State-dependent alteration of respiration in a rat model of Parkinson's disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder. Besides major deficits in motor coordination, patients may also display sensory and cognitive impairments, which are often overlooked despite being inherently part of the PD symptomatology. Amongst those symptoms, respiration, a key mechanism involved in the regulation of multiple physiological and neuronal processes, appears to be altered. Importantly, breathing patterns are highly correlated with the animal's behavioral states. This raises the question of the potential impact of behavioral state on respiration deficits in PD. To answer this question, we first characterized the respiratory parameters in a neurotoxin-induced rat model of PD (6-OHDA) across three different vigilance states: sleep, quiet waking and exploration. We noted a significantly higher respiratory frequency in 6-OHDA rats during quiet waking compared to Sham rats. A higher respiratory amplitude was also observed in 6-OHDA rats during both quiet waking and exploration. No effect of the treatment was noted during sleep. Given the relation between respiration and olfaction and the presence of olfactory deficits in PD patients, we then investigated the odor-evoked sniffing response in PD rats, using an odor habituation/cross-habituation paradigm. No substantial differences were observed in olfactory abilities between the two groups, as assessed through sniffing frequency. These results corroborate the hypothesis that respiratory impairments in 6-OHDA rats are vigilance-dependent. Our results also shed light on the importance of considering the behavioral state as an impacting factor when analyzing respiration.

Nasopharyngeal swab-induced pain for SARS-CoV-2 screening: A randomised controlled trial of conventional and self-swabbing.

BACKGROUND: Massive screening campaigns for SARS-CoV-2 are currently carried out throughout the world, relying on reverse-transcriptase-polymerase chain reaction (RT-PCR) following nasopharyngeal swabbing performed by a healthcare professional. Yet, due to the apprehension of pain induced by nasopharyngeal probing, poor adhesion to those screening campaigns can be observed. To enhance voluntary participation and to avoid unnecessary exposition to SARS-CoV-2, self-swabbing could be proposed. To date, no data have been published concerning pain induced by conventional- or self-swabbing. Thus, the primary objective of the present study was to evaluate pain induced with the conventional swabbing method and compare it to self-swabbing. Secondary objectives focused on swabbing-induced discomfort and acceptability of the two methods. METHODS: The study was conducted in Clermont-Ferrand medical school (France). Overall, 190 students were randomised into two groups and experienced either self- or conventional-swabbing. Each subject had to rate pain, discomfort and acceptability of such swabbing on a 0-10 numeric rating scale. RESULTS: No significant difference was found between the two methods. The mean pain level was 2.5 ± 1.9, 28% rating pain as ≥4/10. Discomfort was 4.8 ± 2.2, 66% indicating significant (≥4/10) discomfort. Higher pain and discomfort were associated with female sex. Acceptability was ≥8/10 for 89.0% of the subjects and all would have accepted to undergo a new test with the same technique if necessary. CONCLUSION: Both conventional and self-swabbing induce low levels of pain for most young healthy volunteers whereas discomfort is very frequent. Nonetheless, both methods are indifferently well-accepted in medical students. Future studies amongst symptomatic subjects are awaited. SIGNIFICANCE: Using the thinnest available swabs, procedural pain induced by nasopharyngeal swabbing for SARS-CoV-2 screening is very low for most subjects and should not limit voluntary participation in screening campaigns. Self-swabbing does not lead to more pain or discomfort compared to conventional swabbing, is well-accepted, and could be proposed to optimize screening campaigns, at least in healthcare professionals.

Ketamine-Magnesium for Refractory Chronic Cluster Headache: A Case Series.

OBJECTIVES: To evaluate the safety and efficacy of ketamine-magnesium combination to reduce attacks in a series of patients with refractory chronic cluster headache (rCCH). BACKGROUND: Refractory chronic cluster headache (CCH) is a rare but highly debilitating condition that needs new treatment options. A previous publication reported that a single infusion of ketamine-magnesium combination was effective in 2 patients with rCCH. METHODS: The treatment was proposed to consecutive patients with rCCH seen in 2 French hospitals between November 2015 and February 2020 and who were resistant to at least 3 preventive treatments. They received a single ketamine infusion (0.5 mg/kg over 2 hours) combined with magnesium sulfate (3000 mg). The main outcome was a comparison of the number of daily attacks 2 weeks prior to the ketamine-magnesium infusion and 1 week after (on days 7 and 8). The second outcome was the percentage of responders (patients with ≥50% reduction in the frequency of daily attacks). Safety was assessed by the recording of adverse events during infusion. Descriptive statistics are presented as mean ± standard deviation. RESULTS: Seventeen patients (14 men), with an age of 35.2 ± 8.1 years, were included. They presented with CCH for 6.6 ± 4.3 years. The number of daily attacks decreased from 4.3 ± 2.4 before treatment to 1.3 ± 1.0 after treatment (difference: -3.1 (95% CI: -4.5 to -1.6), P < .001). Seventy six percent (13/17) were responders. Transient and mild sedation was reported by 7/17 patients (41.2%). CONCLUSIONS: The ketamine-magnesium combination seems an effective and well-tolerated therapy for rCCH. Placebo-controlled studies should be conducted to further confirm these findings.

Involvement of nicotinic and muscarinic receptors in the endogenous cholinergic modulation of the balance between excitation and inhibition in the young rat visual cortex.

This study aims to clarify how endogenous release of cortical acetylcholine (ACh) modulates the balance between excitation and inhibition evoked in visual cortex. We show that electrical stimulation in layer 1 produced a significant release of ACh measured intracortically by chemoluminescence and evoked a composite synaptic response recorded intracellularly in layer 5 pyramidal neurons of rat visual cortex. The pharmacological specificity of the ACh neuromodulation was determined from the continuous whole-cell voltage clamp measurement of stimulation-locked changes of the input conductance during the application of cholinergic agonists and antagonists. Blockade of glutamatergic and gamma-aminobutyric acid (GABAergic) receptors suppressed the evoked response, indicating that stimulation-induced release of ACh does not directly activate a cholinergic synaptic conductance in recorded neurons. Comparison of cytisine and mecamylamine effects on nicotinic receptors showed that excitation is enhanced by endogenous evoked release of ACh through the presynaptic activation of alpha(*)beta4 receptors located on glutamatergic fibers. DHbetaE, the selective alpha4beta2 nicotinic receptor antagonist, induced a depression of inhibition. Endogenous ACh could also enhance inhibition by acting directly on GABAergic interneurons, presynaptic to the recorded cell. We conclude that endogenous-released ACh amplifies the dominance of the inhibitory drive and thus decreases the excitability and sensory responsiveness of layer 5 pyramidal neurons.

Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer.

Several G protein-coupled receptors have been shown to exist as homo-and hetero-oligomeric complexes in living cells. However, the link between ligand-induced receptor activation and its oligomerization state as well as the proportion of the total receptor population that can engage in oligomeric complexes remain open questions. Here, the closely related human MT1 and MT2 melatonin receptors (MT1R, MT2R) were used to address these issues. Bioluminescence resonance energy transfer (BRET) experiments in living HEK 293 cells revealed that these receptors form homo- and hetero-oligomers. Constitutive energy transfer was observed for all receptor combinations at physiological expression levels and could be detected in single cell BRET experiments. Inhibition of the energy transfer by dilution of the BRET partners identified MT1R and MT2R dimers as the predominant receptor species, and this oligomerization state did not change upon agonist and antagonist binding. Agonists, neutral antagonists, and inverse agonists all promoted increases in BRET values for MT2R but not for MT1R homodimers in living cells and isolated plasma membranes. This indicates that no correlation could be inferred between the receptor activation state and the dimerization state of the receptor. This also suggests that ligand-promoted BRET increases represent specific ligand-induced conformational changes of pre-existing dimers rather then increased dimerization. The observation that ligands favored the energy transfer within the hetero-oligomer from MT1R to MT2R but not in the reverse orientation, from MT2R to MT1R, supports this view.