Contribution of the striatum to the effects of 5‐HT1A receptor stimulation in L‐DOPA‐treated hemiparkinsonian rats

Bishop, Christopher; Krolewski, David M.; Eskow, Karen L.; Barnum, Christopher J.; Dupre, Kristin B.; Deak, Terrence; Walker, Paul D.

doi:10.1002/jnr.21978

Cited by 77 publications

(88 citation statements)

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“…However, because they do not express D2 autoreceptors and DA transporter, which are essential for the normal autoregulatory feedback control of DA release from the presynaptic terminal, their activity leads to uncontrolled swings in extracellular DA concentrations (31). Importantly, it has been recently shown that DA released from 5-HT terminals was responsible for the appearance of LIDs in parkinsonian rats (32). Furthermore, either a lesion of 5-HT system by specific toxins, or pharmacological silencing of these neurons by selective 5-HT1A and 5-HT1B agonists dramatically reduced or even completely abolished LIDs in 6-OHDA le-A B C Fig.…”

Section: Discussionmentioning

confidence: 99%

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Ulusoy

Şahin

Kirik

2010

Proc. Natl. Acad. Sci. U.S.A.

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Drug-induced dyskinesias in dopamine-denervated animals are known to depend on both pre-and postsynaptic changes of the nigrostriatal circuitry. In lesion models used thus far, changes occur in both of these compartments and, therefore, it has not been possible to dissect the individual contribution of each compartment in the pathophysiology of dyskinesias. Here we silenced the nigrostriatal dopamine neurotransmission without affecting the anatomical integrity of the presynaptic terminals using a short-hairpin RNA-mediated knockdown of tyrosine hydroxylase enzyme (shTH). This treatment resulted in significant reduction (by about 70%) in extracellular dopamine concentration in the striatum as measured by on-line microdialysis. Under these conditions, the animals remained nondyskinetic after chronic L-DOPA treatment, whereas partial intrastriatal 6-hydoxydopamine lesioned rats with comparable reduction in extracellular dopamine levels developed dyskinesias. On the other hand, apomorphine caused moderate to severe dyskinesias in both groups. Importantly, singledose L-DOPA challenge in apomorphine-primed shTH animals failed to activate the already established abnormal postsynaptic responses. Taken together, these data provide direct evidence that the status of the presynaptic, DA releasing compartment is a critical determinant of both the induction and maintenance of L-DOPA-induced dyskinesias.reatment-induced motor complications are a major problem in management of patients suffering from Parkinson's disease (PD) (1). Dyskinesias induced by L-DOPA, in particular, constitute a significant challenge that impacts a higher proportion of the treated patients with treatment duration. Essentially all patients are expected to develop dyskinesias within a decade from onset of treatment (2). The underlying mechanisms of L-DOPA-induced dyskinesias (LIDs) are still not fully understood. Current views suggest that both presynaptic (i.e., production, storage, controlled release, and reuptake of dopamine by nigrostriatal dopaminergic neurons) and postsynaptic (i.e., status of receptors and second messenger signaling pathways in striatal neurons) components are critical in induction and maintenance of dyskinesias (3-5). However, the destruction of the presynaptic dopamine (DA) terminals, typically obtained by administration of a specific neurotoxin in animals, and the plastic changes induced in the postsynaptic striatal neurons occur at the same time. Moreover, synaptic changes secondary to chronic drug treatment further complicate the interpretation of the observations made in studies using animal models of PD (4-6).The aim of this study was to tease apart the contribution of the pre-and postsynaptic compartments in the pathophysiology of LIDs in the parkinsonian brain. The abnormal response of the striatal neurons to DA receptor stimulation following chronic DA depletion could be determined solely by mechanisms intrinsic to the striatal cells or alternatively, the functional activity of the presynaptic compartment could determin...

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Section: Discussionmentioning

confidence: 99%

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Ulusoy

Şahin

Kirik

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In DA-depleted striatonigral neurons, L-DOPA and D1R agonists increase dynorphin/PPD, GAD65, and GAD67 gene expression 7,28,32,43,44 and these changes are positively correlated with dyskinesia. 7,28,32 Corroborating previous reports, treatment with SKF81297 on test day induced pronounced dyskinesia ( Figure 2A) and augmented PPD, GAD65, and GAD67 mRNA in the DA-depleted striatum compared to vehicle treatment ( Figure 2C−E).…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

“…28,31,32 As such, increases in PPD and GAD mRNA in the DA-depleted striatum in dyskinetic states are often associated with activation D1R and the direct pathway. Interestingly, 5-HT 1A R agonism has been shown to attenuate L-DOPA-induced increases in striatal dynorphin/ PPD and GAD mRNA, 7,32 suggesting 5-HT 1A R stimulation may reduce striatal D1R activity in LID.…”

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Effects of 5-HT_1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

Dupre

Ostock

George

et al. 2013

ACS Chem. Neurosci.

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Accumulating evidence supports the value of 5-HT 1A receptor (5-HT 1A R) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson's disease (PD). Yet, how 5-HT 1A R stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT 1A R agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT 1A R antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT 1A R stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT 1A R agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT 1A R stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT 1A R agonists for the treatment of dyskinesia.

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“…Several lines of evidence have shown that 5-HT1A receptors play an important role in controlling motor functions and ameliorate various extrapyramidal disorders such as PD (5)(6)(7)(8)(9) and L-DOPA-induced motor disabilities (10)(11)(12)(13). In addition, 5-HT1A receptors are implicated in the pathogenesis and treatment of mood disorders (anxiety/ depression) (8).…”

Section: Introductionmentioning

confidence: 99%

Deficits in Striatal Dopamine and Hippocampal Serotonin Following Induction of Anxiety/Depressive-Like Behaviors by Bisphenol A

Jia

Pittman

2014

Arch Neurosci

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Background: Anxiety and depression are common nonmotor symptoms of Parkinson's disease (PD). Objectives: We investigated whether Bisphenol A (BPA) is capable of inducing anxiety/depressive-like behaviors and neurotransmitter alterations that are similar to those observed in PD. Materials and Methods:To test this hypothesis, we used a zebrafish animal model and conducted behavioral and histological assays. Results: BPA produced anxiety/depression-like behavioral signs for 14 days following administration. Altered behavioral responses were accompanied by reductions of striatal dopamine transporter, and decrease in hippocampal 5-HT content. Conclusions: These results suggest that the nigrostriatal pathway might play a role in the etiology of anxiety/depression. Furthermore, dopamine transporter function, in particular, might play a critical role in the pathophysiology of anxiety/depression.

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Contribution of the striatum to the effects of 5‐HT1A receptor stimulation in L‐DOPA‐treated hemiparkinsonian rats

Cited by 77 publications

References 69 publications

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Effects of 5-HT_1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

Deficits in Striatal Dopamine and Hippocampal Serotonin Following Induction of Anxiety/Depressive-Like Behaviors by Bisphenol A

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Contribution of the striatum to the effects of 5‐HT1A receptor stimulation in L‐DOPA‐treated hemiparkinsonian rats

Cited by 77 publications

References 69 publications

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Effects of 5-HT1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

Deficits in Striatal Dopamine and Hippocampal Serotonin Following Induction of Anxiety/Depressive-Like Behaviors by Bisphenol A

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Effects of 5-HT_1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats