the chorea which is a cardinal symptom of HD.