Featured Paper of the Month

Featured Paper of the Month – September 2020
Published in Nature Communications by Plenge, Per; Abramyan, Ara M; Sørensen, Gunnar; Mørk, Arne; Weikop, Pia; Gether, Ulrik; Bang-Andersen, Benny; Shi, Lei; Loland, Claus J

The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations…

Featured Paper of the Month – August 2020
Published in Journal of Neuroscience by Reiner, David J; Lofaro, Olivia M; Applebey, Sarah V; Korah, Hannah; Venniro, Marco; Cifani, Carlo; Bossert, Jennifer M; Shaham, Yavin

Fentanyl is a major contributor to the opioid overdose crisis, but there are few preclinical studies of fentanyl relapse. These studies have used experimenter-imposed extinction or forced abstinence procedures. In humans, however, abstinence is often voluntary, with drug available in the drug environment but forgone in favor of nondrug alternative reinforcers. We recently developed a rat model of drug relapse after palatable food choice-induced voluntary abstinence. Here, we used classical pharmacology, immunohistochemistry, and retrograde tracing to demonstrate a critical role of the piriform and orbitofrontal cortices in relapse to fentanyl seeking after voluntary abstinence…

Featured Paper of the Month – July 2020
Published in Neuropsychopharmacology by Keeley, Robin J; Hsu, Li-Ming; Brynildsen, Julia K; Lu, Hanbing; Yang, Yihong; Stein, Elliot A

Developing brain-based biomarkers to assess drug dependence, including nicotine dependence, are essential to assess and improve the current, marginally effective, treatments. In humans, using brain-based resting state functional connectivity, we have previously identified a circuit between the dorsal anterior cingulate cortex(ACC) and the striatum whose connectivity decreased with increasing nicotine dependence severity. This circuit was unaffected by acute nicotine administration, suggesting a trait marker of nicotine addiction. However, whether this trait circuit dysregulation is predispositional or resultant from nicotine dependence remained unclear…

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…