Biology subjects

Wadsworth, H. A.

Publications and source records attributed to Wadsworth, H. A..

3 recordsLinked to original sources

bioRxiv2026

Microglial and Neuronal Cross-talk in the Nucleus Accumbens

Microglia are the brain's resident immune cells and rapidly migrate toward sites of neuronal stress and neurotransmitter imbalance. The molecular cues directing microglia movement remain poorly understood, particularly in brain regions involved in reward processing, including the nucleus accumbens (NAc). Dopamine (DA) dysregulation and production of reactive oxygen species (ROS) are hallmarks of substance use disorders and neurodegenerative diseases. Dopamine and adenosine triphosphate (ATP) are co-released in the NAc, but the effects of ROS on ATP/DA co-transmission and microglia surveillance remain unknown. Using multiphoton imaging in brain slices with GFP-labeled microglia, we found that ATP consistently and non-selectively drives microglia chemoattraction, whereas DA chemoattraction only occurs in a subset of microglia through D1 but not D2 receptor activation. Microglia enter a reactive state via LPS, and LPS results in enhanced DA/ATP release measured via fast scan cyclic voltammetry. ROS production also transitions microglia to a reactive state, but inhibits DA release, with mixed effects on ATP release. These findings identify ATP- and DA-mediated mechanisms for NAc microglia chemoattraction and opposing immune dysregulation (via LPS or ROS) of DA terminal function.

neuroscience↗

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↗

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↗