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A R Crossman

Publications and source records attributed to A R Crossman.

At least 55 records · Page 3Linked to original sources
PubMed1994

On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus.

In the MPTP-treated primate model of Parkinson's disease, loss of dopaminergic afferents to the striatum leads to increased activity in striatal efferents to the external segment of the globus pallidus. This pathway utilizes both GABA and enkephalin as cotransmitters. Little is known regarding either the role of this cotransmission in the generation of parkinsonian symptoms or of the nature of any functional interaction between GABA and enkephalin. We have investigated the roles played by enkephalin and GABA in mediating parkinsonian symptoms by injection the GABAA antagonist bicuculline and the broad spectrum opioid antagonist naloxone directly into the globus pallidus in the reserpine-treated rat model of parkinsonism. Injections of bicuculline, but not naloxone, had marked antiparkinsonian effects. However, naloxone attenuated the antiparkinsonian effects of bicuculline. We interpret these findings as suggesting that increased GABAergic transmission in the globus pallidus is responsible for the generation of parkinsonian symptoms in the reserpine-treated rat. However, overactive enkephalinergic transmission is not responsible for the generation of symptoms and appears to act to reduce the effects of increased GABAergic transmission. In complementary studies in vitro, we have demonstrated a potential mechanism for this negative interaction. Met-enkephalin (3-10 microM) reduced depolarization-evoked release of GABA from terminals in slices prepared from rat globus pallidus (IC50, 0.38 microM). A better comprehension of the mechanisms by which enkephalin and other peptides modulate the action of amino acid transmitters in the basal ganglia is critical to the understanding of the neural processes underlying basal ganglia function and movement disorders.

Animals↗
PubMed1994

Acute and chronic behavioural sequelae resulting from intrastriatal injection of an NMDA agonist.

Unilateral and bilateral injections of cis-2,4-methanoglutamate, a potent and selective NMDA agonist, were made into the striatum of rats. Unilateral injections elicited MK-801-sensitive dose-related increases in contralateral turning, beginning 10-15 min after injection. Bilateral injections elicited typical seizure-like behaviours commencing approximately 80 min postinjection. Forty-eight hours after unilateral injection, and presumably after lesion development, no spontaneous preference for turning was seen. Upon challenge with apomorphine (1 mg/kg SC), ipsilateral turning lasting approximately 60 min was seen. Correlates are drawn between this model and some of the features of Huntington's disease.

Animals↗
PubMed1994

The projections from the parafascicular thalamic nucleus to the subthalamic nucleus and the striatum arise from separate neuronal populations: a comparison with the corticostriatal and corticosubthalamic efferents in a retrograde fluorescent double-labelling study.

The parafascicular thalamic nucleus projects to the subthalamic nucleus and the striatum. Double-retrograde fluorescent tracing was used to determine whether these projections arise from the same neurons via axon collaterals. True Blue was injected into the subthalamic nucleus and Nuclear Yellow was injected into the striatum of each rat and the parafascicular thalamic nucleus was examined under the fluorescence light-microscope. Individual parafascicular neurons were not double-labelled with the tracers. The True Blue- and Nuclear Yellow-labelled neurons wee located in different parts of the parafascicular nucleus ipsilateral to the injections. In the rostral part of the parafascicular nucleus, True Blue-labelled neurons were located ventral to the fasciculus retroflexus, and in the caudal part of the nucleus. True Blue-labelled neurons were located close to the medial and lateral borders of fasciculus retroflexus. Nuclear Yellow-labelled neurons were found mainly to encircle the fasciculus retroflexus in the rostral part of the parafascicular nucleus and in the dorsolateral sector of the caudal part of the parafascicular nucleus. Double-labelled neurons were, however, found in the cortex. The proportion of neurons projecting to both the subthalamic nucleus and the striatum accounted for 38% of the total number of cortiscosubthalamic neurons in the prefrontal cortex, 15.5% in the cingulate cortex and 9% in the sensorimotor cortex. The present finding of an individualization between the parafascicular efferents to the subthalamic nucleus and the striatum emphasize the importance of this projection and provides further evidence of the associative functions attributable to the subthalamic nucleus.

Animals↗
PubMed1993

Differential effect of chronic dopaminergic treatment on dopamine D1 and D2 receptors in the monkey brain in MPTP-induced parkinsonism.

Dopamine D1 and D2 receptors located within the striatum (caudate nucleus and putamen) were studied autoradiographically, using [3H]SCH 23390 and [3H]sulpiride respectively, in (i) seven monkeys rendered parkinsonian by the systemic administration of MPTP, four of which were chronically exposed to anti-parkinsonian drugs (levodopa or apomorphine), (ii) two hemi-parkinsonian monkeys (induced by intra-carotid infusion of MPTP), one of which received chronic exposure to apomorphine, and (iii) three control monkeys which received neither MPTP nor dopaminergic drugs. Anti-parkinsonian drug exposure resulted in a reversal of symptoms and was accompanied by the development of limb dyskinesias. In parkinsonian monkeys not chronically exposed to drugs. [3H]SCH 23390 binding was slightly but not significantly elevated above control values, whilst in the same animals [3H]sulpiride binding was significantly increased above that found in the control group. Rostrally [3H]SCH 23390 binding was similar in the control and drug-exposed parkinsonian groups but more caudally there was a small consistent, although not significant, increase in [3H]SCH 23390 binding in the drug-exposed animals as compared to the parkinsonian monkeys not exposed to drugs. In contrast at all rostro-caudal levels [3H]sulpiride binding in the drug-exposed parkinsonian group was lower than the corresponding values from the non-drug exposed animals. [3H]SCH 23390 binding showed no major side-to-side difference in the hemi-parkinsonian animal which was not exposed to levodopa/apomorphine, whilst in the hemi-parkinsonian monkey which received apomorphine there was again an increase in binding on the MPTP-treated side of the brain. In both drug- and non-drug exposed hemi-parkinsonian animals there was a greater density of [3H]sulpiride binding in the parkinsonian side of the brain; the general level of binding in the drug-exposed monkey was less than that seen in the other animal. These results would support the idea that in MPTP-induced parkinsonism, dopaminergic denervation results in a greater change in the D2 receptors, but furthermore would indicate a differential effect of levodopa/apomorphine exposure on the D1 and D2 receptor populations. Drug exposure apparently encourages the reversal of the MPTP-induced increase in the D2 receptor binding, whilst the D1 receptor binding appears to proliferate in response to these drugs. These results may have important implications in relation to the development of dyskinesias, subsequent to the chronic use of some anti-parkinsonian drug treatments.

Animals↗
PubMed1993

Thalamotomy for the alleviation of levodopa-induced dyskinesia: experimental studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated parkinsonian monkey.

This work set out to test the hypothesis that thalamotomy in the area of the thalamus which receives the input from the medial segment of the globus pallidus would decrease or prevent levodopa-induced dyskinesia. Peak dose dyskinesia is a major problem in the treatment of parkinsonian patients with levodopa therapy but this remains the best pharmacological agent for treating the condition. The hypothesis was derived from previous work which has suggested that reduced pallidal inhibition of the thalamus results in dyskinesia [Crossman (1990) Movement Dis. 5, 100-108]. A neuroanatomical tracing study was carried out prior to the thalamotomy work, using the anterograde tracer wheatgerm-agglutinin conjugated to horseradish peroxidase. This delineated the anterior part of the ventrolateral thalamus in the primate in terms of its afferent inputs. Wheatgerm agglutinin-horseradish peroxidase was injected into the medial segment of the globus pallidus bilaterally in three Macaca fascicularis and traced to terminals in the ventral thalamus and other brain areas. The appropriate thalamic area involved was plotted on atlas sections in preparation for stereotactic thalamotomy. Previous studies of neuronal input to the ventral thalamus are confusing due to the different nomenclatures used by different workers. Early workers used cytoarchitectonic boundaries which do not correspond with function. There are also differences in nomenclature between man, monkey and other animals. The current study maps the pallidal terminal territory within the thalamus in terms of stereotactic co-ordinates related to a published macaque atlas [Shantha et al. (1968) A Stereotaxic Atlas of the Java Monkey Brain. S. Karger, Basel] and can thus be used by other workers in the field. A well-established primate model of Parkinsonism was used for the thalamotomy study. Eight monkeys (Macaca fascicularis) were rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Regular dosing with levodopa or apomorphine reliably resulted in peak-dose dyskinesia which was scored in terms of its choreic and dystonic components. A radiofrequency electrode was used to create the ablative lesions. Chorea was always reduced and frequently abolished by a thalamotomy located in the pallidal terminal territory. This result was obtained after 10 thalamotomies in a total of six animals. Four animals received bilateral lesions, with an interval between operations and two animals underwent unilateral surgery.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1992

Lipocortin-1 inhibits NMDA receptor-mediated neuronal damage in the striatum of the rat.

Lipocortin-1 (annexin-1), an endogenous phospholipid and calcium binding protein, has been shown to significantly attenuate the damage produced by focal cerebral ischaemia in the rat. In the present study we have therefore investigated its effect on N-methyl-D-aspartate (NMDA) induced neuronal damage. Unilateral intrastriatal infusion of a potent and selective NMDA agonist, cis-2,4-methanoglutamate (MGlu), induced an extensive lesion of the striatum in the rat, which was inhibited (greater than 80%) by prior injection of MK801 (4 mg/kg, i.p.). Infusion of 1.2 micrograms of an active fragment of lipocortin-1 (N-terminal 1-188 aa) immediately after MGlu significantly reduced the extent of damage by 44.2 +/- 8.0%. In contrast, infusion of 3 microliters of neutralizing anti-lipocortin-1 antibody with MGlu increased lesion size by 158.9 +/- 22.0%. These findings indicate that the damage produced by intrastriatal infusion of MGlu is mediated by the NMDA receptor. Lipocortin-1 fragment markedly attenuated, and the neutralizing antibody increased, this NMDA mediated neuronal damage. These observations may explain the neuroprotective action of lipocortin following cerebral ischaemia.

Animals↗
PubMed1992

Changes in dopamine D1 and D2 receptor binding in the substantia nigra following intrastriatal injection of a retrograde neurotoxin (volkensin).

The neurotoxic properties of the proposed retrograde neurotoxin volkensin were investigated. Unilateral intrastriatal injections of volkensin (n = 8) caused a 60-79% decrease in substantia nigra pars compacta (SNc) cell number on the ipsilateral side as compared to the contralateral side. This decrease was associated with a 35-56% decrease in [3H]sulpiride binding to dopamine D2 receptors in the SNc. In the substantia nigra pars reticulata (SNr) there was a 17-24% decrease in [3H]SCH 23390 binding to dopamine D1 receptors on the ipsilateral as compared to the contralateral side. The cell loss and decrease in D2 binding is attributed to the retrograde neurotoxic properties of volkensin. The decrease in D1 binding is believed to reflect loss of presynaptic receptors from terminals of striato-nigral neurons, and thus the anterograde neurotoxicity of volkensin.

Animals↗
PubMed1992

Regional changes in 2-deoxyglucose uptake associated with neuroleptic-induced tardive dyskinesia in the Cebus monkey.

The neural mechanisms that mediate a primate model of tardive dyskinesia have been investigated using the 2-deoxyglucose (2-DG) uptake technique. Three groups of Cebus monkeys were used. Some of the animals received long-term neuroleptic treatment. These animals were allotted to one of two groups depending on whether they developed tardive dyskinesia or not. A third group of animals served as untreated controls. The neuroleptic-treated dyskinetic animals showed reduced uptake of 2-DG in the medial segment of the globus pallidus and in the ventral anterior (VA) and ventral lateral (VL) nuclei of the thalamus relative to that seen in the equivalent structures in the neuroleptic-treated nondyskinetic and untreated control animals. The data are interpreted as suggesting that tardive dyskinesia is mediated by underactivity of the pathways from the subthalamic nucleus to the medial pallidal segment and the substantia pars nigra pars reticulata, which in turn result in a loss of gamma-aminobutyric acid-ergic inhibition of the VA and VL thalamic nuclei. This suggests that tardive dyskinesia shares a common underlying neural mechanism with other hyperkinesias such as chorea and ballism.

Animals↗
PubMed1992

A 2-deoxyglucose study of the effects of dopamine agonists on the parkinsonian primate brain. Implications for the neural mechanisms that mediate dopamine agonist-induced dyskinesia.

The neural mechanisms that underlie both the anti-parkinsonian effects of dopamine agonists and dopamine agonist-induced dyskinesia were studied in parkinsonian primates, using the regional brain uptake of [3H]2-deoxyglucose (2-DG). Parkinsonian symptoms were induced in monkeys by the administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Some of the animals received chronic dopamine replacement therapy for at least 3 mths, which resulted in the appearance of peak-dose dyskinesia. The remaining animals spent an equivalent period of time relatively unexposed to dopaminergic agents, receiving only therapeutic doses, and at no time showed any signs of dopamine agonist-induced dyskinesia. The 2-DG metabolic mapping technique was applied to all of these animals shortly following the administration of a dose of dopamine agonist which was sufficient to alleviate their parkinsonian symptoms and to induce dyskinesia in those prone to this complication. The 2-DG uptake technique permits the autoradiographic measurement of local cerebral glucose uptake which was used as an index of regional synaptic activity. The resultant autoradiographs were compared with those from a previous study which examined 2-DG uptake in parkinsonian and normal brains from animals which had not received dopamine agonists prior to the terminal 2-DG uptake procedure. The pattern of 2-DG uptake in the animals which received a dopamine agonist prior to the terminal procedure was strikingly different to both of the other groups. The most affected structure was the subthalamic nucleus which showed a dramatic increase in 2-DG uptake in animals exposed to dopamine agonist immediately prior to the terminal procedure, especially in the ventral tip of the nucleus. The medial pallidal segment also showed relatively greater levels of 2-DG uptake in the dopamine agonist group compared with the untreated parkinsonian state whereas, in contrast, the lateral pallidal segment showed decreased levels of 2-DG uptake. The parkinsonian animals which had been sacrificed after receiving a dopamine agonist were split into three groups on the basis of their response to the agonist. The first group had their parkinsonism reversed and appeared clinically normal. The remaining animals had their parkinsonism reversed by the dopamine agonist but showed dyskinesia at peak dose. These animals were allotted to two further groups depending on whether their dyskinesia was of a choreic or dystonic nature.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate.

Research into the neural mechanisms underlying the symptoms of parkinsonism utilizing the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate model have shown that the subthalamic nucleus (STN) occupies a central role. As a logical development of this theory, we have studied the effects of thermocoagulative lesions of the STN in the primate model. Such lesions can cause remarkable symptom reversal in the experimental primate model.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Further investigations into the pathophysiology of MPTP-induced parkinsonism in the primate: an intracerebral microdialysis study of gamma-aminobutyric acid in the lateral segment of the globus pallidus.

The technique of intracerebral microdialysis has been employed to examine the extracellular level of gamma-aminobutyric acid (GABA) within the lateral segment of the globus pallidus of two cynomolgus monkeys, before and after the induction of parkinsonism with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Microdialysis probes were acutely implanted through indwelling cannulae positioned at several sites above the lentiform nuclei in the conscious primates, and the basal and potassium (100 mM) evoked amino acid levels were monitored for 3 h. These procedures were repeated at fresh sites within the lateral globus pallidus following the induction of parkinsonism with MPTP. The levels of a number of amino acids, including Asn, Ala, Gln, Ser, and Tau were unchanged following MPTP treatment, whereas both the basal and K(+)-evoked release of GABA was consistently increased. This observation represents further corroboration of the evidence for increased GABAergic input to the lateral globus pallidus in MPTP-induced parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Reduction of [125I]Bolton Hunter CCK8 and [3H]MK-329 (devazepide) binding to CCK receptors in the substantia nigra/VTA complex and its forebrain projection areas following MPTP-induced hemi-parkinsonism in the monkey.

Cholecystokinin (CCK) receptors were visualized autoradiographically using [125I]Bolton Hunter CCK8 ([125I]BHCCK8) in the fore- and midbrain of 3 monkeys rendered hemi-parkinsonian by unilateral intra-carotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). More specifically, CCK-A receptors were detected using [3H]MK-329 (devazepide), a peripheral-type (CCK-A) receptor antagonist. In the substantia nigra pars compacta, ipsilateral to the toxin infusion, where dopamine D2 receptors (labelled with [3H]sulpiride) were lost, there was a decrease in the binding of both [125I]BHCCK8 and [3H]MK-329. Binding of the two CCK ligands was also reduced in the ipsilateral nucleus accumbens and most medial part of the caudate nucleus, whereas 3H-sulpiride binding was increased in the lateral caudate nucleus and putamen. These results indicate that CCK-A receptors may be located on dopaminergic cells within the substantia nigra, which are lost in the parkinsonian brain, and may also be present on dopaminergic terminals within restricted regions of nigral/ventral tegmental area projection sites.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Alleviation of parkinsonism by antagonism of excitatory amino acid transmission in the medial segment of the globus pallidus in rat and primate.

Recent experimental data has made possible the description of the pathophysiological circuitry that mediates parkinsonism. This work has shown that dopamine-denervated striatal cells discharge abnormally and that this ultimately causes cells in the medial segment of the globus pallidus to become abnormally overactive. The main driving force behind the overactive cells in the medial pallidal segment appears to be excess activity in the afferent pathway to it from the subthalamic nucleus. This pathway is known to use an excitatory amino acid (EAA) as its transmitter. It was therefore hypothesized that local blockade of EAA transmission in the medial segment of the globus pallidus should reverse parkinsonism. This hypothesis was tested in rat and primate models of parkinsonism by the direct injection of the EAA antagonist, kynurenic acid, into the medial segment of the globus pallidus. The results demonstrate that this procedure can reverse parkinsonism in a dose-dependent manner, and suggest that manipulation of EAA transmission in the medial segment of the globus pallidus may have therapeutic potential for treating parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Modeling the functional organization of the basal ganglia. A parallel distributed processing approach.

Despite recent advances in the understanding of the pathophysiology of movement disorders, little is known about the precise function the basal ganglia play in the control of movement. We review an approach to studying the function of neural systems that is based on the use of a class of computer models known as parallel distributed processors (PDPs) and indicate its potential range of applications to the study of movement disorders. PDPs can be used to construct computational devices that take into account the anatomical and pharmacological properties of real neural systems. They can also provide computational-level insights that can lead to novel hypotheses concerning brain function. We discuss both these approaches and outline a scheme of the functional organization of the basal ganglia, which predicts some of the pathophysiological mechanisms that mediate movement disorders and which can be formally modeled on a computer.

Basal Ganglia↗
PubMed1990

The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primate: evidence from [3H]flunitrazepam autoradiography.

The GABA/benzodiazepine receptor complex in the basal ganglia of primates treated with the neurotoxin n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied by semi-quantitative autoradiography with [3H]flunitrazepam ([3H]FNZ). Systemic treatment with MPTP produced a stable and lasting parkinsonian condition, with pronounced bradykinesia, akinesia and tremor. In the lateral segment of the globus pallidus (GPL) there was a significant reduction of [3H]FNZ binding compared with non-treated animals. There were no significant changes in the [3H]FNZ binding in the caudate nucleus, putamen and medial globus pallidus (GPM). This suggests that MPTP-treatment increases GABA release within the GPL exclusively. In view of the available evidence suggesting increased striatal output, and reduced unit activity within the GPL of the MPTP-treated primate, it seems likely that the striatal GABAergic output to the GPL is overactive in this model of Parkinson's disease. Furthermore, as there is no evidence for a change in GABA function within the GPM using this measure, the striatal neurones which innervate the GPM may be differentially affected by loss of dopamine innervation. In line with structural evidence and extrastriatal dopamine receptor distribution this suggests that the two striatopallidal systems are functionally heterogeneous. A hemi-parkinsonian primate model has also been used in this study. This model was produced by injection of MPTP directly into one carotid artery. The substantia nigra pars compacta (SNc) was destroyed on the injected side alone, and consequently the appearance of parkinsonian symptoms was confined to the contralateral side. [3H]FNZ binding in the GPL appears to be bilaterally reduced in this model, suggesting an interaction between the treated and non-treated side of the brain. In addition there is increased binding in the putamen and GPM with respect to the non-treated side of the brain. The increased [3H]FNZ binding in the GPM of the unilateral model may be due to the greater disruption of the nigropallidal and/or nigrostiatal dopamine neurones relative to the systemic model. The former would have the effect of uncoupling D1 dopamine receptors located on the terminals of striatal efferents from nigropallidal dopamine input, and as D1 dopamine receptors are implicated in the presynaptic control of GABA release from the terminals of striatal efferents, this would consequently reduce the level of GABA release in the GPM. The latter possibility would suggest that striatopallidal neurones projecting to GPM are more resistant to the effects of dopaminergic denervation than those projecting to GPL.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. I. 6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat.

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from rats which had received unilateral 6-hydroxydopamine (6-OHDA) injections destroying ascending nigrostriatal neurones. The binding of both ligands to striatal sections was first shown to be saturable, reversible and of high affinity and specificity [( 3H]SCH 23390: Bmax 2.16 pmol/mg protein, Kd 1.4 nM; [3H]sulpiride; Bmax 0.67 pmol/mg protein, Kd 10.7 nM). After unilateral stereotaxic 6-OHDA injections, rats rotated contralaterally when challenged with apomorphine (0.5 mg/kg), or specific D1 or D2 agonists, SKF 38393 (1.0-5.0 mg/kg) and LY 171555 (0.05-0.5 mg/kg), respectively. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A loss of approximately 90-95% of uptake sites was reproducibly accompanied by an enhanced density of binding ipsilaterally for the D2 ligand, [3H]sulpiride, in all areas of the striatum, but most markedly in the lateral areas. An increase in the D2 binding site density was also seen in the ipsilateral nucleus accumbens and the olfactory tubercle. In contrast, in the same animals, the striatal D1 receptors were far less affected by dopaminergic denervation, with no consistent changes seen in the binding of [3H]SCH 23390. These results suggest that dopamine D2 receptors are more susceptible than D1 receptors to changes after dopaminergic denervation, which is expressed as an increase in the density of binding sites revealed here with [3H]sulpiride.

Animals↗