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    • Mechanistically NAergic signaling in the VTA

    2023-01-14

    Mechanistically, NAergic signaling in the VTA modulates neuronal activity presumably via α1-AR. The majority of α1-ARs are found in the VTA are located presynaptically on unmyelinated Nocodazole mg and axon terminals of glutamatergic and GABAergic neurons. However, α1-ARs are also found on neuronal dendrites and glial cells in the VTA (Rommelfanger et al., 2009, Mitrano et al., 2012). In addition, α2- and β-AR radioligand binding in the VTA has also been reported, suggesting receptor-specific VTA regulation (Rainbow et al., 1984, Rosin et al., 1993, Lee et al., 1998). Increasing literature demonstrates a variety of effects of ARs on DAergic neuronal activity. Systemic administration of prazosin, an α1-AR antagonist, decreases bursting of DAergic neurons (Grenhoff and Svensson, 1993). Additionally, stimulation of the LC leads to a short increase in DAergic neuronal activity followed by an activity pause (Grenhoff et al., 1993), whereas systemic administration of prazosin attenuates this effect. In contrast, lesion of the LC leads to a robust increase in the firing rate and bursting of VTA DAergic neurons (Guiard et al., 2008b). In addition, systemic clonidine administration (α2-AR agonist) leads to regularization of DAergic cell firing (Grenhoff and Svensson, 1988, Grenhoff and Svensson, 1989), whereas an α2-AR antagonist leads to an increase in firing rate and bursting (Grenhoff and Svensson, 1988, Grenhoff and Svensson, 1989, Grenhoff and Svensson, 1993). These studies strongly demonstrated that NAergic signaling regulates VTA DAergic activity; however, these effects were mediated via whole-brain network alterations, and the exact brain locus was not identified. More detailed studies have demonstrated that presynaptic α1-AR activation in the VTA enhances glutamate release (Velasquez-Martinez et al., 2012) and decreases GABA release (Velasquez-Martinez et al., 2015), potentially leading to increased VTA neuronal activity. Similarly, postsynaptic α1-AR activation enhances the activity of both DAergic (Grenhoff et al., 1995, Williams et al., 2014, Goertz et al., 2015) and non-DAergic neurons (Grenhoff et al., 1995). Accordingly, in vivo pressure application of an α1-AR agonist resulted in enhancement of DAergic neuronal activity (Goertz et al., 2015). In contrast, other studies conducted in vivo show no effects of an α1-AR antagonist (White and Wang, 1984) or report that α1-AR activation leads to inhibition of DAergic neurons (Paladini and Williams, 2004) and elevation of the sIPSP frequency observed in DAergic cells (Grenhoff et al., 1995). The above studies demonstrate opposing effects of α1-AR activation on the activity of VTA DAergic neurons. Despite the established NAergic innervation, as well as the expression and location of ARs in the VTA, the receptor mechanisms that regulate VTA neuronal activity are poorly understood. Moreover, the majority of the VTA α1-AR effects have been shown using in vitro electrophysiological recordings, and the field lacks knowledge of how local activation of different ARs affects the activity of both DAergic and non-DAergic VTA neurons in vivo. Thus, in our study, we aimed to examine the effects of local iontophoretic application of α1-, α2- or β-AR selective agonists on the activity of putative DAergic and putative non-DAergic neurons in the central and lateral parts of the rat VTA.
    Materials and methods
    Results The activity of 66 neurons was recorded in the VTA of 17 rats. Recording and iontophoretic drug application sites in the VTA were confirmed by histological verification (Fig. 1), and the putative phenotype (DAergic, non-DAergic) of studied neurons was determined based on previously used electrophysiological criteria (Grace and Bunney, 1980, Grace and Bunney, 1983, Ungless and Grace, 2012). Importantly, it has been demonstrated that these criteria fail to work properly in minority of cases (Lou et al., 2008, Brischoux et al., 2009). Therefore, in the present study, the length of the action potentials’ shape was measured from its beginning to the peak of the negative through, as it gives better output of proper neuronal classification (>1.1 ms for DAergic neurons) than measuring the whole action potential (Ungless et al., 2004, Mileykovskiy and Morales, 2010, Moorman and Aston-Jones, 2010) (DA neurons: 1.41 ± 0.23 ms, non-DA neurons: 0.61 ± 0.11 ms). Putative DAergic neurons in the VTA (n = 36) displayed a spontaneous firing rate of 4.7 ± 0.3 Hz, whereas the average spontaneous firing rate of putative non-DAergic neurons (n = 30) was 7.2 ± 1.4 Hz. The spontaneous activity of putative DAergic and non-DAergic neurons was similar to that described previously in the literature (Marinelli and McCutcheon, 2014).