Biology subjects

Yorgason, J. T.

Publications and source records attributed to Yorgason, J. T..

4 recordsLinked to original sources

bioRxiv2026

Shared mechanisms of dopamine and ATP transmission in the nucleus accumbens

Dopamine (DA) neurons of the midbrain project throughout the striatum, including the nucleus accumbens core (NAc) and are thought to co-release ATP with DA from vesicles. The mechanisms of evoked NAc ATP release and clearance and their relationship to exocytotic DA transmission are largely unexplored and the focus of the present work. Using fast scan cyclic voltammetry (FSCV), we measured simultaneous ATP and DA transmission in response to pharmacological manipulations of release and reuptake cellular machinery. ATP transmission is tightly coupled to that of DA, though ATP release concentrations are typically smaller. Manipulations that increase DA transmission (increased release via 4-aminopyridine Kv channel blockade or decreased uptake via cocaine) also increase ATP transmission, though to a smaller extent. Blocking DA vesicular packaging (reserpine) or action potentials (lidocaine), results in attenuated DA and ATP release. Interestingly, reserpine or lidocaine can result in completely abolished DA release, but not a complete prevention in ATP release, suggesting a secondary source for ATP transmission thats not dependent on DA terminals. Both transmitters were reduced to a similar extent following nAChR blockade, demonstrating that nAChR activation regulates ATP in addition to DA. Surprisingly, cocaine inhibition of DATs reduced clearance for both ATP and DA, which correlated with one another when cocaine concentration was highest. There was also a strong relationship between the effect of cocaine on release of ATP and DA. As the first FSCV study to examine evoked NAc ATP release, this paper bridges prior work to confirm the strong association between ATP and DA in the mesolimbic circuit and identifies unexpected overlap in mechanisms regulating their transmission. Our results contribute novel evidence of both vesicular and non-vesicular ATP release in the NAc and demonstrate that extracellular ATP is a modulator of DA terminal function.

neuroscience↗

bioRxiv2026

Bile Acids Regulate Accumbal Cholinergic Circuitry and Dopamine Release through TGR5 Activation

BackgroundFatty foods and alcohol (i.e., ethanol) produce strong reinforcing effects, in part by altering cholinergic interneuron (CIN) activity and tonic dopamine (DA) release within the nucleus accumbens (NAc). Ethanol and fatty foods also both stimulate hepatic and possibly local brain bile acid (BA) synthesis, which raises the possibility that BAs may act as a common upstream regulator of these substances shared mesolimbic effects. MethodsThe current study investigated whether BAs can directly alter mesolimbic activity. Electrophysiological data from acute mouse brain slices was collected to assess BA effects on NAc CIN firing, as well as on excitatory and inhibitory postsynaptic CIN inputs. Bile effects on NAc DA release and clearance rates were measured through voltammetry. ResultsWe found that low concentrations of a 1:1 mixture of BAs cholic acid (CA) and deoxycholic acid (DCA; 1-10 M) increased CIN firing rate, whereas high BA concentrations (1-10 mM) decreased CIN firing. We further demonstrated that BA-induced excitatory effects on CIN firing are independently mediated by at least two mechanisms: Takeda G-protein-coupled receptor 5 (TGR5) activation and suppression of inhibitory CIN currents. Additionally, our results indicate that BAs modulate inhibitory input in a complex manner, reducing frequency at low concentrations, but increasing at high concentrations, and increasing amplitude at low concentrations current amplitude, and the distribution of postsynaptic current amplitude sizes across concentrations. Finally, our voltammetry data indicate that while low BA concentrations enhance NAc DA release without affecting DA uptake, high BA concentrations robustly inhibit accumbal DA release. ConclusionOur findings provide evidence that BAs exert direct modulatory effects on neural activity in the striatum.

neuroscience↗

bioRxiv2023

Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function

Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinsons disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVMs potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.

neuroscience↗

bioRxiv2021

Effectiveness and relationship between biased and unbiased measures of dopamine release and clearance

Fast-scan cyclic voltammetry (FSCV) is an effective tool for measuring dopamine (DA) release and clearance throughout the brain, including the ventral and dorsal striatum. Striatal DA terminals are abundant with signals heavily regulated by release machinery and the dopamine transporter (DAT). Peak height is a common method for measuring release but can be affected by changes in clearance. The Michaelis-Menten model has been a standard in measuring DA clearance, but requires experimenter fitted modeling subject to experimenter bias. The current study presents the use of the first derivative (velocity) of evoked DA signals as an alternative approach for measuring dopamine release and clearance and can be used to distinguish the two measures. Maximal upwards velocity predicts reductions in DA peak height due to D2 and GABAB receptor stimulation and by alterations in calcium concentrations. The Michaelis-Menten maximal velocity (Vmax) measure, an approximation for DAT numbers, predicted maximal downward velocity in slices and in vivo. Dopamine peak height and upward velocity were similar between wildtype C57 (WT) and DAT knock out (DATKO) mice. In contrast, downward velocity was considerably reduced and exponential decay (tau) was increased in DATKO mice, supporting use of both measures for changes in DAT activity. In slices, the competitive DAT inhibitors cocaine, PTT and WF23 increased peak height and upward velocity differentially across increasing concentrations, with PTT and cocaine reducing these measures at high concentrations. Downward velocity and tau values decreased and increased respectively across concentrations, with greater potency and efficacy observed with WF23 and PTT. In vivo recordings demonstrated similar effects of WF23 and PTT on measures of release and clearance. Tau was a more sensitive measure at low concentrations, supporting its use as a surrogate for the Michaelis-Menten measure of apparent affinity (Km). Together, these results inform on the use of these measures for DA release and clearance.

neuroscience↗