Striatal Dopamine Uptake Sites Research Articles

Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset.

The psychostimulant drug, modafinil, protects rodents against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, striatal ischemia and partial transection of the nigro-striatal pathway. We now report on the ability of modafinil to reverse motor disability in MPTP-treated common marmosets and to prevent MPTP-induced nigral cell death in this species. In the initial experiments, adult common marmosets were treated with MPTP to produce stable motor deficits. The subsequent administration of modafinil (10, 30 or 100 mg/kg/day, p.o.) produced a dose-dependent reversal of motor disability. In a subsequent experiment, normal common marmosets were concurrently treated with 10, 30 or 100 mg/kg of modafinil once daily by gavage during acute MPTP administration (daily for 5 days), continuing for 2 weeks after the last dose of MPTP. Modafinil dose-dependently prevented the decline in motor activity normally produced by MPTP treatment. MPTP treatment caused a 76% loss of nigral tyrosine-hydroxylase-immunoreactive cells in placebo-treated animals, and this was dose-dependently prevented by modafinil. At the highest dose (100 mg/kg/day) of modafinil, there was no significant loss of tyrosine-hydroxylase-immunoreactive cells in the substantia nigra compared with normal animals. MPTP treatment also reduced striatal dopamine uptake sites by 95%, as measured by specific [3H]-mazindol binding, compared with normal controls. Modafinil treatment dose-dependently reduced the loss of specific [3H]-mazindol binding. Behavioural and morphological evidence in the present study indicate a potential antiparkinsonian and neuroprotective role for modafinil, which may form a new pharmacological approach to the treatment of Parkinson's disease.

Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model

Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa-induced involuntary movements were compared in squirrel monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed > or =95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%-70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa-induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.

Reduction in number of dopamine uptake sites but unchanged number of piperazine-acceptor/CYP450IID6 binding sites in the human caudate nucleus in aging

A substantial decrease in number of striatal dopamine uptake sites is a characteristic finding in aging. This decrease resembles the dopaminergic nigro-striatal degeneration in Parkinson's disease (PD). A dysfunction of cytochrome P450IID6 (debrisoquine-4-hydroxylase) is suggested to be involved in the pathogenesis of PD. In this study, binding sites associated with the neuronal form of P450IID6 were studied in the caudate nucleus from individuals in the age range 20–81 years using [ 3H]GBR 12935 as a radioligand. No significant changes in binding parameters were obtained, while in the same region a significant decrease in number of dopamine uptake sites occurred. Thus, in aging, P450IID6 and dopaminergic degeneration seem not to be functionally related in this region. Whether such a relation exists in PD is still to be examined.

Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain: attenuation in CuZn-superoxide dismutase transgenic mice

Methamphetamine (METH) has long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system of rodents. METH-induced neurotoxicity is thought to involve release of DA in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. We have recently shown that METH-induced striatal DA depletion is attenuated in transgenic (Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme. That study did not specifically address the issue of loss of DA terminals. In the present study, we have used receptor autoradiographic studies of [ 125I]RTI-121-labeled DA uptake sites to evaluate the effects of several doses of METH on striatal DA terminals of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg mice, METH caused decreases in striatal DA uptake sites in a dose-dependent fashion. The loss of DA terminals was more prominent in the lateral region than in the medial subdivisions of the striatum. In SOD-Tg mice, the loss of DA terminals caused by METH was attenuated in a gene dosage-dependent fashion, with the homozygous mice showing the greatest protection. Female mice were somewhat more resistant than male mice against these deleterious effects of METH. These results provide further evidence for a role of superoxide radicals in the long-term effects of METH. They also suggest the notion of a gender-specific handling of oxidative stress.

Pharmacological modifications of dopamine transmission do not influence the striatal in vivo binding of [ 3H]mazindol or [ 3H]cocaine in mice

We have considered the in vivo striatal binding of two ligands of the neuronal dopamine uptake complex: [ 3H]cocaine and [ 3H]mazindol. The [ 3H]cocaine tracer dose labelled the dopamine uptake complex in striatum but not the noradrenaline complex in cerebellum. On the contrary, the [ 3H]mazindol tracer dose induced a marked labelling of the noradrenaline uptake complex in cerebellum; its prevention by desipramine (5 mg/kg) increased simultaneously the cerebral bioavailability and thereby the striatal labelling of the dopamine transporter. In mice submitted to treatments modifying dopaminergic transmission either to decrease it (gammabutyrolactone, 750 mg/kg, i.p.) or to increase it ( l-DOPA, 200 mg/kg, i.p., dexamphetamine, 4 mg/kg, s.c., or their combination), only dexamphetamine pretreatment significantly reduced [ 3H]cocaine and [3H]mazindol binding. Thus it appears that the level of dopamine transmission would not interfere with the in vivo quantification of striatal dopamine uptake sites assessed with either ligands.

Serotonin enhances striatal dopamine outflow in vivo through dopamine uptake sites.

Serotonin (5-HT) administered at 1, 3, and 10 microM into the striatum of halothane-anesthetized rats by in vivo microdialysis increased extracellular dopamine (DA) in a concentration-dependent manner (approximately 65, 190, and 440%, respectively). These effects were reduced by 50% in the presence of 1 microM tetrodotoxin (TTX) or in the absence of Ca2+ ions. The DA uptake blocker nomifensine (0.1 microM) significantly lowered (by 50%) the enhancement of DA outflow induced by 3 microM 5-HT. Nomifensine (1 microM) coperfused with 1 microM TTX abolished the 1 and 3 microM 5-HT-induced DA outflow, whereas the effect of 10 microM 5-HT was significantly reduced by 1 (-55%) and 10 micro M (-70%) nomifensine. These data demonstrate that, in vivo, striatal DA uptake sites are partially involved in the DA-releasing action of 5-HT.

Leukaemia inhibitory factor prevents injury induced proliferation of striatal dopamine uptake sites.

The injury associated with implantation of an inert gelatin matrix (gel foam) into normal mouse striatum induces a long-lived increase in binding of [3H]mazindol to presynaptic dopamine uptake sites, probably due to proliferation of striatal dopaminergic terminals. Because of the known effects of leukaemia inhibitory factor (LIF) on catecholaminergic cells, we tested the hypothesis that LIF may alter the striatal dopaminergic response to injury in vivo. Application of LIF to mouse striatum in a gel foam implant abolished the usual injury induced proliferation of dopamine uptake sites. The ability of LIF to prevent proliferation of dopamine terminals may have important implications for our understanding of neural regeneration, the aetiology of Parkinson's disease and its treatment by intrastriatal grafting.

Time-course of changes in striatal levels of DA uptake sites, DA D 2 receptor and preproenkephalin mRNAs after nigrostriatal dopaminergic denervation in the rat

Changes in striatal dopamine uptake sites, D 2 receptor and preproenkephalin (PPE) mRNA levels provoked by unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic (DA) pathway were studied by quantitative autoradiography and in situ hybridization (ISH) in rats sacrificed at different post-lesion delays. The disappearance of DA terminals as visualized with the labelling of dopamine uptake sites with [ 3H]GBR 12935 became significant 36 h after the lesion and was almost complete at a delay of 7 days. PPE mRNA amounts significantly increase (+24%) already at the shortest delay studied (9 h after the lesion) while the labelling of the uptake sites on DA terminals was not affected. The time course increase of PPE mRNA levels was progressive until 21 days post-lesion where it reached its maximum (+132%) and remained stable up to the latest delay studied (60 days). Conversely D 2 mRNA contents remained unchanged up to 5 days post-surgery and then increased relatively quickly since at 7 days post-lesion their levels were near (+21%) the maximum observed which was reached at 21 days post-lesion (+32%). This study suggests a time-dependent differential sensitivity to the degree of DA denervation of both major components implicated in the striatopallidal output.

Long-term changes in striatal opioid systems after 6-hydroxydopamine lesion of rat substantia nigra

The effects of unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway on striatal opioid peptides and receptors were determined at different time-intervals, from three days up to 24 weeks, post-lesion. Mu, delta and kappa opioid binding site densities in the ipsilateral caudate-putamen were decreased by 25–50% in rats which exhibited a greater than 90% loss of dopamine uptake sites. Differentiation of radioligand binding to kappa 1 and kappa 2 subtypes demonstrated a selective loss of kappa 2 sites post-lesion. The onset of significant 6-hydroxydopamine lesion-induced changes in striatal opioid binding sites was delayed with respect to the loss of dopamine uptake sites. Furthermore, maximal loss of dopamine uptake sites was apparent within seven days post-lesion, but not until two to four weeks for mu, delta and kappa sites. In animals which exhibited an incomplete loss of dopamine uptake sites (less than 80%) there was no significant change in opioid binding site density. Striatal proenkephalin and prodynorphin messenger RNA levels were increased and decreased, respectively, after complete 6-hydroxydopamine lesion. Modulation of peptide messenger RNA levels was apparent within seven days and was maintained up to 24 weeks post-lesion. In contrast, proenkephalin and prodynorphin messenger RNA levels were unchanged in animals which exhibited an incomplete loss of striatal dopamine uptake sites. Taken together, these observations suggest that the majority of mu, delta and kappa 2 opioid binding sites are localized on non-dopaminergic elements in the caudate-putamen, but that substantia nigra innervation plays a role in the control of striatal opioid receptor expression. The 6-hydroxydopamine lesion-induced decreases in striatal opioid binding site density may, in part, be a function of agonist-induced receptor downregulation. Alternatively, both opioid receptor and peptide expression in the caudate-putamen may be directly, but independently, regulated by ventral mesencephalic neurons.

MK-801, a non-competitive antagonist of NMDA receptor, prevents methamphetamine-induced decrease of striatal dopamine uptake sites in the rat striatum

We investigated the effects of MK-801, a non-competitive antagonist of NMDA receptor, on methamphetamine-induced decrease in dopamine (DA) uptake sites in the rat striatum. Repeated administrations of an escalating dose of methamphetamine (2.5, 5, 7.5. 10 mg/kg s.c. ×2, every other day for a week) produced decreased DA uptake sites assayed by binding with [ 3H]GBR 12935 in the striatum. Co-administration of MK-801 and methamphetamine significantly prevented the methamphetamine-induced decrease in striatal [ 3H]GBR 12935 binding. Administration of MK-801 alone did not affect [ 3H]GBR 12935 binding. These results suggest that some neurochemical effects of methamphetamine may be mediated via mechanism involving excitatory amino acids.

Effect of unilateral perinatal hypoxic-ischemic brain injury on striatal dopamine uptake sites and D 1 and D 2 receptors in adult rats

The effect of unilateral perinatal hypoxic-ischemic brain injury on striatal dopamine uptake sites and on D 2 and D 2 receptors was investigated in rat by using in vitro quantitative receptor binding autoradiography, 9–11 weeks after the insult. Saturation experiments revealed a significant 20% decrease in maximal binding capacity ( B max) for [ 3H]spiperone-labeled D 2 receptors on the side of the lesion in comparison to the non-lesioned contralateral side or to either side of control animals. There was no significant change in [ 3H]mazindol-labeled dopamine uptake sites or in [ 3H]SCH 23390-labeled D 1 receptor characteristics ( B max and K d) on the lesioned side. We conclude that the decrease in D 2 receptor binding previously observed in immature animals is persistent, whereas the decrease in D 1 binding is not.

Effect of estradiol and progesterone on rat striatal dopamine uptake sites

Striatal dopamine (DA) uptake sites labelled with [ 3H]GBR-12935 binding were investigated in ovariectomized (OVX) rats acutely treated with 17β-estradiol (E 2) or progesterone (P). One injection of E 2 (100 ng, SC) to OVX rats increased plasma levels of this steroid after 15 min while plasma prolactin (PRL) levels remained unchanged. The E 2 injection left striatal [ 3H]GBR-12935 binding affinity unchanged while the maximum density increased 15 and 30 min after the injection (+ 24% and +18%, respectively). One injection of P (110 μg, SC) to OVX rats increased this steroid plasma level from 15 to 120 min while plasma PRL levels remained unchanged. [ 3H]GBR-12935 binding density and affinity remained unchanged up to 120 min after the injection. Thus, acutely, E 2 but not P, modulated striatal DA uptake sites in OVX rats. The effect of E 2 appeared in coincidence with the peak of this steroid plasma concentration. This increase was rapid and is probably nongenomic and suggests a causal effect relationship as well as a presynaptic site of action of E 2.

Decreased density of human striatal dopamine uptake sites with age

Decreased density of human striatal dopamine uptake sites with age