Automated procedure to detect subtle motor alterations in the balance beam test in a mouse model of early Parkinson's disease.

Parkinson's disease (PD) is the most common motor neurodegenerative disorder, characterised by aggregated α-synuclein (α-syn) constituting Lewy bodies. We aimed to investigate temporal changes in motor impairments in a PD mouse model induced by overexpression of α-syn with the conventional manual analysis of the balance beam test and a novel approach using machine learning algorithms to automate behavioural analysis. We combined automated animal tracking using markerless pose estimation in DeepLabCut, with automated behavioural classification in Simple Behavior Analysis.

Efficacy of invasive and non-invasive methods for the treatment of Parkinson's disease: Nanodelivery and enriched environment.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta and the subsequent motor disability. The most frequently used treatments in clinics, such as L-DOPA, restore dopaminergic neurotransmission in the brain. However, these treatments are only symptomatic, have temporary efficacy, and produce side effects.

Peripheral CB1 receptor blockade acts as a memory enhancer through a noradrenergic mechanism.

Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptor (CB1R) is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing low arousal/non-emotional recognition memory in mice, we found a relevant role of peripheral CB1R in memory persistence.

Changes in Day/Night Activity in the 6-OHDA-Induced Experimental Model of Parkinson's Disease: Exploring Prodromal Biomarkers.

The search for experimental models mimicking an early stage of Parkinson's disease (PD) before motor manifestations is fundamental in order to explore early signs and get a better prognosis. Interestingly, our previous studies have indicated that 6-hydroxydopamine (6-OHDA) is a suitable model to induce an early degeneration of the nigrostriatal system without any gross motor impairment. Considering our previous findings, we aim to implement a novel system to monitor rats after intrastriatal injection of 6-OHDA to detect and analyze physiological changes underlying prodromal PD.

Therapeutic potential of cannabinoids as neuroprotective agents for damaged cells conducing to movement disorders.

The basal ganglia (BG), an organized network of nuclei that integrates cortical information, play a crucial role in controlling motor function. In fact, movement disorders such as Parkinson's disease (PD) and Huntington's disease (HD) are caused by the degeneration of specific structures within the BG. There is substantial evidence supporting the idea that cannabinoids may constitute novel promising compounds for the treatment of movement disorders as neuroprotective and anti-inflammatory agents.

Beneficial effects of n-3 polyunsaturated fatty acids administration in a partial lesion model of Parkinson's disease: The role of glia and NRf2 regulation.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely associated to beneficial effect over different neurodegenerative diseases. In the present study, we tested the potential therapeutic effect of docohexanoic acid (DHA) and its hydroxylated derivate, DHAH, in a partial lesion model of Parkinson's disease (PD). One month before and four months after the striatal lesion with 6-OHDA was made, the animals were daily treated with DHA (50 mg/kg), DHAH (50 mg/kg), vehicle or saline, by intragastric administration.

Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson's disease.

Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson's disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release.

Buspirone anti-dyskinetic effect is correlated with temporal normalization of dysregulated striatal DRD1 signalling in L-DOPA-treated rats.

Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood.

In vivo administration of VEGF- and GDNF-releasing biodegradable polymeric microspheres in a severe lesion model of Parkinson's disease.

In this work, the neuroregenerative potentials of microencapsulated VEGF, GDNF and their combination on a severely lesioned rat model were compared with the aim of developing a new strategy to treat advanced stages of Parkinson's disease. Both neurotrophic factors were separately encapsulated into polymeric microspheres (MSs) to obtain a continuous drug release over time. The regenerative effects of these growth factors were evaluated using a rotation behaviour test and quantified by the number of surviving TH+cells.

The role of the subthalamic nucleus in L-DOPA induced dyskinesia in 6-hydroxydopamine lesioned rats.

L-DOPA is the most effective treatment for Parkinson's disease (PD), but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration.

Endocannabinoid modulation of dopaminergic motor circuits.

There is substantial evidence supporting a role for the endocannabinoid system as a modulator of the dopaminergic activity in the basal ganglia, a forebrain system that integrates cortical information to coordinate motor activity regulating signals. In fact, the administration of plant-derived, synthetic or endogenous cannabinoids produces several effects on motor function. These effects are mediated primarily through the CB(1) receptors that are densely located in the dopamine-enriched basal ganglia networks, suggesting that the motor effects of endocannabinoids are due, at least in part, to modulation of dopaminergic transmission.

Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

Rationale: It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density.

Objective: The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats.

Results: We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity.

Regulation of subthalamic neuron activity by endocannabinoids.

High levels of anandamide are located in the basal ganglia. The subthalamic nucleus (STN) is considered to be an important modulator of basal ganglia output. The present study aims at characterizing the modulation of the electrical activity of STN neurons by exogenous anandamide or endocannabinoids.

Levodopa-induced dyskinesias in Parkinson disease are independent of the extent of striatal dopaminergic denervation: a pharmacological and SPECT study.

The physiopathology of levodopa-induced dyskinesias (LIDs) is unclear. Presynaptic pharmacokinetic and postsynaptic pharmacodynamic mechanisms may be involved. We have analyzed several clinical and pharmacological parameters, as well as the status of the presynaptic dopamine nigrostriatal pathway by using DaTSCAN, in 14 patients with Parkinson disease who developed early and severe LID despite using low doses of levodopa and 10 patients without this complication despite the use of high levodopa doses.

Two opposite effects of Delta(9)-tetrahydrocannabinol on subthalamic nucleus neuron activity: involvement of GABAergic and glutamatergic neurotransmission.

Activation of CB1 cannabinoid receptors in the basal ganglia interferes with movement regulation. The aim of this study was to characterize the effect of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) on neurons in the subthalamic nucleus (STN) and to elucidate the mechanisms involved in this effect using single-unit extracellular recordings in anesthetized rats. Administration of Delta(9)-THC (0.

Excitatory regulation of noradrenergic neurons by L-arginine/nitric oxide pathway in the rat locus coeruleus in vivo.

To elucidate conflicting findings about the role of L-arginine/nitric oxide (NO) pathway in the locus coeruleus (LC), we investigated the effects of different drugs affecting NO concentrations by single-unit extracellular recordings from LC neurons in vivo and in vitro. In anesthetized rats, central (3.8-15.

Electrophysiological characterization of substantia nigra dopaminergic neurons in partially lesioned rats: effects of subthalamotomy and levodopa treatment.

Progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta is the main histopathological characteristic of Parkinson's disease. We studied the electrophysiological characteristics of the spontaneous activity of substantia nigra pars compacta dopaminergic neurons in rats with a partial, unilateral, 6-hydroxydopamine lesion of the nigrostriatal pathway. In addition, the effects of subthalamotomy and prolonged levodopa treatment on the activity of dopaminergic neurons were investigated.

Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties.

Rationale: Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants.

Objectives: We examined in biochemical, electrophysiological and behavioural assays the antidepressant properties of (S)-(-)-4-[(3-fluorophenoxy)-phenyl]methyl-piperidine (F-98214-TA), a compound that displays very high affinity for 5-HT and NE transporters.

Results: F-98214-TA potently inhibited the uptake of both 5-HT and NE into rat brain synaptosomes (IC50 = 1.

Short-term effects of 3,4-methylenedioximethamphetamine on noradrenergic activity in locus coeruleus and hippocampus of the rat.

This study was undertaken to investigate the effects of the administration of 3,4-methylenedioxymethamphetamine (MDMA) on the locus coeruleus firing rate, on the sensitivity of the alpha(2)-adrenoceptors which regulate neuronal activity and on the in vivo tyrosine hydroxylase activity in hippocampus. The basal firing rate was not modified by either a single dose or repeated doses of MDMA, although the latter produced a shift to the right in the dose-response curve for clonidine-induced inhibition of the firing rate (ED(50) increased by 59%) and a reduction in tyrosine hydroxylase activity (20%) in the hippocampus. However, 8 days after the final dose alpha(2)-adrenoceptor sensitivity and tyrosine hydroxylase activity had returned to control values.