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PubMed1992

Do NMDA receptor antagonists protect against MPTP-toxicity? Biochemical and immunocytochemical analyses in black mice.

We investigated whether excitatory amino acids acting at the N-methyl-D-aspartate (NMDA) subtype of the L-glutamate receptor contribute to the dopaminergic neurotoxicity induced by systemic administration of the Parkinson's syndrome-inducing toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl/6 mice. The MPTP-regimen chosen (30-40 mg/kg body weight subcutaneously) resulted a 60-70% depletion of striatal dopamine (DA) content and a 20% reduction of tyrosine hydroxylase immunoreactive (TH-IR) cells in the substantia nigra pars compacta 20 days after administration. Repeated systemic coadministration of the non-competitive NMDA receptor antagonist MK-801 or of the novel competitive NMDA receptor antagonist CGP 40116 did not protect against MPTP-induced striatal DA depletion 20 days after toxin administration. Additionally, no short-term protective effects of MK-801 on striatal DA content were observed 24, 48, and 96 h, respectively, after exposure to MPTP. A slight and non-significant attenuation (approximately 10%) of the MPTP-induced decrease in the number of nigral TH-IR cells was observed after MK-801- and CGP 40116-treatment. We conclude that neurotoxicity of systemically administered MPTP is not substantially antagonized by NMDA receptor antagonists in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
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↗
PubMed1995

Enhanced restoration of striatal dopamine concentrations by combined GM1 ganglioside and neurotrophic factor treatments.

Intraperitoneal injection of GM1 ganglioside or intracerebroventricular infusion of basic fibroblast growth factor (FGF-2) or epidermal growth factor (EGF) partially restored dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum of young MPTP-treated mice. Combined treatments of GM1 ganglioside with FGF-2 or EGF produced a greater restoration of striatal dopamine levels than treatments with GM1 or either of the neurotrophic factors alone. GM1 treatment, but not trophic factor treatments caused significant sparing of substantia nigra pars compacta (SNc) tyrosine hydroxylase (TH)-positive neurons. These results confirm previous findings that GM1 provides trophic support for damaged dopamine neurons and suggests that GM1, FGF-2, and EGF may also enhance dopaminergic function in residual neurons. The results also suggest that a potentially fruitful approach to treating degenerative disorders of the dopamine system may be the use of combined trophic factor therapies.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

On the regional distribution of heparan sulfate proteoglycan immunoreactivity in the rat brain.

By means of two monoclonal antibodies specific for heparan sulfate (HS)-related epitopes, one (10E4) against native HS chains and one (3G10) against desaturated uronates, a highly regional and differential distribution of these two epitopes have been observed in the adult rat brain. The 10E4 epitope immunoreactivity (IR) is mainly found in the substantia nigra, the red nucleus and the subgranular zone of the dentate gyrus, while the 3G10 epitope IR is mainly found in the CA2 area of the hippocampal formation and the pyramdial cells in the layer V of the frontoparietal cortex. The codistribution of both types of IRs with basic fibroblast growth factor (bFGF, FGF-2) in neurons and astroglia supports the notion that heparan sulfate proteoglycans (HSPG) in the extracellular matrix may serve as a site for storage of bFGF and assist in the bFGF-induced activation of the high-affinity FGF receptors linked to astroglia and neurons in these discrete areas.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

(+)MK-801 prevents the DDC-induced enhancement of MPTP toxicity in mice.

In order to reach deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, MK-801, a non-competitive antagonist of NMDA receptors, has been used as a tool to study the role of excitatory amino acids. In agreement with previous reports, (+)MK-801 did not significantly affect either striatal dopamine (DA) or tyrosine-hydroxylase (TH) activity in MPTP-treated animals. On the contrary (+)MK-801, but not (-)MK-801 significantly reduced the DDC + MPTP-induced fall in striatal DA and TH activity. A similar preventing effect on DA metabolites (DOPAC and HVA) and HVA/DA ratio was observed. The number of TH+ neurons in the substantia nigra (SN) of (+)MK-801-pretreated mice was not significantly different from that of control animals, indicating that this treatment specifically antagonized the extensive DDC-induced lesion of dopaminergic cell bodies in this brain area. (+)MK-801 treatment did not affect the DDC-induced changes of striatal MPP+ levels, suggesting that the observed antagonism of MK-801 against DDC is not due to MPP+ kinetic modifications. Pretreatment with the MAO-B inhibitor, L-deprenyl, or with the DA uptake blocker, GBR 12909, completely prevented the marked DA depletion elicited by DDC + MPTP within the striatum. Both treatments also protected from the fall in DA metabolites and TH activity as well. This indicates that DDC-induced potentiation is dependent upon MPP+ production and its uptake by the dopaminergic nerve terminals. All these findings suggest that NMDA receptors play a crucial role in the DDC-induced enhancement of MPTP toxicity.

1-Methyl-4-phenylpyridinium↗
PubMed1994

Locus coeruleus lesions potentiate neurotoxic effects of MPTP in dopaminergic neurons of the substantia nigra.

The observation that Parkinson's disease (PD) is associated with locus coeruleus (LC) noradrenergic neuronal degeneration suggests that the LC noradrenergic system may be involved in the pathogenesis and natural progression of the destruction of the substantia nigra (SN) dopaminergic neurons in Parkinson's disease. The relationship of these two systems was examined by injection of subtoxic doses of MPTP into unilateral LC 6-hydroxydopamine (6-OHDA) lesioned mice. A significant loss of dopaminergic cells was only found in the SN on the side of the LC lesions. These results suggest that the LC may have protective effects on SN dopaminergic neurons.

Animals↗
PubMed1995

Effect of MPTP on dopaminergic neurons in the goldfish brain: a light and electron microscope study.

The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes a Parkinsonian syndrome in the goldfish (Carassius auratus), characterized by transient bradykinesia, the accumulation of MPP+ in the brain, and a decrease in the forebrain and midbrain content of catecholamines (Pollard et al., FASEB J., 6 (1992) 3108-3116). Using light and electron microscopy, we studied the effect of MPTP on the distribution and ultrastructure of tyrosine hydroxylase (TH)-immunoreactive, dopaminergic neurons, and on the ultrastructure of other selected areas of the goldfish brain. Goldfish were treated with MPTP (50 mg/kg) in the absence or presence of L-deprenyl (10 mg/kg) or clorgyline (10 mg/kg). In the medial part of the central telencephalon, the nucleus telencephali, pars medialis, MPTP caused a decrease in the number of TH-immunoreactive neurons and distortions in their labelling pattern. Electron microscopic observations showed that MPTP caused swelling of cell processes, changes in neuronal nuclear profiles, dilation of endoplasmic reticulum, intracellular vacuolization and membrane distortions, and degeneration of neuronal fibers in this brain area. MPTP also caused a small reduction and some diffuseness in the labelling of dopaminergic neurons in several diencephalic periventricular nuclei. Moreover, MPTP induced cell swelling and degeneration in the subependymal cell layers along the forebrain ventricles. In all areas, L-deprenyl appeared to partially prevent the MPTP-induced degenerative changes. We conclude that in the goldfish MPTP causes marked histochemical changes in selected dopaminergic brain systems coincident with the Parkinson-like locomotor and neurochemical deficits.

Animals↗
PubMed1995

MPTP- and MPP(+)-induced effects on body temperature exhibit age- and strain-dependence in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is toxic toward the dopaminergic nigrostriatal system of a plethora of species including rodents, nonhuman primates and humans. The present study was designed to evaluate if systemic administration of MPTP or its metabolite, 1-methyl-4-phenylpyridinium ion (MPP+), has significant effects on body temperature (BT) and whether such effects might play a role in the neurotoxicity. A single intraperitoneal (i.p.) dose of either MPTP (50 mg/kg) or MPP+ (12.5 mg/kg) leads to a decrease in BT in both C57BL/6N (C57) and CD-1 mice. The hypothermia induced by MPTP can be blocked by pretreatment with deprenyl (30 mg/kg, i.p.), an MAO-B inhibitor. However, the hypothermia elicited by MPP+ is refractive to MAO-B inhibition. These findings suggest that MPP+ is responsible for the BT reduction and that the primary site of action lies outside the blood-brain barrier. An initial hyperthermic phase in the CD-1 mice, which leads to the induction of heat shock protein-72 (HSP-72) throughout the brain, differentiates their response to MPTP from that of C57 mice. This initial hyperthermia appears to be protective since its prevention by dosing at a low ambient temperature enhances striatal dopamine (DA) depletion in CD-1 mice. The temperature effects of both MPTP and MPP+ also display an age-dependence in the C57 strain of mice, with the magnitude of the effects correlating positively with age. However, profound hypothermia could be induced by MPP+ in the absence of striatal DA depletion. The latter finding suggests that while a positive correlation was found between age and the magnitude of the hypothermia, DA depletion and hypothermia are not causally related. The apparent protective effect of the initial hyperthermia in the CD-1 strain of mice, however, suggests that BT is an important parameter in the neurotoxicity of MPTP.

1-Methyl-4-phenylpyridinium↗
PubMed1996

Effects of testosterone upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system of C57/B1 mice.

We have recently reported that treatment of gonadectomized female and male C57/B1 mice with the gonadal steroid hormone, estrogen, reduced nigrostriatal dopaminergic neurotoxicity resulting from the Parkinson's-like inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the present report we examined whether the predominantly male gonadal steroid hormone, testosterone, would similarly modulate MPTP-induced neurotoxicity. Male C57/B1 mice were assigned to one of the following five treatment conditions: (1) Intact, (2) Orchidectomized, (3) Intact + MPTP, (4) Orchidectomized + Testosterone + MPTP and (5) Orchidectomized + MPTP. Corpus striatal and olfactory tubercle dopamine. DOPAC and norepinephrine concentrations were determined from the animals within each of the five treatment conditions. Orchidectomy alone failed to alter striatal dopamine and DOPAC concentrations, with levels obtained being similar to that of Intact animals. MPTP treatment significantly reduced striatal reduced striatal dopamine and DOPAC concentrations, regardless of hormonal condition of the animal. Similar results were obtained for olfactory tubercle determinations, with the exception that DOPAC levels from Orchidectomized mice were significantly greater than Intact males. No significant differences were obtained for norepinephrine within either brain area sampled. These results show that unlike estrogen, testosterone is devoid of any capacity to modulate nigrostriatal dopaminergic neurotoxicity resulting from MPTP. These findings may be related to the gender differences which exist in the prevalence of Parkinson's disease.

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

Behavioural effects and supersensitivity in the rat following intranigral MPTP and MPP+ administration.

Unilateral intranigral injections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ (1-methyl-4-phenylpyridine) were given to young rats and unilateral intranigral injections of MPTP were given to old rats. MPTP in old rats and MPP+ in young rats induced ipsiversive circling for at least one week after injection and contraversive circling after the systemic administration of apomorphine; the number of D-2 receptors (Bmax) in the striatum of the injected hemisphere increased compared with that of control rats. MPTP in young rats induced only short-lasting ipsiversive circling and no contraversive circling after apomorphine; the number of striatal D-2 receptors did not increase. These results suggest that the neurotoxicity of MPTP is age-dependent in the rat, and that MPTP has neurotoxic effects on the nigrostriatal dopaminergic system in old rats and induces dopamine receptor supersensitivity in the denervated striatum.

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

1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) is less neurotoxic than MPTP in the common marmoset.

Four adult marmosets were treated with increasing doses of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) in the range 0.23-4.3 mg/kg i.p. to give a cumulative dose of 11.0-11.6 mg/kg over a 6-10 day period. After 4 days of treatment, and as the dosage was gradually increased, the animals exhibited mild motor deficits. These abnormalities slowly declined over the following 1-6 week period. In contrast, similar treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p.) for 3-5 days in a cumulative dose of 6.9-9.2 mg/kg produced gross impairment of motor function which persisted throughout the 5 weeks period of observation. Administration of 2'-methyl-MPTP for 6-10 days caused some decrease in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), but not homovanillic acid (HVA) content in the caudate nucleus in animals 5-6 weeks after the start of treatment. There was a small decrease in [3H]dopamine uptake into putamen synaptosomes. This contrasted with the marked decreases in all these parameters observed after MPTP treatment of common marmosets. Histological examination of the substantia nigra from the four animals treated with 2'-methyl-MPTP did not show degeneration or loss of dopamine-containing cell bodies in the zona compacta. In contrast, MPTP caused severe destruction of these pigmented nigral neurones. In the common marmoset 2'-methyl-MPTP does not appear to show the same neurotoxic action as MPTP itself. This contrasts with findings in the mouse where 2'-methyl-MPTP is more toxic to dopamine-containing cells of substantia nigra than MPTP.

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

Differential recovery of dopamine synthetic enzymes following MPTP and the consequences of GM1 ganglioside treatment.

After 7 days of treatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), 30 mg/kg i.p., tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD) activities are decreased by more than 50% in the mouse striatum. Within 30 days, AAAD activity returns while TH activity remains depressed. TH activity can be restored to near normal by chronic treatment with GM1 ganglioside, 30 mg/kg i.p.

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

Effects of chronic treatment of MPTP monkeys with bromocriptine alone or in combination with SKF 38393.

Eight monkeys developed a severe parkinsonian syndrome after i.v. administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Treatment with bromocriptine (5 mg/kg) relieved the parkinsonian symptoms, but the efficacy of this treatment appeared to decrease slightly with time. The addition of SKF38393 (5 mg/kg) to the bromocriptine treatment in four monkeys prevented and even reversed the tendency to decreased efficacy with an increased response in three out of four animals. Neither of these two treatments induced dyskinesia in these monkeys. Dopamine D1 and D2 receptors, assayed in the caudate nucleus, the putamen and nucleus accumbens with [3H]SCH 23390 and [3H]spiperone binding respectively, were not significantly different in MPTP monkeys treated with bromocriptine or with bromocriptine plus SKF38393. Monkeys in the two treatment groups had a similar extent of denervation of the striatum and accumbens as assessed by the content of dopamine and its metabolites. These results suggest that in MPTP monkeys, the behavioral response to the D2 agonist bromocriptine can be enhanced by concomitant activation of the D1 receptors while this combination of agonists does not induce dyskinesia. The addition of the D1 agonist does not appear to cause further alteration of the D1 or D2 receptors.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Age-related effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets.

The effect of treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on juvenile (6-8 months), young adult (2-4 years) and aged (8-10 years) common marmosets were compared. Juvenile marmosets were more resistant to the actions of MPTP and required a greater cumulative dose over a longer period to induce the same degree of motor disability observed in older animals. Young adult and aged marmosets showed an equivalent motor recovery in the 4-5 weeks following cessation of MPTP treatment, but juvenile animals were less able to compensate for the motor impairments. Losses of putamen [3H]dopamine uptake and caudate nucleus dopamine content were equivalent in young adult and aged animals. However, juvenile animals showed a more marked degree of dopamine depletion and reduction in [3H]dopamine uptake. Histological analysis showed cell loss in the substantia nigra to be most prominent in juvenile animals although it was evident in all groups. No loss of cells in the locus coeruleus was apparent in any of the groups studied, and no intraneuronal eosinophilic inclusions were seen. Greater nigral cell loss and dopamine depletion were required in juvenile animals to impair motor function. The degree of behavioural recovery was less in juvenile animals than in young adult and aged marmosets. The extent of behavioural recovery appeared linked to the severity of cell loss and was not reduced in old age.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

The selective dopamine D1 receptor agonist, SKF 81297, stimulates motor behaviour of MPTP-lesioned monkeys.

The alleged selective, high efficacy dopamine D1 receptor agonist, SKF 81297 (0.05-0.3 mg/kg i.m.), induced rotational behaviour away from the lesion and stimulated use of the dominant right hand in unilaterally (left side) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys (Macaca mulatta). The effects of SKF 81297 were completely blocked by the dopamine D1 receptor antagonist, SCH 23390 (0.05 mg/kg), but not by the dopamine D2 receptor antagonist, remoxipride (1 mg/kg), and were similar to those induced by the selective dopamine D2 agonist, LY 171555 (0.01 mg/kg). These results suggest a functional stimulatory role for the dopamine D1 receptor on motor behaviour in a non-human primate model of Parkinson's disease when stimulated with a high efficacy selective dopamine D1 receptor agonist.

Analysis of Variance↗
PubMed1993

L-deprenyl confers specific protection against MPTP-induced Parkinson's disease-like movement disorder in the goldfish.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the goldfish causes a reversible, Parkinson's disease-like syndrome which includes loss of noradrenaline and dopamine from the brain, accumulation of the toxic metabolite 1-methyl-4-phenylpyridinium species (MPP+), and substantial reduction in movement. L-Deprenyl, a selective monoamine oxidase-B inhibitor, protects the goldfish from loss of movement, but clorgyline, a selective monoamine oxidase-A inhibitor, has no such protective action. L-Deprenyl and clorgyline primarily inhibit goldfish brain monoamine oxidase-B and monoamine oxidase-A, respectively. The mechanism by which MPTP causes reduced movement in goldfish is to cause an increase in resting time. Otherwise normal average velocity occurred during periods of movement. L-Deprenyl protection results in entirely 'normal' levels of resting time and average velocity during times of movement. Equivalent observations regarding l-deprenyl and clorgyline have been made in primate models of MPTP toxicity, and l-deprenyl is used for treatment of Parkinson's disease in humans. Therefore it is suggested that the evolutionarily equivalent subcortical circuitry and neural density of the goldfish brain may provide a useful model upon which to search for drugs relevant to human Parkinson's disease.

Animals↗
PubMed1994

Antiparkinsonian activity of talipexole in MPTP-treated monkeys: in combination with L-dopa and as chronic treatment.

We examined whether or not the antiparkinsonian activity of talipexole (B-HT 920, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) could be optimised by combination with L-3,4-dihydroxyphenylalanine (L-dopa). Additionally, the effects of chronic treatment with talipexole on motor behavior were investigated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and normal common marmosets. Administration of MPTP (0.5 mg/animal i.v. once or twice) to marmosets induced persistent parkinsonian motor deficits. The antiparkinsonian activity of talipexole (40 micrograms/kg s.c.) was significantly enhanced by its combination with L-dopa (30 mg/kg i.p.). This may further support the postulated postsynaptic dopamine D2 receptor agonist properties of talipexole. Chronic treatment with talipexole (a daily dose of 40 micrograms/kg s.c. for 21 days) did not lead to tolerance to the antiparkinsonian activity in MPTP-treated animals. No obvious dyskinesia was seen throughout the chronic treatment. In contrast, in normal marmosets, talipexole at a dose of 80 micrograms/kg which is a dose sufficient to induce hyperactivity did not increase motor activity during the treatment repeated for 21 days. These results suggest that talipexole is a selective dopamine D2 receptor agonist drug of potential use in the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Functional interaction between dopamine D1 and D2 receptors in 'MPTP' monkeys.

We have studied the motor response induced by independent administration of 4 different doses of a dopamine D2 [(+)-PHNO] and a dopamine D1 (CY 208-243) receptor agonist in 5 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkeys. Both drugs had similar antiparkinsonian effects and both elicited choreic dyskinesias. Simultaneous administration of (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine] and CY 208-243 [(-)4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3a-b]phenan thyxidine] did not result in modification of the dose-response curve induced by each dopamine receptor agonist given alone. Pretreatment with the dopamine D1 receptor antagonist SCH 23390 (0.8 mg/kg) and the dopamine D2 receptor antagonist sulpiride (60 mg/kg) reduced the magnitude and the duration of the motor response induced by (+)-PHNO and CY 208-243, respectively, but did not modify the intensity and characteristics of choreic dyskinesias. These results demonstrate that the motor effects and the dyskinesias cannot be dissociated by selective dopamine D1 and D2 receptor stimulation. It appears that stimulation of dopamine D1 and D2 receptors by endogenous dopamine is required to obtain the full motor response induced by selective dopamine receptor agonists as demonstrated by the reduction of the motor improvement found after pretreatment with SCH 23390 and sulpiride.

Animals↗