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An illustration by the study author.
Hideaki Yano, Ph.D.

hot off the press!

Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor.

Nat Commun, 9 (1), pp. 486, 2018, ISSN: 2041-1723 (Electronic); 2041-1723 (Linking).

Yano, Hideaki; Cai, Ning-Sheng; Xu, Min; Verma, Ravi Kumar; Rea, William; Hoffman, Alexander F; Shi, Lei; Javitch, Jonathan A; Bonci, Antonello; Ferre, Sergi

The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf.

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Study Author Leslie Whitaker
Featured paper of the Month!

February 2018 - Bidirectional Modulation of Intrinsic Excitability in Rat Prelimbic Cortex Neuronal Ensembles and Non-Ensembles after Operant Learning

J Neurosci. 2017 Sep 6;37(36):8845-8856. doi: 10.1523/JNEUROSCI.3761-16.2017. Epub 2017 Aug 4.

Whitaker LR, Warren BL, Venniro M, Harte TC, McPherson KB, Beidel J, Bossert JM, Shaham Y, Bonci A, Hope BT.

Learned associations between environmental stimuli and rewards drive learning and motivated behavior. These memories are thought to be encoded by alterations within specific patterns of sparsely distributed neurons called neuronal ensembles that are selectively activated by reward-predictive stimuli. Here we use the Fos promoter to identify strongly activated neuronal ensembles in rat prelimbic cortex (PLC) and assess altered intrinsic excitability following 10 days of operant food self-administration training. First, we selectively ablated Fos-expressing PLC neurons that were active during food self-administration. Selective removal of these neurons decreased food seeking.

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hot off the press!

Dopamine Neurons Respond to Errors in the Prediction of Sensory Features of Expected Rewards.

Neuron. 2017 Sep 13;95(6):1395-1405.e3. doi: 10.1016/j.neuron.2017.08.025.

Takahashi YK, Batchelor HM, Liu B, Khanna A, Morales M, Schoenbaum G.

Associative learning is driven by fundamental instructive or teaching signals that reflect errors in the prediction of rewards and other events. Previously dopamine neurons in the midbrain that project widely in the brain have been shown to signal these errors only for value. Here NIDA researchers show that these value errors are a special case of a more general error signal represented in the firing of midbrain dopamine neurons. This signal reflects errors in the prediction of sensory events or features. This expansion of the model puts this critical system in a position to support a much wider array of real-world behaviors than was previously possible.

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Study Authors David H Epstein and William J Kowalczyk
Study Authors David H Epstein
and William J Kowalczyk.
Reviews to Read

January 3, 2018 - Compulsive Seekers: Our take. Two Clinicians’ Perspective on a New Animal Model of Addiction

Neuropsychopharmacology, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking).

Epstein, David H; Kowalczyk, William J

In this invited commentary, Bill Kowalczyk and I weighed in on a new rat model of addiction developed by Chiara Giuliano in Barry Everitt’s lab at the University of Cambridge. Like other recently developed models of addiction, this one goes beyond the older approach of just letting rats press levers for drug injections. These rats learned that they had to press one lever just to gain access to a second lever that would give them access to drug. By drawing things out across two successively accessed levers—sort of like inserting an “are you sure?” pop-up window in a chain of computer commands—the researchers made it easier to study the phases across which a rat starts merely seeking a drink and then finally decides to take the drink. Oh, and one more thing. Pressing the second lever sometimes gave the rats an electric shock instead of a drink...

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Study authors Susanne Bäck, Emily Wires and Kathleen Trychta.
Featured paper of the Month!

High fat diet disrupts endoplasmic reticulum calcium homeostasis in the rat liver.

J Hepatol. 2017 Nov;67(5):1009-1017. doi: 10.1016/j.jhep.2017.05.023. Epub 2017 Jul 17.

Wires, E.S., Trychta, K.A., Bäck, S., Sulima, A., Rice, K.C., and Harvey, B.K.

The endoplasmic reticulum (ER) is cellular organelle that performs critical functions such as the production and processing of proteins, lipids and drugs. The ER also serves as the primary storage site for calcium inside the cell. Using a novel biological sensor protein called GLuc-SERCaMP developed by our laboratory at the NIDA IRP, we show that high fat diets causes changes to ER calcium in the livers of rats. Unrestricted access to high fat food pellets caused molecular changes to regulators of ER calcium and an increase in markers of fatty liver disease. Animals treated with dantrolene, a drug that stabilizes ER calcium, reduced the levels of our sensor and reduced food intake. The study describes a novel technique for liver research and provides insight into cellular processes that may contribute to the pathogenesis of obesity and fatty liver disease.

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Dr. Jeremy P. Waletzky

Dr. Kenner Rice

NIDA IRP NEWS!

Kenner Rice Elected 2017 National Academy of Inventors Fellow

Congratulations to Dr. Kenner Rice for being chosen as a 2017 Fellow by the National Academy of Inventors. Dr. Rice joins over 900 other Fellows, representing over 250 research universities and governmental and non-profit research institutes. Dr. Rice is Chief of the Drug Design and Synthesis Section at the NIDA IRP and also runs the Chemical Biology Research Branch at the National Institute of Alcohol Abuse.

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A figure from this study.
A figure from this study.
Featured paper of the Month!

Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats.

Cell Rep. 2017 Jul 11;20(2):319-332.

Yang HJ, Zhang HY, Bi GH, He Y, Gao JT, Xi ZX.

The etiology and pathophysiology of drug addiction are still not well understood. In this research paper, we show that genetic deletion of mGluR2, a presynaptic glutamate autoreceptor, decreases sensitivity to cocaine reward that causes a compensatory increase in cocaine intake and a decrease in relapse to cocaine-seeking behavior in rats.

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Study Authors Leigh Panlilio
and Zuzana Justinova
Reviews to Read

November 21, 2017 - Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure

Neuropsychopharmacology. 2017 Aug 28. doi: 10.1038/npp.2017.193. [Epub ahead of print]

Panlilio, Leigh V; Justinova, Zuzana

Cannabis use has become increasingly accepted socially and legally, for both recreational and medicinal purposes. Without reliable information about the effects of cannabis, people cannot make informed decisions regarding its use. Like alcohol and tobacco, cannabis can have serious adverse effects on health, and some people have difficulty discontinuing their use of the drug...

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Dr. Jeremy P. Waletzky

Dr. Jeremy P. Waletzky

NIDA IRP NEWS!

Dr. Jeremy P. Waletzky Event

The Jacob P. Waletzky Award of the Society for Neuroscience is given to a young scientist (within 15 years of his/her Ph.D. or M.D. degree) whose independent research has led to significant conceptual and empirical contributions to the understanding of drug addiction. Both basic and clinical researchers are eligible for the award. Future plans to continue to make significant contributions to addiction research and treatment is one of the selection criteria. This year's awards winners were Garret Stuber (University of North Carolina) and Karen Ersche from (University of Cambridge).

This year, Dr. Jeremy P. Waletzky was also honored at a special event at the NIDA IRP where he received a lifetime achievement award. Most of the previous winners of the Waletzky Award traveled from around the country to attend and discuss their research.

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A figure from this article.
Reviews to Read

November 2017 - Misuse of Novel Synthetic Opioids: A Deadly New Trend.

J Addict Med. 2017 Jul/Aug;11(4):256-265.

Prekupec MP, Mansky PA, Baumann MH.

Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl...

You can read more about this paper on PubMed.


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