Featured Paper of the Month

Featured Paper of the Month – June 2020
Published in Sci Rep by Perekopskiy, David; Afzal, Anum; Jackson, Shelley N; Muller, Ludovic; Woods, Amina S; Kiyatkin, Eugene A

One of the deadliest effects of opioids, such as heroin, is respiratory depression followed by brain hypoxia. While it is known that opioid receptors are densely expressed in both the brain and periphery, it is widely accepted that the hypoxic effects of opioids result solely from their direct action in the CNS. To examine the role of peripheral opioid receptors in triggering brain hypoxia, we used oxygen sensors in freely moving rats to examine how naloxone-HCl and naloxone-methiodide affect brain oxygen responses induced by intravenous heroin at low, human-relevant doses…

Featured Paper of the Month – May 2020
Published in Elife by Lane, Robert J; Abramyan, Ara M; Adhikari, Pramisha; Keen, Alastair C; Lee, Kuo-Hao; Sanchez, Julie; Verma, Ravi Kumar; Lim, Herman D; Yano, Hideaki; Javitch, Jonathan A; Shi, Lei

Lane et al. proposed that different types of antagonists could prefer specific types of inactive conformations of the dopamine D₂ and D₃ receptors. Based on the structures of these two receptors, the conformations of D₂ bound with the drugs risperidone and eticlopride (two dopamine antagonists) were simulated and compared. The results show that the inactive conformations of D₂ were very different when it was bound to eticlopride as opposed to risperidone…

Featured Paper of the Month – Apil 2020
Published in Elife by Nakamura, Yoki; Dryanovski, Dilyan I; Kimura, Yuriko; Jackson, Shelley N; Woods, Amina S; Yasui, Yuko; Tsai, Shang-Yi; Patel, Sachin; Covey, Daniel P; Su, Tsung-Ping; Lupica, Carl R

By studying brain tissue and neurons in vitro, Nakamura, Dryanovski et al. show that cocaine stimulates the release of endocannabinoids via extracellular vesicles. In essence, cocaine causes neurons to synthesize endocannabinoids that are then enclosed within membrane-bound packages. These packages – or extracellular vesicles – can then fuse with the cell’s membrane. Multiple protein interactions are necessary to permit this extracellular vesicle release, and the authors show that disrupting these control points prevents vesicle release…

Featured Paper of the Month – March 2020
Published in Elife by Stalnaker, Thomas A; Howard, James D; Takahashi, Yuji K; Gershman, Samuel J; Kahnt, Thorsten; Schoenbaum, Geoffrey

Midbrain dopamine neurons have long been thought to collectively signal a value prediction error, indicating whether the value of an event is greater or less than expected.  A few years ago, our lab showed that these neurons also signal if an event is different than expected, without regard for value.  In this paper, we build on this prior result by showing in both rats and humans that dopamine neurons or midbrain BOLD voxels, as a group, signal which unexpected event has occurred…

Featured Paper of the Month – February 2020
Published in Nature Communications by Bonaventura, Jordi; Eldridge, Mark A G; Hu, Feng; Gomez, Juan L; Sanchez-Soto, Marta; Abramyan, Ara M; Lam, Sherry; Boehm, Matthew A; Ruiz, Christina; Farrell, Mitchell R; Moreno, Andrea; Faress, Islam Mustafa Galal; Andersen, Niels; Lin, John Y; Moaddel, Ruin; Morris, Patrick J; Shi, Lei; Sibley, David R; Mahler, Stephen V; Nabavi, Sadegh; Pomper, Martin G; Bonci, Antonello; Horti, Andrew G; Richmond, Barry J; Michaelides, Michael

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications…

Featured Paper of the Month – January 2020
Published in Neuropsychopharmacology by Baeg, Eunha; Jedema, Hank P; Bradberry, Charles W

Drug-associated cues can intrude upon thinking, making relapse more likely. A measure of how strongly cues engage cognitive resources is called attentional bias. This is reflected in slightly longer response times on trials on a stimulus response task when drug cues are present compared to non-drug cues. In both cases, the cue is an irrelevant distractor that should just be ignored. Attentional bias is clinically important, because, across individuals, it correlates with extent of current use, and risk of relapse among those attempting abstinence…

Featured Paper of the Month – December 2019
Published in European Journal of Neuroscience by Mongia, Smriti; Yamaguchi, Tsuyoshi; Liu, Bing; Zhang, Shiliang; Wang, Huiling; Morales, Marisela

Unraveling the mystery of the glutamate-dopamine connection
The ventral tegmental area (VTA) is a brain structure that participates in the rewarding effects of drug use, but the role of specific neurons within the VTA is unclear. Scientists at NIDA’s Intramural Research Program conducted a set of studies to better understand the function of glutamate neurons in this addiction-relevant brain region. Glutamate is an excitatory neurotransmitter that plays an important role in brain development, normal brain processes, and pathological conditions like addiction…

Featured Paper of the Month – November 2019
Published in PLoS One by Schiffino, Felipe L; Siemian, Justin N; Petrella, Michele; Laing, Brenton T; Sarsfield, Sarah; Borja, Cara B; Gajendiran, Anjali; Zuccoli, Maria Laura; Aponte, Yeka

Motivated states such as food-seeking and consumption are essential for survival. A brain region called the lateral hypothalamus (LH) plays a fundamental role in regulating feeding and reward-related behaviors, but the contributions of specific neuronal subpopulations in the LH have not been thoroughly characterized. Here we examine how lateral hypothalamic leptin receptor-expressing (LH^LEPR) neurons, a subset of GABAergic cells, regulate motivation in mice. We trained mice to lever-press for food pellets on a progressive ratio schedule, a model commonly used to assess motivation to obtain a reinforcer…

Featured Paper of the Month – October 2019
Published in The Journal of Neuroscience by Hsu, Li-Ming; Keeley, Robin J; Liang, Xia; Brynildsen, Julia K; Lu, Hanbing; Yang, Yihong; Stein, Elliot A

Smoking remains a major public health burden, with approximately 20% of the world’s population engaging in regular smoking. Given the high relapse rate among smokers who enter treatments programs, early identification of vulnerable individuals, before the conversion from casual experimentation to regular smoking and addiction, is an important milestone to understand, prevent and potentially minimize nicotine dependence. Using a rodent model of nicotine dependence, we developed a quantitative predictor of subsequent nicotine dependence severity using graph theory-based analyses of fMRI BOLD resting state data collected at baseline, prior to any drug experience…

Featured Paper of the Month – September 2019
Published in ACS Pharmacology & Translational Science by Bonifazi, Alessandro; Yano, Hideaki; Guerrero, Adrian M; Kumar, Vivek; Hoffman, Alexander F; Lupica, Carl R; Shi, Lei; Newman, Amy Hauck

The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D₂ receptor (D₂R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D₂R agonists linking the D₂R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D₂R affinity and selectivity over sumanirole…