The purpose of this study was to determine what dose of quipazine, a serotonergic agonist, facilitates air-stepping and induces postural control and patterns of locomotion in newborn rats. Subjects in both experiments were 1-day-old rat pups. In Experiment 1, pups were restrained and tested for air-stepping in a 35-min test session. Immediately following a 5-min baseline, pups were treated with quipazine (1.0, 3.0, or 10.0 mg/kg) or saline (vehicle control), administered intraperitoneally in a 50 microliter injection. Bilateral alternating stepping occurred most frequently following treatment with 10.0 mg/kg quipazine, however the percentage of alternating steps, interlimb phase, and step period were very similar between the 3.0 and 10.0 mg/kg doses. For interlimb phase, the forelimbs and hindlimbs maintained a near perfect anti-phase pattern of coordination, with step period averaging about 1 second. In Experiment 2, pups were treated with 3.0 or 10.0 mg/kg quipazine or saline, and then were placed on a surface (open field, unrestrained). Both doses of quipazine resulted in developmentally advanced postural control and locomotor patterns, including head elevation, postural stances, pivoting, crawling, and a few instances of quadrupedal walking. The 3.0 mg/kg dose of quipazine was the most effective at evoking sustained locomotion. Between the 2 experiments, behavior exhibited by the rat pup varied based on testing environment, emphasizing the role that environment and sensory cues exert over motor behavior. Overall, quipazine administered at a dose of 3.0 mg/kg was highly effective at promoting alternating limb coordination and inducing locomotor activity in both testing environments.

Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.

Aim There is an increasing awareness of the impact of age and sex on cardiovascular diseases (CVDs). Differences in physiology are suspected. Beta‐adrenoceptors (beta‐ARs) are an important drug target in CVD and potential differences might have significant impact on the treatment of many patients. To investigate whether age and sex affects beta‐AR function, we analysed a large data set on beta‐AR‐induced inotropy in human atrial trabeculae. Methods We performed multivariable analysis of individual atrial contractility data from trabeculae obtained during heart surgery of patients in sinus rhythm (535 trabeculae from 165 patients). Noradrenaline or adrenaline were used in the presence of the beta2‐selective antagonist (ICI 118 551, 50 nmol/L) or the beta1‐selective antagonist (CGP 20712A, 300 nmol/L) to stimulate beta1‐AR or beta2‐AR respectively. Agonist concentration required to achieve half‐maximum inotropic effects (EC50) was taken as a measure of beta‐AR sensitivity. Results Impact of clinical variables was modelled using multivariable mixed model regression. As previously reported, chronic treatment with beta‐blockers sensitized beta‐AR. However, there was no significant interaction between basal force, maximum force and beta‐AR sensitivity when age and sex were modelled continuously. In addition, there was no statistically significant effect of body mass index or diabetes on atrial contractility. Conclusion Our large, multivariable analysis shows that neither age nor sex affects beta‐AR‐mediated inotropy or catecholamine sensitivity in human atrial trabeculae. These findings may have important clinical implications because beta‐ARs, as a common drug target in CVD and heart failure, do not behave differently in women and men across age decades.

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Parkinson’s disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. We have shown that environmental toxins can trigger the disease by acting on the ENS and on the autonomic nervous system. Oral exposure to the pesticide rotenone, a mitochondrial Complex I inhibitor, leads to decreased stool depositions in mice. Here we analyzed the effect of rotenone on the function and structure of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations makes them ideal candidates to be used as biomarkers for the detection of Parkinson’s disease in its early stages.