Behavioral and Neurochemical Recovery from Partial 6-Hydroxydopamine Lesions of the Substantia Nigra Is Blocked by Daily Treatment with D1/D5, But Not D2, Dopamine Receptor Antagonists

Emmi, Adriana; Rajabi, Heshmat; Stewart, Jane

doi:10.1523/jneurosci.17-10-03840.1997

Cited by 12 publications

(7 citation statements)

References 54 publications

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“…Blocking glutamate activity for the first week after insult results in increased behavioral asymmetry and decreased extracellular DA (Emmi et al, 1996). Blockade of D1/D5 receptors in the same paradigm resulted in decreased behavioral sparing and decreased DA recovery (Emmi et al, 1997). In addition, glutamate was found to play a crucial role in our previous work showing exaggeration of cortical injury caused by forced use.…”

Section: Discussionmentioning

confidence: 65%

Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine

Tillerson¹,

Cohen²,

et al. 2001

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Rats with unilateral depletion of striatal dopamine (DA) show marked preferential use of the ipsilateral forelimb. Previous studies have shown that implementation of motor therapy after stroke improves functional outcome (Taub et al., 1999). Thus, we have examined the impact of forced use of the impaired forelimb during or soon after unilateral exposure to the DA neurotoxin 6-hydroxydopamine (6-OHDA). In one group of animals, the nonimpaired forelimb was immobilized using a cast, which forced exclusive use of the impaired limb for the first 7 d after infusion. The animals that received a cast displayed no detectable impairment or asymmetry of limb use, could use the contralateral (impaired) forelimb independently for vertical and lateral weight shifting, and showed no contralateral turning to apomorphine. The behavioral effects were maintained throughout the 60 d of observation. In addition to the behavioral sparing, these animals showed remarkable sparing of striatal DA, its metabolites, and the expression of the vesicular monoamine transporter, suggesting a decrease in the extent of DA neuron degeneration. Behavioral and neurochemical sparing appeared to be complete when the 7 d period of immobilization was initiated immediately after 6-OHDA infusion, only partial sparing was evident when immobilization was initiated 3 d postoperatively, and no sparing was detected when immobilization was initiated 7 d after 6-OHDA treatment. These results suggest that physical therapy may be beneficial in Parkinson's disease.

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Section: Discussionmentioning

confidence: 65%

Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine

Tillerson¹,

Cohen²,

et al. 2001

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“…We have found that recovery can be blocked by daily injections of NMDA antagonists given during the first week after injury (Emmi et al, 1996), making it appear that the compensatory changes in the remaining DA neurons are stimulated, at least in part, by glutamatergic activity. These findings suggest some similarity between the compensatory mechanisms seen after 6-OHDA lesions and those that underlie amphetamine-induced sensitization (Emmi et al, 1996(Emmi et al, , 1997. This idea is made more compelling by the fact that both after 6-OHDA lesions and after repeated exposure to amphetamine there is a sustained increase in astrocytic bFGF-IR in the SNc and VTA.…”

Section: Discussionmentioning

confidence: 88%

Long-Lasting Induction of Astrocytic Basic Fibroblast Growth Factor by Repeated Injections of Amphetamine: Blockade by Concurrent Treatment with a Glutamate Antagonist

1998

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Repeated administration of stimulant drugs leads to lasting changes in their behavioral and neurochemical effects. These changes are initiated by drug actions in the somatodendritic regions of midbrain dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) and continue to develop for a period of time after termination of drug treatment. Here we show that repeated administration of amphetamine (3.0 mg/kg, i.p.; three injections, once every other day) results in sustained increases in basic fibroblast growth factor immunoreactivity (bFGF-IR) in both VTA and SNc, 200-500% over that seen in saline-treated animals. Increases were observed 24 hr, 72 hr, 1 week and 1 month after the last drug injection. Because glutamate participates in the development of sensitization to stimulant drugs, we assessed the effect of the glutamate antagonist, kynurenic acid (KYN), on amphetamineinduced bFGF-IR. Coadministration of KYN prevented the increases in bFGF-IR in both VTA and SNc assessed 1 week after the amphetamine treatment. No changes in bFGF-IR were observed in the nucleus accumbens or dorsal striatum. bFGF-IR was found to be associated with astrocytes and not with dopaminergic neurons. These findings suggest that sustained enhancement of astrocytic bFGF expression in DA somatodendritic regions is a mechanism whereby stimulant drugs exert enduring effects on midbrain DA function. We hypothesize that increased glutamatergic activity elicited by amphetamine and other stimulant drugs places excessive demands on the functioning of DA neurons recruiting regulatory and neuroprotective processes that lead to enduring changes in DA neuron functioning and connectivity.

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“…Unilateral DA denervation by 6-OHDA injection into the substantia nigra blocks cortical striatal LTP in rats (Centonze et al, 1999b), providing direct evidence that the nigrostriatal dopamine system is required for the expression of corticostriatal LTP. The subtype specificity in the striatum seems to be the same as in the hippocampus, in which the D1 receptor activation augments LTP (Emmi et al, 1997). Because the hippocampus receives DA innervation from the ventral tegmental area and the substantia nigra (Gasbarri et al, 1994;Goldsmith and Joyce, 1994), it would be interesting to see whether hippocampal LTP is affected and/or restored by GPI-1046 treatment as well.…”

Section: Discussionmentioning

confidence: 99%

Regeneration of Dopaminergic Function in 6-Hydroxydopamine-Lesioned Rats by Neuroimmunophilin Ligand Treatment

Zhang

Steiner²,

Hamilton

et al. 2001

J. Neurosci.

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Nonimmunosuppressant immunophilin ligands have been found previously to stimulate neurite growth in culture and to promote regeneration of peripheral and central nerve fibers in vivo. To further characterize the effectiveness of these ligands, we have investigated the effect of the immunophilin ligand GPI-1046 in 6-hydroxydopamine (6-OHDA)-lesioned rats. In unlesioned rats, tetanic stimulation of the white matter induced long-term potentiation (LTP) of corticostriatal synaptic transmission as indicated by a 40-100% increase in the field potential amplitudes recorded in striatal brain slices. Unilateral microinjection of 6-OHDA into the substantia nigra resulted in a loss of corticostriatal LTP and in significant abnormality of motor behavior as assessed by amphetamine-induced ipsilateral rotations. Daily treatment of 6-OHDA-lesioned rats with GPI-1046 (10 mg/kg, s.c.) for 1 week reduced amphetamineinduced rotations by 75% and greatly restored the striatal tyrosine hydroxylase immunostaining. In addition, GPI-1046 almost completely restored corticostriatal LTP in 6-OHDAlesioned animals. LTP in normal animals and that restored by GPI-1046 in lesioned animals were both blocked by the NMDA receptor antagonist APV, suggesting mediation by NMDA receptors. Both LTPs were sensitive to dopamine (DA) receptor antagonists. The nonselective DA receptor antagonist chlorpromazine and the selective D1-D5 receptor antagonist SCH23390 reduced the LTP by 90%. These results demonstrate that the immunophilin ligand GPI-1046 can reverse the abnormalities in the substantia nigra-striatal dopaminergic system that are caused by 6-OHDA, thus providing a potential therapeutic agent for Parkinson's disease. Key words: 6-OHDA; LTP; striatum; dopamine; substantia nigra; Parkinson's diseaseParkinson's disease (PD) has been a focus of intense study since it was first characterized more than a century ago. The pathophysiological basis of PD is the degeneration of the nigrostriatal dopaminergic system. Although replenishment of dopamine (DA) in the brain by administration of the DA precursor L-3,4-dihydroxyphenylalanine has shown a certain usefulness in the treatment of PD, this treatment is at best palliative and does not address the underlying pathophysiology. A more desirable treatment would be the restoration of the dopaminergic system. To this end, cell-replacement therapy has been attempted with varying degrees of success. However, ethical concerns (using human fetal tissue) as well as cross-infection issues from xenotransplantation (from pig tissue) have limited this treatment strategy.The search for PD treatments has received a boost from recent studies showing that immunophilin ligands such as GPI-1046 regenerate brain tissue in a number of neurodegenerative models (Steiner et al., 1997b). Immunophilins are a family of small protein molecules, of which FK506 binding proteins (FKBPs) and cyclophilins are members. They serve as cytosolic receptors for immunosuppressant drugs (e.g., FK506) and create a complex that binds to and inhibits t...

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Behavioral and Neurochemical Recovery from Partial 6-Hydroxydopamine Lesions of the Substantia Nigra Is Blocked by Daily Treatment with D1/D5, But Not D2, Dopamine Receptor Antagonists

Cited by 12 publications

References 54 publications

Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine

Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine

Long-Lasting Induction of Astrocytic Basic Fibroblast Growth Factor by Repeated Injections of Amphetamine: Blockade by Concurrent Treatment with a Glutamate Antagonist

Regeneration of Dopaminergic Function in 6-Hydroxydopamine-Lesioned Rats by Neuroimmunophilin Ligand Treatment

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