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  • SB525334 br Discussion Here we show opposing effects of iont

    2024-05-23


    Discussion Here, we show opposing effects of iontophoretically administered phenylephrine,aselective α1-AR agonist, on firing of putatively DAergic and non-DAergic neurons recorded in vivo in the VTA of urethane anaesthetized rats. Phenylephrine application caused a relatively weak decrease in firing of putative DAergic neurons, whereas drug application induced a strong and prolonged excitation and increased bursting of putative non-DAergic neurons. In addition, application of selective α2- or β-AR agonists (clonidine and isoprenaline, respectively) affected activity pattern, but not firing rate, of putative non-DAergic neurons while leaving activity of putative DAergic neurons intact.
    Conclusions Our results showed that VTA neuronal activity in the anaesthetized rat SB525334 is preferentially modulated via α1-AR selective agonist. We demonstrated that activation of α1-AR in vivo evokes a modest inhibitory effect on putative DAergic neurons with no changes observed in bursting activity. In contrast, activation of α1-AR led to a strong, prolonged excitation of putative non-DAergic neurons located in the VTA. We propose that NA acting primarily via α1-ARs affects activity of the VTA by the regulation of DAergic and GABAergic neurons, with contrasting functional consequences. NA acting on α1-AR located on GABAergic neurons’ cell bodies and/or terminals increases VTA GABAergic tone, leading to inhibition of DAergic neuronal firing. We also demonstrated that activation of β-AR and α2-AR, to a lesser extent, modulate the firing pattern of putative non-DAergic neurons. Thus NAergic modulation of VTA activity can involve mechanisms relying on various types of AR located on GABAergic neurons. However, physiologically occurring NA has some unique properties that cannot be mimicked by selective adrenergic receptor agonists. NA has been shown in vivo and in vitro to have profound potency to inhibit DAergic neurons via the D2 receptor (Aghajanian and Bunney, 1977, White and Wang, 1984, Grenhoff et al., 1995, Arencibia-Albite et al., 2007, Guiard et al., 2008a). In addition, participation of α2-AR in the inhibitory impact of NA on VTA neuronal activity has been suggested, as blocking these receptors attenuated the NA-induced inhibition of DAergic neurons in vivo (White and Wang, 1984, Guiard et al., 2008a), even though this effect was not confirmed by in vitro studies (Arencibia-Albite et al., 2007, Williams et al., 2014). Additionally, NAergic signaling might also facilitate the excitatory glutamatergic drive on DAergic neurons (Velasquez-Martinez et al., 2012, Williams et al., 2014) and responsiveness of DAergic neurons to glutamate (Almodovar-Fabregas et al., 2002) via an α1-AR-dependent mechanism. Such a scenario might occur in a state of high activity of excitatory inputs to the VTA, such as during exposure to salient stimuli, potentially leading to an increase in phasic DAergic signaling (Goertz et al., 2015). Arguably, such a modulation may not be observed in an anaesthetized brain, when glutamatergic tone is attenuated. Therefore, NA can attenuate basal, extraburst activity of DAergic neurons, as described in our study (serving as a noise reducer), and at the same time, it can amplify excitatory inputs, as described by others (serving as a signal facilitator). These observations allow us to put forward the hypothesis that NA modulates VTA neuronal activity, leading to an increased signal-to-noise ratio of information encoded by DAergic neurons (Almodovar-Fabregas et al., 2002, Goertz et al., 2015), potentially increasing the value of important environmental stimuli.
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    Introduction Pancreatic β-cells secrete insulin to regulate glucose homeostasis. The primary mechanism underlying glucose stimulated insulin secretion (GSIS) is the metabolism of glucose to increase the ratio of ATP/ADP, which closes ATP-sensitive K+ channels and depolarizes the plasma membrane (Giannaccini et al., 1998, Seino, 1999). This activates voltage dependent Ca2+ channels causing an influx of Ca2+ that stimulates insulin exocytosis (Malaisse et al., 1978). β-cells optimize coupling between blood glucose concentration and insulin secretion through metabolic coupling factors and mitochondrial shuttles (Prentki et al., 2013).