Tyrosine hydroxylase-like immunoreactive neurons in the striatum of the rat

doi:10.1016/0304-3940(89)90130-4

Neuroscience Letters

Volume 97, Issues 1–2, 13 February 1989, Pages 6-10

https://doi.org/10.1016/0304-3940(89)90130-4 Get rights and content

Abstract

Striatal neurons exhibiting tyrosine hydroxylase-like immunoreactivity (TH-LI) were found in the adult rat. Most of these neurons had a cell body with a 10–20 μm diameter and several spiny dendrites. The number of striatal neurons with TH-LI was increased on the side ipsilateral to an electrothermic or 6-hydroxydopamine-induced lesion which had been placed in the regions around the substantia nigra.

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Since the late 80s it has been repeatedly shown that besides dopaminergic neurons, the brain contains so-called monoenzymatic neurons possessing one of the enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC). However, the data on the existence of monoenzymatic neurons in the striatum remain controversial, and little is known about their functional significance. The aim of this study was to test our hypothesis that monoenzymatic TH-containing neurons produce DA in cooperation with the neurons containing AADC, which might help to compensate DA deficiency under the failure of the nigrostriatal dopaminergic system. Using a combination of techniques: retrograde tracing, qPCR and immunolabeling for TH, AADC and MAP2, we showed that the striatum of mice with normal and degraded dopaminergic system comprises of monoenzymatic TH- and AADC-containing neurons. To provide evidence for cooperative synthesis of DA, we used an ex vivo model of inhibiting of DA synthesis by blocking transport of l-DOPA, produced in monoenzymatic TH-containing neurons, to neurons containing AADC by means of l-leucine, a competitive inhibitor of the membrane transporter of large neutral amino acids, and l-DOPA. With this original approach, cooperative synthesis of DA in the striatum was proven in MPTP-treated mice but not in the control. Furthermore, we demonstrated that the proportion of DA produced through cooperative synthesis in the striatum of MPTP-treated mice increases as the degradation of dopaminergic system proceeds. An increase in the proportion of cooperative synthesis of DA alongside degradation of the dopaminergic system is also proved by an increase of both TH gene expression and the number of TH-immunoreactive structures in the striatum. Thus, these data suggest that the cooperative synthesis of DA in the degraded striatum is an up-regulated compensatory reaction, which plays an increasing role as DA deficiency rises, and might be considered among the principal mechanisms of neuroplasticity in neurodegenerative diseases.
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l-3,4-Dihydroxyphenylalanine (l-DOPA) is the therapeutic gold standard in Parkinson’s disease. However, most patients develop debilitating abnormal involuntary movements termed l-DOPA-induced dyskinesia (LID) as therapy-complicating side effects. The underlying mechanisms of LID pathogenesis are still not fully understood. Recent evidence suggests an involvement of striatal tyrosine hydroxylase (TH) protein-expressing neurons, as they are capable of endogenously producing l-DOPA and possibly dopamine. The aim of this study was to elucidate changes of TH transcription in the striatum and nucleus accumbens that occur under experimental conditions of LID.
Mice with a unilateral 6-hydroxydopamine-induced lesion of the medial forebrain bundle were treated daily with l-DOPA for 15 days to provoke dyskinesia. In situ hybridization analysis revealed a significant numerical decrease of TH mRNA-positive neurons in the striatum and nucleus accumbens of mice not exhibiting LID, whereas dyskinetic animals failed to show this reduction of TH transcription. Interestingly, similar changes were observed in intact non-deafferentiated striata, demonstrating an l-DOPA-responsive transcriptional TH regulation independently from nigrostriatal lesion severity.
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Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice
2015, Neuroscience
Citation Excerpt :
In the predecessor work of the current study, it was shown that TH+ neurons exist in target areas of DAergic ventral midbrain neurons - striatum, nucleus accumbens and cortex – in mice, and that they increase in number following DAergic deafferentiation induced by 6-OHDA lesion of the MFB (Depboylu, 2014; Depboylu et al., 2014). Such compensatory numerical increment upon DAergic denervation has previously only been reported for TH+ neurons in the striatum (Tashiro et al., 1989; Betarbet et al., 1997; Meredith et al., 1999; Lopez-Real et al., 2003), based on initiated TH expression in GABAergic interneurons or projection neurons of the direct and indirect pathways (Tandé et al., 2006; Darmopil et al., 2008). In this study we further reported a significant increase of striatal TH+ cell numbers in L-DOPA-treated mice when compared to saline-treated animals.
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the therapeutic gold standard in Parkinson’s disease. However, long-term treatment is complicated by the induction of debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesias (LIDs). Until today the underlying mechanisms of LID pathogenesis are not fully understood. The aim of this study was to reveal new factors, which may be involved in the induction of LID. We have focused on the expression of striatal tyrosine hydroxylase-positive (TH+) neurons, which are capable of producing either L-DOPA or dopamine (DA) in target areas of ventral midbrain DAergic neurons.
To address this issue, a daily L-DOPA dose was administered over the course of 15 days to mice with unilateral 6-hydroxydopamine-induced lesions of the medial forebrain bundle and LIDs were evaluated. Remarkably, the number of striatal TH+ neurons strongly correlated with both induction and severity of LID as well as ΔFosB expression as an established molecular marker for LID. Furthermore, dyskinetic mice showed a marked augmentation of serotonergic fiber innervation in the striatum, enabling the decarboxylation of L-DOPA to DA. Axial, limb and orolingual dyskinesias were predominantly associated with TH+ neurons in the lateral striatum, whereas medially located TH+ neurons triggered locomotive rotations. In contrast, identified accumbal and cortical TH+ cells did not contribute to the generation of LID.
Thus, striatal TH+ cells and serotonergic terminals may cooperatively synthesize DA and subsequently contribute to supraphysiological synaptic DA concentrations, an accepted cause in LID pathogenesis.
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Dopamine replacement therapy effectively relieves the typical motor features of Parkinson disease (PD), but it can cause complications that limit its utility. Dyskinesia (abnormal involuntary movements) and motor fluctuations (abrupt changes in the patients’ motor status) occur in most PD patients after a few years of 3,4-dihydroxyphenyl-l-alanine (l-DOPA) pharmacotherapy. Animal models reproducing these motor complications can be obtained in mice and rats if the nigrostriatal dopamine pathway is severely damaged. Within the large arsenal of neurotoxic and genetic models of PD, rodents with unilateral 6-hydroxydopamine lesions have the best characteristics for the sake of modeling l-DOPA-induced dyskinesia. When treated chronically with high doses of l-DOPA, these rodent models may also display motor response alterations reminiscent of the wearing-off fluctuations that occur in PD patients. Because of research performed on these animal models, our understanding of the molecular and biochemical mechanisms of l-DOPA-induced dyskinesia has made great advances, and several pharmacological approaches to treatment have been recently identified and successfully tested in proof-of-concept trials in PD patients. It is now well recognized that dopaminergic therapies for PD also cause nonmotor fluctuations (e.g., abrupt changes in mood and cognitive performance) and impulse control disorders. Valid rodent models of these nonmotor complications need to be developed as an important tool for basic and translational research on the cognitive and psychiatric features of PD.

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^∗: Present address: Department of Anatomy (2nd Division), Kansai Medical University, Moriguchi, Osaka 570, Japan.

^∗∗: On leave from the Department of Anatomy, University of Toronto, Toronto, Ont. M5S 1A8, Canada.

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Tyrosine hydroxylase-like immunoreactive neurons in the striatum of the rat

Abstract

Brain Res.

Neurosci. Lett.

Neuroscience

Neurosci. Res.

Brain Res.