L‐DOPA‐induced modulation of GABA and glutamate release in substantia nigra pars reticulata in a rodent model of Parkinson's disease

Ochi, Minoru; Shiozaki, Shizuo; Kase, Hiroshi

doi:10.1002/syn.20006

Cited by 21 publications

(12 citation statements)

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“…Therefore, the administration of exogenous GABA may further reduce this impact by dampening ERK1/2 phosphorylation, as found in this study. speculated that the increase in GABA release in the SNr following L-DOPA administration may be attributed to the amelioration of PD symptoms by L-DOPA rather than the induction of the dyskinetic side effect [33]. Additional reports show that, independent of L-DOPA, local activation of GABA-A receptors in the striatum or SNr provides beneficial effects.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, vesicular GABA transporter (vGAT) mRNA codes for a protein responsible for regulating GABA release via synaptic vesicles; levels of vGAT mRNA were reported to be decreased in the DA denervated striatum, and increased following subchronic L-DOPA administration [35]. The SN also displays changes in GABA transmission following D1 activation [33,[36][37][38]. The substantia nigra pars compacta (SNc) contains the majority of DA neurons with dendrites extending to the SN pars reticulata (SNr), which primarily contains GABA projection neurons [60] lacking postsynaptic DA receptors [64].…”

Section: Discussionmentioning

confidence: 99%

“…This GABAergic modulation in the direct DA pathway of the basal ganglia leads to the facilitation of movement via inhibition of MSNs in the SN followed by disinhibition of thalamocortical neurons, whereas activation in the indirect DA pathway leads to the suppression of movement via the inhibition of thalamocortical neurons [16,21,[29][30]. Numerous reports have found that DA imbalance indeed influences GABA transmission [32][33][34][35][36][37][38]. However, the role of GABA in DA-mediated effects as far downstream as ERK1/2 has yet to be evaluated.…”

Section: Introductionmentioning

confidence: 99%

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GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

Lynch¹,

Sivam²

2013

JBBS

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L-DOPA is the primary drug used to treat Parkinson's disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the basal ganglia to induce extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pair of MAP-kinase proteins that may be involved in induction of motor side effects. Since GABA is known to be intimately involved in basal ganglia function, we investigated whether elevating GABA levels via a GABA-transaminase (GABA-T) inhibitor affects the L-DOPA-induced ERK1/2 phosphorylation in the striatum and substantia nigra (SN) using a rat model of PD. Unilateral dopaminergic lesions of median forebrain bundle neurons were done using the neurotoxin 6-hydroxydopamine. Rats were prescreened for the extent of the lesion by apomorphine-induced rotation test. Lesioned rats were treated with aminooxyacetic acid (AOAA, a GABA-T inhibitor), L-DOPA, or in combination. Immunohistochemistry of tyrosine hydroxylase (TH, a direct indicator of dopaminergic lesion), substance P (SP, an indirect marker that decreases after lesion), and phospho-ERK1/2 was done using slices at the level of striatum and SN. Unilateral dopaminergic lesioned rats, as expected, exhibited >90% TH loss and a modest SP loss in the striatum and SN. L-DOPA alone induced a 343% and 330% increase in phospho-ERK1/2 in the striatum and SN, respectively. We report here a novel finding that pretreatment with AOAA attenuated the L-DOPA induced increase in phospho-ERK1/2 by 62% and 68% in the striatum and SN, respectively, suggesting a DA-GABA-ERK1/2 link in the therapeutic and/or side effects of L-DOPA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

Lynch¹,

Sivam²

2013

JBBS

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“…However, we propose that the mechanism of action of immepip in reducing dyskinesia may reflect an interaction with glutamatergic and GABAergic transmission within the basal ganglia. It has been suggested that a primary mechanism related to the appearance of L ‐dopa–induced dyskinesia is an overactivity of the direct striatal output pathway due to increased corticostriatal glutamatergic10, 11, 46 and striatonigral GABAergic projections 47, 48. Within the basal ganglia, H3 receptors are expressed on striatal glutamatergic nerve terminals19, 20 and on GABAergic nerve terminals32 from the direct pathway, where they inhibit glutamatergic and GABAergic release, respectively.…”

Section: Discussionmentioning

confidence: 99%

Histamine H3 receptor agonists reduce L‐dopa–induced chorea, but not dystonia, in the MPTP‐lesioned nonhuman primate model of Parkinson's disease

et al. 2006

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L-dopa-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease. The neural mechanisms underlying LID are thought to involve overactivity of striatal glutamatergic neurotransmission, with resultant underactivation of the output regions of the basal ganglia. Histamine H3 heteroreceptors can reduce glutamate and gamma-aminobutyric acid (GABA) transmission in the striatum and substantia nigra reticulata, respectively. Thus, we tested whether the histamine H3 receptor agonists immepip and imetit can alleviate LID in the MPTP-lesioned marmoset model of Parkinson's disease. Coadministration of immepip (1 mg/kg) with L-dopa (15 mg/kg) was associated with significantly less total dyskinesia than L-dopa alone. When dyskinesia was separately rated as chorea and dystonia, coadministration of L-dopa with either immepip or imetit (both 10 mg/kg) significantly reduced chorea but had no effect on dystonia. The antidyskinetic actions of the H3 agonists were not accompanied by alteration of the antiparkinsonian actions of L-dopa. However, immepip (10 mg/kg), when administered as monotherapy, significantly increased parkinsonian disability compared to vehicle. Overall, the results obtained in this study suggest that histamine H3 receptors may be involved in the neural mechanisms underlying L-dopa-induced dyskinesia in Parkinson's disease.

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“…In turn, it projects to thalamic motor nuclei where it inhibits the activity of thalamocortical neurons, and to various brain stem motor areas (Bolam et al, 2000;Parent and Hazrati, 1995). Recent studies demonstrated that L-Dopa administration in animals with a unilateral 6-OHDA lesion as a model of Parkinson's disease (PD) increases extracellular GABA levels in the ipsilateral SNr (Ochi et al, 2004;Yamamoto et al, 2006). Furthermore, it was shown that L-Dopa treatment increases glutamic acid decarboxylase (GAD; GABA synthesizing enzyme) mRNA expression in striatonigral neurons (Carta et al, 2003;Cenci et al, 1998;Katz et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Normalization of GABA_A receptor specific binding in the substantia nigra reticulata and the prevention of L‐dopa‐induced dyskinesias in MPTP parkinsonian monkeys

Samadi¹,

Morissette²,

Tahar³

et al. 2007

Synapse

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L-Dopa therapy in Parkinson's disease (PD) is counfounded by the development of involuntary movements such as L-Dopa-induced dyskinesias (LIDs). In this study GABA(A) receptor autoradiography was assessed using [(3)H]flunitrazepam binding to the benzodiazepine site of the GABA(A) receptor and [(35)S]t-butylbicyclophosphorothionate (TBPS) binding to the chloride channel of GABA(A) receptors in the substantia nigra reticulata (SNr) and subthalamic nucleus (STN). L-Dopa-treated parkinsonian monkeys experiencing LIDs were compared to animals in which LIDs was prevented by adjunct treatments with CI-1041, a selective antagonist of the NR1A/2B subtype of NMDA receptor, or low doses of the dopamine D2 receptor agonist, cabergoline. Our results demonstrated a decrease of GABA(A) receptor specific binding in the posterior part of the SNr in dyskinetic monkeys compared to nondyskinetic animals, while no modulation has been observed in the STN. These results provide evidence for the first time that pharmacological treatments preventing LIDs in nonhuman primate model of PD are associated with normalization of GABA(A) receptor-mediated signalling in the SNr.

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L‐DOPA‐induced modulation of GABA and glutamate release in substantia nigra pars reticulata in a rodent model of Parkinson's disease

Cited by 21 publications

References 13 publications

GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

Histamine H3 receptor agonists reduce L‐dopa–induced chorea, but not dystonia, in the MPTP‐lesioned nonhuman primate model of Parkinson's disease

Normalization of GABA_A receptor specific binding in the substantia nigra reticulata and the prevention of L‐dopa‐induced dyskinesias in MPTP parkinsonian monkeys

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L‐DOPA‐induced modulation of GABA and glutamate release in substantia nigra pars reticulata in a rodent model of Parkinson's disease

Cited by 21 publications

References 13 publications

GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

Histamine H3 receptor agonists reduce L‐dopa–induced chorea, but not dystonia, in the MPTP‐lesioned nonhuman primate model of Parkinson's disease

Normalization of GABAA receptor specific binding in the substantia nigra reticulata and the prevention of L‐dopa‐induced dyskinesias in MPTP parkinsonian monkeys

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Normalization of GABA_A receptor specific binding in the substantia nigra reticulata and the prevention of L‐dopa‐induced dyskinesias in MPTP parkinsonian monkeys