Effect of chronic treatment of MPTP monkeys with dopamine D-1 and/or D-2 receptor agonists

doi:10.1016/0014-2999(90)94802-5

European Journal of Pharmacology

Volume 178, Issue 1, 13 March 1990, Pages 115-120

https://doi.org/10.1016/0014-2999(90)94802-5 Get rights and content

Abstract

A severe parkinsonian syndrome developed in four monkeys after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). One monkeys subsequently remained untreated, and each of the three others were treated daily for at least one month with Sinemet, bromocriptine or SKF 38393. An intact control monkey (not MPTP-treated) was also included in the experiment. Sinemet and bromocriptine relieved the parkinsonian symptoms, whereas SKF 38393 was ineffective. The animal treated with Sinemet developed dyskinesia while those treated with bromocriptine or SKF 38393 did not. MPTP decreased dopamine levels by more than 99% in the striatum of all monkeys. Striatal D-1 and D-2 dopamine receptor densities as evaluated by autoradiography of [³H]SCH 23390 and [³H] spiperone binding were increased by 66 and 51%, respectively, after MPTP. Sinemet, bromocriptine or SKF 38393 treatment decreased D-2 receptor density, respectively, by 17, 84 and 35% and D-1 receptor density by 28, 33 and 6% vs. that in MPTP-treated animals. Our results suggest that dopamine receptor changes could be implicated in the loss of efficacy and in the side-effects of these treatments.

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Cited by (83)

Subthalamotomy-induced changes in dopamine receptors in parkinsonian monkeys
2014, Experimental Neurology
Citation Excerpt :
In the pre-commissural striatum, D1 receptors are reported to remain unchanged after exposure to MPTP (Aubert et al., 2005; Calon et al., 1995) and to increase with l-DOPA (Aubert et al., 2005; Guigoni et al., 2005; Rioux et al., 1997). On the contrary, no change (Alexander et al., 1993; Graham et al., 1993) or a decrease is observed in the post-commissural striatum (Gagnon et al., 1990; Morin et al., 2014) after l-DOPA treatment. In the present study, we observed significant decreases in the post-commissural D1 receptor specific binding after MPTP in all subdivisions of the striatum.
Subthalamotomy allows a reduction of doses of l-DOPA in dyskinetic patients while its antiparkinsonian benefits are preserved. However, the mechanisms of the potentiation of this response to medication remain to be elucidated. Hence, dopamine D₁ and D₂ receptors as well as the dopamine transporter were investigated using receptor binding autoradiography. D₁ and D₂ receptors as well as preproenkephalin and preprodynorphin mRNA levels were measured by in situ hybridization. Four dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys that underwent unilateral subthalamotomy were compared to four controls, four saline-treated and four l-DOPA-treated MPTP monkeys. Dopamine, its metabolites and its transporter were extensively and similarly decreased in all parkinsonian monkeys. D₁ receptor specific binding was decreased in the striatum of all MPTP monkeys. The l-DOPA-induced decrease in D₁ receptor specific binding was reversed in the striatum ipsilateral to subthalamotomy. D₁ receptor mRNA levels followed a similar pattern. D₂ receptor specific binding and mRNA levels remained unchanged in all groups. Striatal preproenkephalin mRNA levels were overall increased in MPTP monkeys; the STN-lesioned parkinsonian group had significantly lower values than the saline-treated and l-DOPA-treated parkinsonian monkeys in the dorsolateral putamen. Striatal preprodynorphin mRNA levels remained unchanged in MPTP monkeys compared to controls whereas it increased in all monkeys treated with l-DOPA compared to controls; subthalamotomy induced a decrease in the dorsolateral putamen ipsilateral to surgery. The improved motor response to l-DOPA after subthalamotomy in the parkinsonian monkeys investigated may be associated with an increased synthesis and expression of D₁ receptors ipsilateral to STN lesion of the direct pathway.
Modeling dyskinesia in animal models of Parkinson disease
2014, Experimental Neurology
Citation Excerpt :
Denervation-induced supersensitivity of DA receptors is generally recognized as a plausible mechanism of LID. Post-mortem studies have shown that striatal DA receptors particularly of the D2 subtype were increased in PD patients (Bokobza et al., 1984; Guttman et al., 1986; Lee et al., 1978), while both D1 and D2 DA receptor subtypes were increased in MPTP-lesioned monkeys (Bedard et al., 1986; Falardeau et al., 1988; Gagnon et al., 1990; Graham et al., 1993). l-DOPA reverses this increase in humans (Guttman et al., 1986; Lee et al., 1978) and monkeys (Berretta et al., 1997; Falardeau et al., 1988; Gagnon et al., 1990).
The treatment of motor symptoms of Parkinson disease (PD) with the dopamine (DA) precursor, l-3,4-dihydroxyphenylalanine (l-DOPA) introduced 50 years ago still remains a very effective medication. However, involuntary movements termed l-DOPA-induced dyskinesias (LID) appear in the vast majority of PD patients after chronic treatment and may become disabling. Once they appeared, the first dose after a several-weeks drug holiday will trigger them again, showing that l-DOPA has permanently or persistently modified the brain response to DA. LID are very difficult to manage and no drug is yet approved for dyskinesias, aside from a modest benefit with amantadine. New drugs are needed for PD to alleviate parkinsonian symptoms without inducing dyskinesias. Hence, animal models have been developed to seek the mechanisms involved in LID and new drug targets. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was discovered as a contamination of a derivative of heroin taken by drug users and produced similar motor symptoms as idiopathic PD. Since then, MPTP is used extensively to model PD and LID in non-human primates and mice in addition to the classical PD model in rats with a 6-hydroxydopamine (6-OHDA) lesion. This article reviews rodent and non-human primate models of PD that reproduce motor complications induced by DA replacement therapy. Moreover, key biochemical changes in the brain of post-mortem PD patients with LID will be compared to those observed in animal models. Finally, the translational usefulness of drugs found to treat LID in animal models will be compared to their clinical activities.
Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys
2014, Neuropharmacology
Citation Excerpt :
As compared to D1 receptor, autoradiography studies on D2 receptors show more consistent results. Levels of D2 receptor in the striatum were reported to be unchanged (Calon et al., 1995; Gagnon et al., 1995; Goulet et al., 1996; Pifl et al., 1992) or increased with MPTP in monkeys (Alexander et al., 1993; Falardeau et al., 1988; Gagnon et al., 1990, 1995; Graham et al., 1990; Graham et al., 1993; Guigoni et al., 2005) and in untreated PD patients (Lee et al., 1978). Such DA denervation-induced increase in the expression of D2 receptor was shown to be reversed with the administration of l-DOPA (Alexander et al., 1993; Gagnon et al., 1990; Graham et al., 1993) or has no influence (Calon et al., 1995; Guigoni et al., 2005).
Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs decrease L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID); the implication of dopamine neurotransmission is not documented in this anti-LID activity. Therefore, we evaluated changes of dopamine receptors, their associated signaling proteins and neuropeptides mRNA, in normal control monkeys, in saline-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in L-DOPA-treated MPTP monkeys, without or with an adjunct treatment to reduce the development of LID: 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist. All de novo treatments were administered for 1 month and the animals were sacrificed thereafter. MPTP monkeys treated with l-DOPA + MPEP developed significantly less LID than MPTP monkeys treated with l-DOPA alone. [³H]SCH-23390 specific binding to D1 receptors of all MPTP monkeys was decreased as compared to controls in the basal ganglia and no difference was observed between all MPTP groups, while striatal D1 receptor mRNA levels remained unchanged. [³H]raclopride specific binding to striatal D2 receptors and mRNA levels of D2 receptors were increased in MPTP monkeys compared to controls; l-DOPA treatment reduced this binding in MPTP monkeys while it remained elevated with the l-DOPA + MPEP treatment. Striatal [³H]raclopride specific binding correlated positively with D2 receptor mRNA levels of all MPTP-lesioned monkeys. Striatal preproenkephalin/preprodynorphin mRNA levels and phosphorylated ERK1/2 and Akt/GSK3β levels increased only in L-DOPA-treated MPTP monkeys as compared to controls, saline treated-MPTP and l-DOPA + MPEP treated MPTP monkeys. Hence, reduction of development of LID with MPEP was associated with changes in D2 receptors, their associated signaling proteins and neuropeptides.
Therapy adherence issues in Parkinson's disease
2010, Journal of the Neurological Sciences
The response to dopamine replacement therapy in patients with degenerative parkinsonism is variable. Reasons for a poor therapy response include the type of parkinsonism, comorbidities, and differential effects on clinical features. An additional explanation, which has received much less attention, is sub-optimal therapy compliance. Single and multicentre studies of therapy compliance report significant under- and overuse of dopamine replacement therapy resulting in poor symptomatic control, or features of the dopamine dysregulation syndrome or other signs of dopaminergic excess (dyskinesia, confusion, visual hallucinations). In this article, the evidence for sub-optical adherence in Parkinson's disease (PD) is reviewed, and factors associated with sub-optimal compliance were examined, with two case vignettes to illustrate clinical consequences of deviation from the prescribed therapy regimen.
Cabergoline and pramipexole fail to modify already established dyskinesias in an animal model of parkinsonism
2008, Behavioural Brain Research
Levodopa-induced dyskinesias are one of the major limiting side effects encountered in the treatment of Parkinson's disease. Dopamine agonists of the D2 family are less prone to induce these abnormal involuntary movements (AIMs), and in some instances it has been proposed that they could counteract them once already established. As differences in the plasma half-life of a given DA agonist could be related with a greater or lesser propensity to induce or to counteract AIMs, we compared the effects of two D2 agonists (cabergoline and pramipexole) with different half-lives, and levodopa, at doses producing similar improvement in purposeful forelimb use, in rats with severe nigrostriatal lesion, previously sensitized to levodopa. The same therapeutic regime was subsequently used in pharmacologically naïve rats. We found that: (i) prior induction of AIMs by levodopa administration primes rats for the occurrence of AIMs during mono-therapy with pramipexole (but not with cabergoline); (ii) an intervening period of D2 agonist mono-therapy does not modify the severity of AIMs induced by subsequent mono-therapy with levodopa; iii. de novo treatment with D2 agonists is associated with a lower risk of AIMs (regardless of the severity of the lesion) and does not modify AIMs during subsequent mono-therapy with levodopa. An unexpected finding was that prior levodopa therapy sensitized rats to the therapeutic effects of D2 agonists given in mono-therapy. In summary, the use of the rat with nigrostriatal lesion to model relevant therapeutic conditions does not support that D2 agonists prevent the development of AIMs during subsequent levodopa mono-therapy or can revert the dysfunction underlying it.
Early administration of entacapone prevents levodopa-induced motor fluctuations in hemiparkinsonian rats
2005, Experimental Neurology
The purpose of this study was to investigate the effect of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, in the reversal and prevention of “wearing-off” phenomena in hemiparkinsonian rats. Catechol-O-methyltransferase (COMT) inhibitors increase the half-life and bioavailability of levodopa, providing more continuous dopamine receptor stimulation. This raises the possibility of using levodopa and a COMT inhibitor not only to treat motor complications, but also to prevent their development. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily (b.i.d.), intraperitoneally (i.p.) for 22 days. On day 23, animals received either entacapone (30 mg/kg, i.p.) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg/day, i.p.) plus entacapone (30 mg/kg/day, i.p.) or levodopa (50 mg/kg/day, i.p.) plus vehicle, administered two or three times daily [b.i.d. or thrice daily (t.i.d.), respectively] for 22 consecutive days. Entacapone both reversed and prevented the shortening of the motor response duration that defines “wearing-off” motor fluctuations. Entacapone also decreased the frequency of failures to levodopa. The combination of levodopa and entacapone may reduce the likelihood of motor fluctuation development and may thus become a valuable approach to treat Parkinson disease whenever levodopa is needed.

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Short communicationEffect of chronic treatment of MPTP monkeys with dopamine D-1 and/or D-2 receptor agonists

Abstract

Brain Res.

European J. Pharmacol.

Dopaminergic mechanisms in hemiparkinsonian monkeys

Neurology

A primate model for parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine

Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity

Science

Short communication
Effect of chronic treatment of MPTP monkeys with dopamine D-1 and/or D-2 receptor agonists