Biology subjects

Whistler, J.

Publications and source records attributed to Whistler, J..

4 recordsLinked to original sources

bioRxiv2025

D3 dopamine receptors implicate a subtype of medium spiny neuron in the aversive effects of antipsychotic medications

Second generation antipsychotics (SGAs) are widely used clinical tools; yet, they often cause negative side effects and take weeks to become effective, leading to poor patient compliance. The effect/side effect profile of individual SGAs is highly variable, and the mechanisms that underlie this variability are not well understood. Here, we identify a role of type 3 dopamine receptor (D3R) neurons in the Nucleus Accumbens (NAc) that mimics the aversive effects of quetiapine. Using single-nucleus RNA sequencing, we show that D3R is expressed in a subpopulation of D1R neurons and defines a distinct NAc cell type. We found that both clozapine and quetiapine cause acute conditioned place aversion in mice, but aversion subsides only after 21 days of treatment with quetiapine, a drug characterized as an arrestin-biased agonist at D3R. We provide evidence at both the cellular and population level that quetiapine inhibits D3R-expressing neurons in the lateral shell (LatSh) of the NAc. We also demonstrate that local injection of quetiapine into LatSh NAc is sufficient to cause place aversion. Selective optogenetic inhibition of D3R-neurons in the LatSh produces real time place aversion in mice, correlating this cell type to the aversive effects of quetiapine. These findings suggest a cell-type-specific mechanism underlying quetiapine-induced aversion and its potential attenuation with chronic treatment, offering insight into the cell types and circuitry that shape the quetiapine side effect profile.

neuroscience↗

bioRxiv2024

G protein-Coupled Receptor Associated Sorting ProteinGASP1 mediated trafficking of the Glucagon Like Peptide-1Receptor contributes to the development of tolerance toincretin drugs

Incretin mimetic drugs are in widespread use for the treatment of type 2 diabetes and obesity and more recently have been prescribed for weight loss in otherwise healthy individuals. These drugs are all agonists of the glucagon-like peptide 1 receptor (GLP-1R) and function by supplementing effects produced by the endogenous hormone agonist glucagon-like peptide 1 (GLP-1). The therapeutic benefits of these medications, including improved glucose control and weight loss, require continued usage and wane with time. The molecular mechanisms underlying this loss of effect to incretin drugs remain unknown. Following activation by agonist and signaling to G protein, the GLP-1R engages arrestins and is endocytosed. Here we investigated the role of G protein-coupled receptor associated sorting protein 1 (GASP1), a critical regulator of the post-endocytic trafficking of GLP-1R, on tolerance to GLP-1R agonist drug. We found that tolerance to incretin drug was prevented at the cellular, tissue and whole animal level in mice with a selective disruption of the GASP1 protein in beta cells of the pancreatic islet. These studies implicate post-endocytic sorting of the GLP-1R in the loss of effectiveness of incretin therapeutics with prolonged use. These findings also suggest a novel strategy to prevent tolerance by biasing incretin drugs for G protein and away from arrestin engagement.

cell biology↗

bioRxiv2024

Nucleus accumbens sub-regions experience distinct dopamine release responses following acute and chronic morphine exposure

It is well established that dopamine neurons of the ventral tegmental area (VTA) play a critical role in reward and aversion as well as pathologies including drug dependence and addiction. The distinct effects of acute and chronic opioid exposure have been previously characterized at VTA synapses. Recent work suggests that distinct VTA projections that target the medial and lateral shell of the nucleus accumbens (NAc), may play opposing roles in modulating behavior. It is possible that these two anatomically and functionally distinct pathways also have disparate roles in opioid reward, tolerance, and withdrawal in the brain. In this study we monitored dopamine release in the medial or lateral shell of the NAc of male mice during a week-long morphine treatment paradigm. We measured dopamine release in response to an intravenous morphine injection both acutely and following a week of repeated morphine. We also measured dopamine in response to a naloxone injection both prior to and following repeated morphine treatment. Morphine induced a transient increase in dopamine in the medial NAc shell that was much larger than the slower rise observed in the lateral shell. Surprisingly, chronic morphine treatment induced a sensitization of the medial dopamine response to morphine that opposed a diminished response observed in the saline-treated control group. This study expands on our current understanding of the medial NAc shell as hub of opioid-induced dopamine fluctuation. It also highlights the need for future opioid studies to appreciate the heterogeneity of dopamine neurons. Significance StatementThe social and economic consequences of the opioid epidemic are tragic and far-reaching. Yet, opioids are indisputably necessary in clinical settings where they remain the most useful treatment for severe pain. To combat this crisis, we must improve our understanding of opioid function in the brain, particularly the neural mechanisms that underlie opioid dependence and addictive behaviors. This study uses fiber photometry to examine dopamine changes that occur in response to repeated morphine, and morphine withdrawal, at multiple stages of a longitudinal opioid-dependence paradigm. We reveal key differences in how dopamine levels respond to opioid administration in distinct sub-regions of the ventral striatum and lay a foundation for future opioid research that appreciates our contemporary understanding of the dopamine system.

neuroscience↗

bioRxiv2024

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

systems biology↗