Variability among brain regions in the specificity of 6-hydroxydopamine (6-OHDA)-induced lesions

Commins, Deborah; Shaughnessy, Rita A.; Axt, Karen J.; Vosmer, Georgetta; Seiden, Lewis S.

doi:10.1007/bf01248932

Cited by 31 publications

(11 citation statements)

References 22 publications

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“…However, in some cases, opposite results were obtained using the same 6-OHDA-lesioned rodent model (Guiard et al 2008b ;Kaya et al 2008). It is important to remember that in animal models of PD, striatal serotonin levels have been reported to be increased (Balcioglu et al 2003 ;Commins et al 1989 ;Karstaedt et al 1994 ;Zhou et al 1991) unchanged (Breese et al 1984 ;Carta et al 2006) or decreased (Aguiar et al 2006(Aguiar et al , 2008. These findings indicate that these changes in the serotonergic system may be highly dependent on the location and extension of dopaminergic degeneration.…”

Section: Discussionmentioning

confidence: 52%

Locus coeruleus and dorsal raphe neuron activity and response to acute antidepressant administration in a rat model of Parkinson's disease

Miguélez

Grandoso

Ugedo

2010

Int. J. Neuropsychopharm.

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In addition to noradrenergic and serotonergic systems, dopaminergic neurotransmission seems to play an important role in the aetiopathogenesis of, and recovery from, depression. Moreover, the incidence of depression is higher in patients affected by diseases where the dopaminergic system is highly impaired, such us Parkinson's disease. Here, we investigated the effects of dopamine degeneration on the activity and response to antidepressants of locus coeruleus (LC) noradrenergic and dorsal raphe nucleus (DRN) serotonergic neurons. To this end, single-unit extracellular recordings were performed in control and 6-hydroxydopamine (6-OHDA)-lesioned animals. In this latter group, LC neurons showed a lower basal firing rate as well as less sensitivity to the administration of the serotonin reuptake inhibitor, fluoxetine. The rest of electrophysiological parameters and the response to the administration of the a 2 -adrenoceptor agonist, clonidine and the noradrenaline reuptake inhibitor, reboxetine remained unaltered. In the DRN, dopamine depletion did not modify the basal electrophysiological characteristics and the response to clonidine or fluoxetine administration. In contrast, the administration of reboxetine more efficiently induced an inhibitory effect in the lesioned group. In additional analyses it was observed that while in control animals, LC and DRN basal firing rate was significantly correlated, this relationship was lost after the 6-OHDA lesion. In conclusion, dopaminergic degeneration alters LC neuron basal activity, the relationship/syntony between both nuclei, and their response to antidepressants. These findings shed fresh light on our understanding of the role of dopamine in depression and the mechanism action of antidepressants.

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Section: Discussionmentioning

confidence: 52%

Locus coeruleus and dorsal raphe neuron activity and response to acute antidepressant administration in a rat model of Parkinson's disease

Miguélez

Grandoso

Ugedo

2010

Int. J. Neuropsychopharm.

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“…Finally, we examined levels of serotonin in our tissue. Although serotonin neurons are not directly affected by 6-OHDA, there have been conflicting reports about changes in serotonin levels in the dorsal striatum following dopamine depletion (Breese, Baumeister et al 1984, Commins, Shaughnessy et al 1989, Karstaedt, Kerasidis et al 1994, Frechilla, Cobreros et al 2001, Balcioglu, Zhang et al 2003, Carta, Lindgren et al 2006, Rylander, Parent et al 2010) and this has been hypothesized to play a role in L-dopa induced dyskinesias (Nagatsua and Sawadab 2009, Rylander, Parent et al 2010). Interestingly, serotonin levels remained constant until ~60% of dopamine had been lost, then suddenly increased by 10–20% (ANOVA with Dunnett t, p < 0.05 from saline).…”

Section: Resultsmentioning

confidence: 99%

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

2015

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Parkinson’s disease (PD) is a movement disorder whose cardinal motor symptoms arise due to the progressive loss of dopamine. Although this dopamine loss typically progresses slowly over time, currently there are very few animal models that enable incremental dopamine depletion over time within the same animal. This type of gradual dopamine depletion model would be useful in studies aimed at the prodromal phase of PD, when dopamine levels are pathologically low but motor symptoms have not yet presented. Utilizing the highly characterized neurotoxin 6-hydroxydopamine (6-OHDA), we have developed a paradigm to gradually deplete dopamine levels in the striatum over a user-defined time course – spanning weeks to months – in C57BL/6 mice. Dopamine depletions were achieved by administration of five low dose injections (0.75 µg) of 6-OHDA through an implanted intracranial bilateral cannula targeting the medial forebrain bundle. Levels of dopamine within the striatum declined linearly with successive injections, quantified using tyrosine hydroxylase immunostaining and high-performance liquid chromatography. Behavioral testing was carried out at each time point to study the onset and progression of motor impairments as a function of dopamine loss over time. We found that spontaneous locomotion, measured in an open field, was robust to loss of dopamine until ~70% of striatal dopamine was lost. Beyond this point, additional dopamine loss caused a sharp decline in motor performance, reaching a final level comparable to that of acutely depleted mice. Similarly, although rearing behavior was more sensitive to dopamine loss and declined linearly as a function of dopamine levels, it eventually declined to levels similar to that seen in acutely depleted mice. In contrast, motor coordination, measured on a vertical pole task, was only moderately impaired in gradually depleted mice, despite severe impairments observed in acutely depleted mice. These results demonstrate the importance of the temporal profile of dopamine loss on the magnitude and progression of behavioral impairments. Our gradual depletion model thus establishes a new paradigm with which to study how circuits respond and adapt to dopamine loss over time, information which could uncover important cellular events during the prodromal phase of PD that ultimately impact the presentation or treatability of behavioral symptoms.

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“…Several researchers have reported hyperinnervation (Zhou et al, 1991; Rozas et al, 1998; Balcioglu et al, 2003; Maeda et al, 2003), while others found no sprouting (Prinz et al, 2013), or even a decrease in striatal serotonergic fibers after dopaminergic damage (Takeuchi et al, 1991; Rylander et al, 2010). Along the same lines, striatal 5-HT levels have been found to be increased (Commins et al, 1989; Zhou et al, 1991; Karstaedt et al, 1994; Balcioglu et al, 2003), unchanged (Breese et al, 1984; Carta et al, 2006), or decreased (Frechilla et al, 2001; Aguiar et al, 2006, 2008). As detailed in Figure 1, studies performed in different animal models report unequal modification in serotonergic receptor expression along the BG nuclei.…”

Section: Implication Of the Serotonergic System In Parkinson's Diseasementioning

confidence: 88%

Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease

Miguélez

Morera-Herreras

Torrecilla

et al. 2014

Front. Neural Circuits

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The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4–7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.

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Variability among brain regions in the specificity of 6-hydroxydopamine (6-OHDA)-induced lesions

Cited by 31 publications

References 22 publications

Locus coeruleus and dorsal raphe neuron activity and response to acute antidepressant administration in a rat model of Parkinson's disease

Locus coeruleus and dorsal raphe neuron activity and response to acute antidepressant administration in a rat model of Parkinson's disease

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease

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