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Featured paper of the Month!

Salience and default mode network dysregulation in chronic cocaine users predict treatment outcome.

Brain. 2017 Feb 20. doi: 10.1093/brain/awx036. [Epub ahead of print]

Geng X, Hu Y, Gu H, Salmeron BJ, Adinoff B, Stein EA, Yang Y.

The goal of the study was to identify imaging biomarkers that predict the treatment outcome of cocaine addiction. Impairments of cortical thickness and functional connectivity were identified in a cohort of non-treatment-seeking cocaine users compared with matched healthy controls. These brain structural and functional measures were used, together with clinical assessments and demographic information, to predict treatment outcome of a separate cohort of treatment-seeking cocaine users who underwent a residential psychosocial treatment . Functional connectivity between the temporal pole (TP) and medial prefrontal cortex (mPFC), together with years of education, predicted the treatment outcome at an accuracy up to 88% at 150 days after the discharge from the treatment. The TP-mPFC circuit identified in this study may serve as a new therapeutic target for cocaine addiction using brain stimulation techniques, such as transcranial magnetic stimulation (TMS).

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Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia.

Neuron. 2017 Jul 19;95(2):341-356.e6. doi: 10.1016/j.neuron.2017.06.020. Epub 2017 Jul 6.

De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, Zhang HY, Liu QR, Shen H, Xi ZX, Goldman D, Bonci A.

Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG)....

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Chemogenetics revealed: DREADD occupancy and activation via converted clozapine.

Science. 2017 Aug 4;357(6350):503-507. doi: 10.1126/science.aan2475.

Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa-Shah P, Rodriguez LA, Ellis RJ, Richie CT, Harvey BK, Dannals RF, Pomper MG, Bonci A, Michaelides M.

Designer receptors exclusively activated by designer drugs (DREADDs) constitute a powerful chemogenetic strategy that can modulate nerve cell activity in freely moving animal preparations. NIDA scientists used radioligand receptor occupancy measurements and in vivo positron emission tomography to show that DREADDs expressed in the brain are not activated by the designer compound CNO. Instead, they are activated by the CNO metabolite clozapine, a drug with multiple endogenous targets. This may have important implications for the interpretation of results obtained with this popular technology.

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Elise Lesage
Elise Lesage

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Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers: A Randomized Trial.

JAMA Psychiatry. 2017 Jun 1;74(6):632-640. doi: 10.1001/jamapsychiatry.2017.0400.

Lesage E, Aronson SE, Sutherland MT, Ross TJ, Salmeron BJ, Stein EA.

In this paper, NIDA scientists wanted to answer the question : ”How are reward sensitivity, in brain regions thought to be involved in drug abuse, and cognitive flexibility affected by acute abstinence and stimulation of the nicotinic acetylcholine receptors in dependent smokers?” In this placebo-controlled crossover study they found a “double dissociation” between decreased neural signatures of reward sensitivity...

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Study authors Study authors Haiying Zhang, Zheng-Xiong Xi, and Guohua Bi.
Haiying Zhang, Zheng-Xiong Xi, Guohua Bi.
Featured paper of the Month!

The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic

Neuropsychopharmacology. 2017 Aug;42(9):1871-1883. doi: 10.1038/npp.2017.41. Epub 2017 Mar 7.

Zhang HY, Bi GH, Yang HJ, He Y, Xue G, Cao J, Tanda G, Gardner EL, Newman AH, Xi ZX.

JJC8-016, a recently discovered (±) modafinil analogue and atypical dopamine transporter (DAT) inhibitor, was compared to R-modafinil for its effects in several rodent models of psychostimulant abuse. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, while R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior ...

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Study authors Vikek Kumar and Amy Moritz.
Vikek Kumar and Amy Moritz.
Featured paper of the Month!

July 2017 - Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R).

J Med Chem. 2017 Feb 23;60(4):1478-1494. doi: 10.1021/acs.jmedchem.6b01688. Epub 2017 Feb 10.

Kumar V, Moritz AE, Keck TM, Bonifazi A, Ellenberger MP, Sibley CD, Free RB, Shi L, Lane JR, Sibley DR, Newman AH.

The development of bitopic ligands directed toward D2-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D3 receptor (D3R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing...

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Reviews to Read

June 2017 - Ventral tegmental area: cellular heterogeneity, connectivity and behaviour

Nat Rev Neurosci. 2017 Feb;18(2):73-85. doi: 10.1038/nrn.2016.165. Epub 2017 Jan 5. Review.

Morales M, Margolis EB.

Dopamine-releasing neurons of the ventral tegmental area (VTA) have central roles in reward-related and goal-directed behaviours. VTA dopamine-releasing neurons are heterogeneous in their afferent and efferent connectivity and, in some cases, release GABA or glutamate in addition to dopamine. Recent findings show that motivational signals arising from the VTA can also be carried by non-dopamine-releasing projection neurons, which have their own specific connectivity...

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Photo of 2017 Mentoring Award winners (left to right): Geoffrey Schoenbaum, MD, PhD (Investigator Award); Lindsay De Biase, PhD (Postdoctoral Fellow Award); and Karran Phillips, MD (Staff Clinician Award).
2017 Mentoring Awardees

NIDA IRP NEWS!

Congratulations to the 2017 NIDA IRP Mentoring Award winners.

Award recipients are (left to right): Geoffrey Schoenbaum, MD, PhD (Investigator Award); Lindsay De Biase, PhD (Postdoctoral Fellow Award); and Karran Phillips, MD (Staff Clinician Award). They were presented with plaques at the 6th annual NIDA Poster Day and Mentoring Awards Ceremony on May 17, 2017.

The Mentoring Awards recognize individuals who have served as exceptional mentors to trainees in the institute, and are given annually in the spring.

More about our Research Training program here

Barry J. Hoffer Receiving the Award
Barry J. Hoffer Receiving the Award

NIDA IRP NEWS!

Barry J. Hoffer awarded Honorary Doctors of the Faculty of Philosophy at the University of Helsinki

Dr. Barry J. Hoffer, the former Scientific Director of the NIDA IRP, has been awarded an Honorary Doctors of the Faculty of Philosophy from the University of Helsinki for his lifelong work in neuropharmacology. The Faculty of Philosophy of the University of Helsinki confers distinguished persons from the fields of science, culture and society as honorary doctors each year May. Angela Merkel was also among this year's award recipients.

More information here

Agustin Zapata and Eun-Kyung Hwang

Agustin Zapata and Eun-Kyung Hwang
Featured paper of the Month!

June 2017 - Lateral Habenula Involvement in Impulsive Cocaine Seeking

Neuropsychopharmacology. 2017 Apr;42(5):1103-1112. doi: 10.1038/npp.2016.286. Epub 2016 Dec 27.

Zapata A, Hwang EK, Lupica CR.

The lateral habenula (LHb) is a brain structure involved in sleep control, reward-based decision making, avoidance of punishment, and responses to stress. Additional work has established that the LHb mediates negative feedback in response to aversive events. As a hallmark of drug addiction is the inability to limit drug use despite negative consequences, we hypothesize that LHb dysfunction may have a role in lack of control over drug seeking. We find that inhibition of the LHb did not alter suppression of cocaine self-administration in response to punishment nor cocaine’s reinforcing efficacy. However, LHb inhibition increased cocaine seeking when the drug was not available in rats trained to discriminate its presence using an environmental cue. This effect was mimicked by intra-LHb muscarinic cholinergic (mAch) antagonist injection, and activation of mACh receptors ...

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The National Institute on Drug Abuse (NIDA), is part of the National Institutes of Health (NIH), the principal biomedical and behavioral research agency of the United States Government. NIH is a component of the U.S. Department of Health and Human Services.

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