Behavioral characterization of the 6-hydroxidopamine model of Parkinson’s disease and pharmacological rescuing of non-motor deficits

Abstract

BackgroundParkinson’s disease (PD) is a chronic neurodegenerative condition that is characterized by motor symptoms as a result of dopaminergic degeneration, particularly in the mesostriatal pathway. However, in recent years, a greater number of clinical studies have focused on the emergence of non-motor symptoms in PD patients, as a consequence of damage on the mesolimbic and mesocortical dopaminergic networks, and on their significant impact on the quality of life of PD patients. Herein, we performed a thorough behavioral analysis including motor, emotional and cognitive dimensions, of the unilateral medial forebrain bundle (MFB) 6-hydroxidopamine (6-OHDA)-lesioned model of PD, and further addressed the impact of pharmacological interventions with levodopa and antidepressants on mood dimensions.ResultsBased on apomorphine-induced turning behaviour and degree of dopaminergic degeneration, animals submitted to MFB lesions were subdivided in complete and incomplete lesion groups. Importantly, this division also translated into a different severity of motor and exploratory impairments and depressive-like symptoms; in contrast, no deficits in anxiety-like and cognitive behaviors were found in MFB-lesioned animals. Subsequently, we found that the exploratory and the anhedonic behavioural alterations of MFB-lesioned rats can be partially improved with the administration of both levodopa or the antidepressant bupropion, but not paroxetine.ConclusionsOur results suggest that this model is a relevant tool to study the pathophysiology of motor and non-motor symptoms of PD. In addition, the present data shows that pharmacological interventions modulating dopaminergic transmission are also relevant to revert the non-motor behavioral deficits found in the disease.

Activation of serotonin2C receptors in the lateral habenular nucleus increases the expression of depression-related behaviors in the hemiparkinsonian rat

“…Although depression is a common non-motor symptom in PD, previous studies into depressive-like behaviors in different rat models of PD were less consistent (Winter et al, 2007;Branchi et al, 2008;Tadaiesky et al, 2008;Eskow Jaunarajs et al, 2010Santiago et al, 2010Santiago et al, , 2014Zhang et al, 2011;Delaville et al, 2012;Sourani et al, 2012;Carvalho et al, 2013;Hui et al, 2014). The discrepancy could be related to the site of 6-OHDA injection, the extent of DA depletion, unilateral or bilateral lesions, used depression paradigms and time frame for the behavior tests.…”

“…Previous studies into depressive-like behaviors in 6-hydroxydopamine (6-OHDA)-lesioned rats have been limited and divergent. These studies reported increased or unchanged depressive-like behaviors in different 6-OHDA rat models of PD (Winter et al, 2007;Branchi et al, 2008;Tadaiesky et al, 2008;Eskow Jaunarajs et al, 2010Santiago et al, 2010Santiago et al, , 2014Zhang et al, 2011;Delaville et al, 2012;Sourani et al, 2012;Carvalho et al, 2013;Hui et al, 2014). Further, a dysfunctional 5-HT system is generally regarded as a risk factor for depression, and accumulating lines of evidences also suggest that degeneration of the nigrostriatal pathway leads to an impairment of 5-HT system, with evidence including the loss of 5-HT neurons, reduction of brain 5-HT content, hyperactivity of 5-HT neurons and alterations in various types of 5-HT receptors (Scholtissen et al, 2006;Wang et al, 2009;Huot et al, 2011).…”

Short-Term Treatment with Silymarin Improved 6-OHDA-Induced Catalepsy and Motor Imbalance in Hemi-Parkisonian Rats

“…Catalepsy which is commonly assessed by bar test is a valid marker of the nigrostriatal neurodegeneration. 11,20 In rodents, this is a standard test for evaluation of 6-OHDA and neuroleptic drugsinduced akinesia. [21][22][23][24] In the present study we observed that intra-SNc injection of 6-OHDA resulted in motor impairments (increased catalepsy and decreased motorbalance) in rats which were attenuated by short term treatment with SM.…”

“…In rotarod, which is considered as a standard test for evaluation of motor-balance, performance is measured by the period of time that an animal stays up and walks on the rod and the latency to fall off the drum was recorded. 20,25,36 In 6-OHDA-lesioned rats loss of dopaminergic neurons and reduction of striatal dopamine levels is an essential cause of motor incoordination. In fact, unilateral lesion of SNc obliges animal to change its weight irregularly for movement and balance; therefore this lead to motor disturbance and asymmetry.…”

Embryonic Stem Cells Derived Neuron Transplantation Recovery in Models of Parkinsonism in Relation to Severity of the Disorder in Rats

“…[24][25][26][27] A good correlation between the drug-induced rotations and the severity of the disease was established in intra-nigral 6-hydroxydopamine (6-OHDA)-infused rats. 28 We investigated correlation, if any, between dopaminergic cell loss in the substantia nigra pars compacta (SNpc) and unilateral bias in turning to find if the rotational severity, nigral dopaminergic cell loss, and striatal DA content, singularly or together, could be set as a scale for the severity of or stage the disease in rats unilaterally lesioned with 6-OHDA or 1-methyl-4-phenyl pyrinidium (MPP + ). A change from negative to positive correlation of nigral neuronal loss or striatal denervation with that of the performance in behavioral tests provides a scale for the assessment of functional recovery in cell transplantation studies.…”