Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa-induced dyskinesias.

Levodopa (L-DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L-DOPA-induced dyskinesias (LIDs). Dysregulation of the nitric oxide-cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham-operated and 6-hydroxydopamine-lesioned rats chronically treated with vehicle or L-DOPA, respectively. In sham-operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6-hydroxydopamine-lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L-DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs.

Brazilian Adaptation of the Coronavirus Anxiety Scale: A Psychometric Investigation of a Measure of Coronaphobia.

This study examined the psychometric properties of a Brazilian adapted version of the Coronavirus Anxiety Scale (CAS-BR) in a sample of adults in Brazil. Confirmatory factor analyses demonstrated that the CAS-BR produces a reliable (α = .84), unidimensional construct whose structure was shown to be invariant across gender, race, and age. However, some items of the CAS-BR were stronger indicators of the coronavirus anxiety construct for women and younger adults. Although the CAS-BR demonstrated evidence of discrimination ability for functional impairment (AUC = .77), Youden indexes were low to identify a clinical cut-score. Construct validity was demonstrated with correlations between CAS-BR scores and measures of functional impairment, generalized anxiety, and depression. Exploratory analyses revealed that CAS-BR total scores were higher among women and participants with a history of anxiety disorder. These findings are consistent with previous investigations and support the validity of CAS-BR for measuring coronavirus anxiety with Brazilian adults.

Phosphodiesterase 10A Inhibition Modulates the Corticostriatal Activity and L-DOPA-Induced Dyskinesia.

The facilitation of corticostriatal transmission is modulated by the pharmacological inhibition of striatal phosphodiesterase 10A (PDE10A). Since L-DOPA-induced dyskinesia is associated with abnormal corticostriatal transmission, we hypothesized that inhibition of PDE10A would modulate L-DOPA-induced dyskinesia (LID) by regulating corticostriatal activity. 6-OHDA-lesioned rats were chronically treated with L-DOPA for one week. After that, for two additional weeks, animals were treated with the PDE10A inhibitor PDM-042 (1 and 3 mg/kg) one hour before L-DOPA. Behavioral analyses were performed to quantify abnormal involuntary movements (AIMs) and to assess the antiparkinsonian effects of L-DOPA. Single-unit extracellular electrophysiological recordings were performed in vivo to characterize the responsiveness of MSNs to cortical stimulation. The low dose of PDM-042 had an antidyskinetic effect (i.e., attenuated peak-dose dyskinesia) and did not interfere with cortically evoked spike activity. Conversely, the high dose of PDM-042 did not affect peak-dose dyskinesia, prolonged AIMs, and increased cortically evoked spike activity. These data suggest that the facilitation of corticostriatal transmission is likely to contribute to the expression of AIMs. Therefore, cyclic nucleotide manipulation is an essential target in controlling LID.

Parkinson's disease rodent models: Are they suitable for DBS research?

Deep brain stimulation (DBS) appeared in the therapeutic framework for Parkinson's disease in the late 1980 s and early 1990 s, conceived as an alternative to ablative treatments, using inhibitory electrical stimulation parameters still clinically in force today, with frequencies above 130 Hz, a pulse width of 60 ms and current intensity around 3 mA into deep brain structures, to relieve the motor symptoms of the disease. This context expands into a technique not only restricted to the targets traditionally used in lesional procedures, supported by the knowledge acquired with non-human primate (NHP) animal models during the early 1990 s, initiated by Benazzouz and collaborators. Currently, NHP animal models have lost ground to research models in rodents, which have assumed a prominent position in scientific research on DBS. However, how can an animal so small and different from Homo sapiens provide relevant information that may guide the evolution of treatment for a condition that occurs only in humans, like PD? The scope of this review is to address recent advances in PD pathogeny, DBS principles, and different in vivo experimental DBS models in rodents, their limitations and relevance, as well as the future directions in animal models for scientific research.

The 6-hydroxydopamine Rat Model of Parkinson's Disease.

Motor symptoms of Parkinson's disease (PD)-bradykinesia, akinesia, and tremor at rest-are consequences of the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and dopaminergic striatal deficit. Animal models have been widely used to simulate human pathology in the laboratory. Rodents are the most used animal models for PD due to their ease of handling and maintenance. Moreover, the anatomy and molecular, cellular, and pharmacological mechanisms of PD are similar in rodents and humans. The infusion of the neurotoxin, 6-hydroxydopamine (6-OHDA), into a medial forebrain bundle (MFB) of rats reproduces the severe destruction of dopaminergic neurons and simulates PD symptoms. This protocol demonstrates how to perform the unilateral microinjection of 6-OHDA in the MFB in a rat model of PD and shows the motor deficits induced by 6-OHDA and predicted dopaminergic lesions through the stepping test. The 6-OHDA causes significant impairment in the number of steps performed with the contralateral forelimb.

Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease.

L-DOPA-induced dyskinesias (LIDs) refer to motor complications that arise from prolonged L-DOPA administration to patients with Parkinson's disease (PD). The most common pattern observed in the clinic is the peak-dose dyskinesia which consists of clinical manifestations of choreiform, dystonic, and ballistic movements. The 6-hydroxydopamine (6-OHDA) rat model of PD mimics several characteristics of LIDs. After repeated L-DOPA administration, 6-OHDA-lesioned rats exhibit dyskinetic-like movements (e.g., abnormal involuntary movements, AIMs). This protocol demonstrates how to induce and analyze AIMs in 6-OHDA-lesioned rats with 90%-95% dopaminergic depletion in the nigrostriatal pathway. Repeated administration (3 weeks) of L-DOPA (5 mg/kg, combined with 12.5 mg/kg of benserazide) can induce the development of AIMs. The time course analysis reveals a significant increase in AIMs at 30-90 min (peak-dose dyskinesia). Rodent models of LIDs are an important preclinical tool to identify effective antidyskinetic interventions.