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Wheeler, D. S.

Publications and source records attributed to Wheeler, D. S..

2 recordsLinked to original sources

Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured in an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted escape attempts. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.

neuroscience↗

Norepinephrine activates β1-adrenergic receptors localized to the inner nuclear membrane in cortical astrocytes

Studies in cardiomyocytes have established that adrenergic receptors, conventionally thought to initiate signaling events exclusively from the plasma membrane, can also localize to and signal from the nuclear membrane. Activation of these receptors by their endogenous cationic ligands requires transmembrane uptake mediated by organic cation transporter 3 (OCT3). We have demonstrated that OCT3 is densely localized to outer nuclear membranes in neurons and astrocytes, suggesting that nuclear adrenergic signaling is also present in the central nervous system. In this study, we examined the subcellular localization of {beta}1-adrenergic receptors, their G-protein signaling partners, and catecholamine transporters in mouse astrocytes. We identified a population of {beta}1-adrenergic receptors localized to astrocyte inner nuclear membranes. We demonstrated that key components of Gs-mediated signaling are localized to the nuclear compartment and identified OCT3 and other catecholamine transporters localized to plasma and nuclear membranes. Treatment of astrocytes with norepinephrine induced rapid increases in nuclear PKA activity which were blocked by pretreatment with inhibitors of catecholamine transport. These data indicate that nuclear {beta}1-adrenergic receptors are functionally coupled to Gs-coupled signaling mediators and that their activation by norepinephrine requires transporter-mediated uptake. These receptors represent a powerful mechanism by which norepinephrine may alter astrocyte gene expression and brain function.

cell biology↗