Serotonin, 5-hydroxytryptamine (5-HT), plays various roles in the fruit fly, Drosophila melanogaster. Previous studies have shown that 5-HT modulates the heart rate in third instar larvae. However, the receptor subtypes that mediate 5-HT action in larval cardiac tissue had yet to be determined. In this study, various 5-HT agonists and antagonists were employed to determine which 5-HT receptor subtypes are responsible for the positive chronotropic effect by 5-HT. The pharmacological results demonstrate that a 5-HT2B agonist significantly increases the heart rate; however, 5-HT1A, 5-HT1B, and 5-HT7 agonists do not have a significant effect on the heart rate. Furthermore, 5-HT2 antagonist, ketanserin, markedly reduces the positive chronotropic effect of 5-HT in a dose-response manner. Furthermore, we employed genetic approaches to confirm the pharmacological results. For this purpose, we used RNA interference line to knock down 5-HT2ADro and also used 5-HT2ADro and 5-HT2BDro insertional mutation lines. The results show that 5-HT2ADro or 5-HT2BDro receptor mutations reduce the response of the heart to 5-HT. Given these results, we conclude that these 5-HT2 receptor subtypes are involved in the action of 5-HT on the heart rate in the larval stage.
IntroductionIntermittent hypoxemia (IH) is defined as episodic drops in oxygen saturation (SpO2). Preterm infants are at increased risk for IH due to their immature respiratory control/apnea of prematurity. The clinical relevance of IH is a relatively new observation with rising evidence linking IH to neonatal morbidities and long-term impairment. Hence, assessing factors that influence IH in preterm infants is imperative. Given the epidemic of opioid misuse in the USA, there is an urgent need to understand the impact of prenatal opioid exposure on neonatal outcomes. Hence, we wanted to assess the relationship between isolated prenatal opioid exposure and IH in preterm infants.MethodsIn order to accurately calculate IH, SpO2 data were prospectively collected using high-resolution pulse oximeters during the first 8 weeks of life in preterm infants less than 30 weeks gestational age. Data related to prenatal opioid misuse were retrospectively collected from medical charts. Infants with tobacco or poly-drug exposure were excluded. The primary outcome measure is percent time spent with SpO2 below 80% (%time-SpO2 < 80). The secondary outcome measure is the number of severe IH events/week with SpO2 less than 80% (IH-SpO2 < 80).ResultsA total of 82 infants with isolated opioid exposure (n = 14) or who were unexposed (n = 68) were included. There were no significant differences in baseline characteristics between opioid exposed and unexposed groups. There was a statistically significant increase of 0.23 (95% CI: 0.03, 0.43, p = 0.03) in mean of the square root of %time-SpO2 < 80. The number of IH-SpO2 < 80 events was higher in the opioid exposed group (mean difference = 2.95, 95% CI: −0.35, 6.25, p-value = 0.08), although statistical significance was not quite attained.ConclusionThis study shows that preterm infants prenatally exposed to opioids have increased IH measures compared to unexposed infants. Interestingly, the increased IH in the opioid exposed group persists beyond the immediate postnatal period.
Fruit fly, Drosophila melanogaster, is a good model organism to study the underlying ionic mechanism of heart rate (HR) regulation. It is already known that many neuromodulators (serotonin, dopamine, octopamine, acetylcholine) change the HR in larvae. We used genetic and pharmacological approaches to investigate the extent to which cAMP‐PKA signaling mediates the effects of serotonin (5‐HT) and dopamine (DA) on larval HR. One approach involved the use of transgenic flies that express designer receptors exclusively activated by designer drugs (DREADDs). These engineered G‐protein coupled receptors helped to demonstrate that the effect of 5‐HT, which increases HR, could be overridden by the action of Gái which in turn inhibits adenylyl cyclase (AC). Moreover, activation of AC by forskolin increased HR. However, application of dbcAMP (cAMP analogue, PKA activator) and SQ, 22,536 and ddadenosine (AC inhibitors) did not have a substantial effect on the HR. DA activates parallel signaling cascades in cardiac cells with the end result of increased HR. SKF38393 (a vertebrate D1 agonist) and quinpirole (a vertebrate D2 agonist) increase HR to various degrees. SCH23390 and spiperone (D1 and D2 antagonists) each inhibit the stimulatory effect of DA. And SQ22536 inhibits the effect of DA. Together these results indicate that serotonin and dopamine regulate fruit fly HR through canonical GPCR pathways.
Serotonin, 5‐HT, plays various roles in the fruit fly, Drosophila melanogaster. Previous studies have shown that 5‐HT modulates the heart rate in third instar larvae. However, 5‐HT receptor subtypes that mediate 5‐HT action in larval cardiac tissue has not yet been determined. In this study, various 5‐HT agonists and antagonists were employed to determine which 5‐HT receptor subtypes are responsible for the positive chronotropic effect by 5‐HT. The pharmacological results demonstrate that a 5‐HT2B agonist significantly increases the heart rate; however, 5‐HT1A, 5‐HT1B, and 5‐HT7 agonists do not have a significant effect on the heart rate. Furthermore, 5‐HT2 antagonist, ketanserin, markedly reduces the positive chronotropic effect of 5‐HT in a dose‐response manner. Furthermore, we employed genetic approaches to confirm the pharmacological results. For this propose, we used RNA interference (RNAi) line to knock down 5‐HT2ADro and also used 5‐HT2ADro and 5‐HT2BDro insertional mutation lines. The results show that 5‐HT2ADro or 5‐HT2BDro receptors mutation reduces the response of heart to 5‐HT. Given these results, we conclude that 5‐HT2 receptors activation are involved in the action of 5‐HT on the heart rate in the larval stage.
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