Ventromedial Tegmental Lesions Research Articles

Monkeys with unilateral ventromedial tegmental lesions of the brain stem: Models for parkinson's disease and lesch-nyhan syndrome

1. Monkeys with surgical unilateral ventromedial tegmental lesions of the brain stem served as models for investigating abnormalities in Parkinson's disease and Lesch-Nyhan syndrome. 2. The animals exhibited some neurological deficits which are similar to those observed in Parkinson's disease or Lesch-Nyhan syndrome. 3. In monkeys with unilateral ventrolateral tegmental lesions, the levels of dopamine and the activities of catecholamine-synthesizing enzymes were reduced on the lesion side of the striatum, and hypokinesia and tremor developed on the contralateral extremities. 4. Dopa or dopamine agonists relieve tremor and evoke abnormal involuntary movements which are similar to the responses observed in patients with Parkinson's disease. 5. The antitremor effect of Dopa is potentiated by catechol-O-methyltransferase inhibition, suggesting a therapeutic potential for these types of agents. 6. Evidence was obtained that stimulation of D 2 dopamine receptors by selective dopamine agonists exerts antitremor activity and evokes abnormal involuntary movements. 7. Combined administration of D 1 and D 2 dopamine agonists seems to enhance the antitremor activity. 8. Partial dopamine agonists exert antitremor activity and produce less severe abnormal involuntary movements than full dopamine agonists. 9. In a group of monkeys with unilateral ventromedial tegmental lesions of the brain stem the administration of mixed D 1/D 2 dopamine agonists results in the occurrence of self-biting behavior of the forelimb digits and spasticrty of the hindlimbs and these symptoms are similar to those observed in patients with Lesch-Nyhan syndrome 10. The self-biting behavior seems to be associated with the stimulation of central D 1 dopamine receptors and therefore the possible involvement of dopamine neuronal abnormalities in Lesch-Nyhan syndrome deserves further investigation.

A special role of the parvocellular red nucleus in lesion-induced spontaneous tremor in monkeys

The neural mechanisms underlying spontaneous tremor were investigated in monkeys. Tremor-producing ventromedial tegmental (VMT) lesions involve at least three major neural elements. (1) Parvocellular division of the red nucleus (RNpc); (2) cerebellothalamic fibers passing through the red nucleus, and, (3) nigrostriatal fibers. These three elements were destroyed stereotaxically in areas remote from the VMT area separately and/or in various combinations, and correlation between the site of lesions and tremor was made. Lesion-induced tremor appeared only when the three elements were destroyed. A possible, particular role of the RNpc in the production of the spontaneous tremor is discussed.

Biochemical and functional characterization of central dopamine receptors.

In order to characterize the D2 dopamine receptors at the molecular level we have developed procedures for purification and characterization of the receptor binding protein. The ligand binding sites of the D2 dopamine receptor have been identified by photoaffinity labeling with 3H-7-azidofluphenazine. The D2 dopamine receptor protein was partially purified by Fast Performance Liquid Chromatography on a Mono Q column and on a wheat-germ agglutinin agarose column. Some behavioral expressions which are probably mediated by D1 dopamine receptors were described. Evidence was obtained that catalepsy is associated with the blockade of D1 dopamine receptors and that D1 and D2 dopamine receptor systems interact either directly or indirectly in mediating this behavior. The administration of a dopamine agonist to monkeys with unilateral ventromedial tegmental lesions of the brainstem produced a biting behavior which, in some aspects, resembles the behavior in Lesch-Nyhan patients. The prevention of the dopamine agonist-induced biting behavior by the D1 dopamine antagonists indicates that D1 dopamine receptors are involved in the control of the expression of this behavior. The biting behavior, like other motor functions, might be controlled by the mesolimbic dopamine systems, and supersensitive mesolimbic D1 dopamine receptors might be associated with the pathology of this behavior.

Neural circuits involved in parkinsonian motor disturbance studied in monkeys.

The outline of neurophysiological studies on a parkinsonian model in monkeys with mesencephalic ventromedial tegmental lesions was presented. By radiologically and physiologically controlled, selective deep-seated lesions, rigidity with or without tremor could be produced separately. From the results obtained mainly by microrecording from various levels of the brain, a neural circuit involved in production of rigidity and tremor has been proposed.

Dopamine agonist induced self-multilative biting behavior in monkeys with unilateral ventromedial tegmental lesions of the brainstem: Possible pharmacological model for Lesch-Nyhan syndrome

We have investigated the effects of various dopamine (DA) agonists on induction of abnormal involuntary movements (AIM) in a group of monkeys which had denervated nigro-striatal DA neurons for 10–14 years rendered by a unilateral surgical ventromedial tegmental (VMT) lesion of the brainstem. The surgical lesions were placed when the monkeys were 2–4 years old. The administration of mixed DA agonists, such as l-DOPA, apomorphine (Apo) and abeorphine 201–678, elicit a self-multilative biting behavior (SMB) of the forelimb digits contralateral to the lesion, and spasticity of the contralateral hindlimb. These dysfunctions resemble, in some aspects, the neurological disturbances associated with Lesch-Nyhan syndrome. The SMB behavior was elicited by mixed DA agonists which predominantly stimulate D 1, but not D 2 DA receptors, and was prevented or abolished by the D 1 DA antagonist SCH 23390 or by the D 1 and D 2 DA antagonist fluphenazine (Flu), but not by the D 2 antagonist (±)sulpiride. These results suggest that DA agonist-induced SMB behavior is mediated by D 1 and/or by both D 1 and D 2 DA receptor pathways. To study the relationships between HPRT, the defective enzyme in Lesch-Nyhan syndrome, and the DA neuronal systems, we have measured the effects of nigro-striatal DA degeneration and intrastriatal neuronal degeneration on HPRT activity. The unilateral 6-OHDA-induced nigro-striatal DA degeneration does not significantly alter the HPRT activity on the lesioned side of the striatum, while the quinolinic acid-induced intrastriatal neuronal degeneration significantly reduces the enzyme activity. These results suggest that HPRT is localized on intrastriatal neurons which are also known to contain DA receptors. It is postulated that HPRT deficiency in Lesch-Nyhan syndrome results in abnormal guanine nucleotide metabolism which may affect the regulation of DA receptors.

Central dopamine agonist activity on the 8-α-amino-ergoline CU 32-085

The effects of the 8-α-amino-ergoline CU 32-085 on central dopamine neuronal systems was investigated. Two h after administration of CU 32-085 a slight increase of dopamine levels was observed in the nucleus caudatus-putamen. Radioligand binding studies in vitro have shown that CU 32-085 has a low affinity for striatal dopamine receptors labeled by [ 3H]n-propylapomorphine or [ 3H]spiroperidol. However, CU 32-085 effectively displaces in vivo [ 3H]n-propylapomorphine and [ 3H]spiroperidol from their respective binding sites in the mouse striatum. Functional studies have shown that CU 32-085 elicits contralateral rotation in rats with unilateral 6-OH-dopamine induced lesions of the meso-striatal dopamine neurons, and ipsilateral rotation in rats with unilateral intrastriatal ibotenic acid lesions. CU 32-085 relieves tremor in monkeys with ventromedial tegmental lesions and produces only slight abnormal involuntary movements. The biochemical and functional studies suggest that CU 32-085 and/or its metabolite exerts central dopamine agonist activity in vivo. Studies in monkeys with ventromedial tegmental lesions suggest that CU 32-085 might be an effective antiparkinsonian agent which produces less dyskinesias than the other tested dopamine agonists.

Therapeutic potentials of centrally acting dopamine and alpha 2-adrenoreceptor agonists.

The antiparkinsonian activity of several dopamine agonists was investigated in an animal model and clinically in parkinsonian patients. The semisynthetic ergoline, pergolide, the partial ergoline, LY 141865 and the 8-alpha-aminoergoline, CU 32-085 were found to be effective antitremor agents in monkeys with ventromedial tegmental lesions. The administration of pergolide or LY 141865 results in a relief of tremor with a concomitant occurrence of severe abnormal involuntary movements, while the administration of CU 32-085 results in a relief of tremor with the occurrence of only minor abnormal involuntary movements. Clinical studies have revealed that pergolide is an effective drug in patients with advanced Parkinson's disease, and it reduces the "on-off" phenomena. The possible regulation of dopamine neurotransmission by the norepinephrine neuronal systems was reviewed. Preliminary data suggest that clonidine may interact with presynaptic dopamine receptors.

Stimulation of pre- and postsynaptic dopamine receptors by an ergoline and by a partial ergoline

The capacity of the ergoline, pergolide, and of the partial ergoline, LY 141865, to stimulate pre- and postsynaptic dopamine (DA) receptors was investigated. Binding studies have revealed that pergolide has a high affinity, while the partial ergoline, LY 141865, has a low affinity for the postsynaptic striatal DA receptors in vitro. Two behavioral animal models were used to assess the DA agonist potencies of these compounds for the postsynaptic DA receptors in vivo. Pergolide induced turning behavior in rats with 6-hydroxydopamine (6-OH-DA) lesions, and relief of tremor in monkeys with ventromedial tegmental lesions, at a lower dose and for a longer duration than LY 141865. An in vivo and an in vitro biochemical test was use to measure the ability of these compounds to stimulate presynaptic DA receptors. In the in vitro test, pergolide and LY 141865 were found to have low inhibitory activity for synaptosomal tyrosine hydroxylase, while in the in vivo test, both drugs were effective even in low doses in reversing the gamma-butyrolactone elicited increased accumulation of striatal DOPA. These results suggest that pergolide has a high affinity for pre- and postsynaptic DA receptors, while its partial ergoline analogue has a high affinity for the presynaptic, but not for the postsynaptic DA receptors. The data also suggest that dopamine synthesis in vitro and in vivo may be regulated by different presynaptic DA receptors.

Interaction of pergolide with central dopaminergic receptors.

The activity of pergolide, an N-propylergoline derivative, has been tested for stimulation of central dopaminergic receptors. Binding to dopamine receptors shows that pergolide acts as an agonist with respect to these receptors. GTP decreases the potencies of dopamine agonists and of pergolide, but not of bromocriptine, to displace [3H]spiroperidol ([3H]Spi) from striatal membrane sites. The GTP-sensitive site labeled by [3H]Spi seems to be localized on intrastriatal dopamine receptors. The potency of dopamine agonists and of pergolide to displace [3H]Spi from striatal receptor sites is reduced in membranes exposed to higher temperatures. Pergolide, but not hitherto-tested dopaminergic ergots, stimulates dopamine-sensitive adenylate cyclase in striatal homogenates. Thus, pergolide, unlike other dopaminergic ergots, acts as an agonist on GTP-sensitive components of [3H]Spi binding and stimulates dopamine receptors linked to dopamine-sensitive adenylate cyclase. The drug also induces turning behavior in rats with 6-OH-dopamine lesions and relieves tremor in monkeys with ventromedial tegmental lesions for a longer time at a lower dose than other tested dopaminergic ergots. Other studies have shown that it is effective in the treatment of patients with advanced parkinsonism.

Chemical Aspect of the Thalamus of the Rhesus Monkeys

Thalamic lesions failed to affect the biosynthesis and storage of monoamines on the lesion side of the striatum of normal monkeys and of monkeys with ventromedial tegmental lesions. Distribution of cholinesterase in histochemical coronal, horizontal and sagittal sections suggest a strong chemical modulation of thalamic activity from basal ganglia and related structures projecting to neo- and paleostriatum. It is suggested that the thalamus is the second or third order modulator of the brain.

Action of m-tyrosine in experimental models: Evidence for possible antiparkinsonian activity

The antiparkinsonian acitivity of m-tyrosine was investigated in two experimental animal models. In rats with a unilateral 6-OH-dopamine (DA)-induced lesion of the nigro-neostriatal DA pathway, the administration of d,1- or 1-m-tyrosine in combination with an extracerebral 3,4-dihydroxyphenylalanine (Dopa) decarboxylase inhibitor or with a monoamine oxidase inhibitor causes marked turning of the rat towards the intact side and mimicks the action of Dopa in this model. The present results indicate that d,1- and 1-m-tyrosine treatment results in preferential stimulation of denervated DA receptors, the 1-form probably being the active form. Pharmacological analysis involving also cerebral decarboxylase inhibition, treatment with a DA-β-hydroxylase inhibitor or a DA-receptor blocking agent, spiroperidol, indicates that m-tyramine formed from m-tyrosine was acting as a false transmitter on Dd receptors. Negative results were obtained with α-methyl-Dopa, α-methyl-m-tyrosine and 5-hydropxyptophan (5-HTP), indicating that α-methyl-DA, α-methyl-m-tyrosine and 5-hydroxytryptamine (5-HT) are poor stimulators of DA-receptor sites. In monkeys with unilateral ventromedial tegmental lesions, d,1- and 1-m-tyrosine alone or in combination with an extracerebral Dopa-decarboxylase inhibitor causes a transient relief of the tremor of the ipsilateral extremities. The tremor relief induced by m-tyrosine but not only Dopa is potentiated when the animals are pretreated with a monoamine oxidase inhibitor. In both experimental models, m-tyrosine exhibited a weaker pharmacological activity than Dopa. The results suggest that m-tyrosine could be of therapeutic value in the treatment of Parkinsonism. Unlike Dopa, m-tyrosine is not metabolized by catechol-O-methyltransferase and, owing to its weaker DA-receptor stimulation could elicit less hyperk9nesias than Dopa.

Effect of harmaline in monkeys with central nervous system lesions

Harmaline produced shivering in normal monkeys and intensified the resting tremor or evoked a resting tremor in monkeys with ventromedial tegmental lesions. In monkeys with such lesions, thalamic or globus pallidus destruction abolished the spontaneous tremor, blocked the harmaline-evoked tremor, but did not prevent the shivering induced by harmaline.

The effects of centrally acting drugs on tremor in monkeys with mesencephalic lesions.

The effects of centrally acting drugs on tremor were investigated in monkeys with ventromedial tegmental lesions exhibiting hypokinesia or hypokinesia and tremor. In monkeys with resting tremor, the administration of DL-5-HTP (5-hydroxytryptophan) or of DL-DOPA (3,4-dihydroxyphenylalanine) relieves the tremor, but the simultaneous administration of DL-5-HTP or DL-DOPA and atropine results in a much more pronounced relief. These results point to an imbalance between the cholinergic and adrenergic-serotonergic systems in parkinsonism. In monkeys exhibiting hypokinesia, the administration of harmaline evokes a marked resting tremor of the extremities contralateral to the tegmental lesion. The production of tremor by harmaline is not abolished by lowering the striatal amine levels with specific inhibitors of amine synthesis. Administration of DL-5-HTP protects monkeys from tremors induced by harmaline, which might affect the functions of the central nervous system by interaction with receptors for serotonin. The present results further demonstrate the apparent role of biogenic amines in the extrapyramidal dysfunctions.

Studies of amines in the striatum in monkeys with nigral lesions. The disposition, biosynthesis and metabolites of [3H]dopamine and [14C]serotonin in the striatum.

Abstract—The effects of ventromedial tegmental lesions on the biosynthesis and disposition of biogenic amines in the striatum of monkeys were investigated. The concentrations of endogenous dopamine and of the intraventricularly injected [3H]dopamine were distinctly lower in the striatum on the lesion side than on the intact side.The storage of [3H]dopamine in the caudate nucleus was impaired to a much greater extent than the storage of the newly synthesized [3H]norepinephrine.The concentrations of endogenous serotonin and of the intraventricularly injected [14C]serotonin were lower in the striatum on the lesion side than on the intact side. However following MAO inhibition, the concentration of [14C]serotonin did not differ significantly on the two sides of the caudate nucleus.The in vivo biosynthesis of dopamine from tyrosine was significantly reduced in the striatum on the lesion side. Tyrosine hydroxylase and DOPA decarboxylase activities were decreased on the lesion side of the striatum as compared with the intact side. Thus, the ventromedial tegmental lesions affect the storage and the synthesis of dopamine and serotonin in the ipsilateral striatum.

The effects of ventromedial tegmental lesions on the disposition of dopamine in the caudate nucleus of the monkey

The effects of ventromedial tegmental lesions on the disposition of dopamine in the caudate nucleus of the monkey

The effects of ventromedial tegmental lesions on the biosynthesis of catecholamines in the striatum

Following ventromedial tegmental lesions in the brain stem of monkeys, tyrosine hydroxylase activity is significantly lower on the lesion side of the caudate nucleus and putamen. The in vivo formation of dopamine-C 14 from tyrosine-C 14 is impaired on the lesion side in these two regions of the CNS. The present findings support the idea that ventromedial tegmental lesions produce a degeneration of dopamine neurons in the ipsilateral caudate nucleus and putamen.