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Featured Research Papers

Study authors Vikek Kumar and Amy Moritz.

Study authors 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. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D3R-selective antagonists SB269,652 (1) and SB277011A (2) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a trans-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D3R-selective antagonists, 18a and 25a, which further delineates SAR associated with allosterism at D3R and provides leads toward novel drug development.

You can read more about this paper on PubMed.

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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. Both dopamine-releasing and non-dopamine-releasing VTA neurons integrate afferent signals with local inhibitory or excitatory inputs to generate particular output firing patterns. Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward- or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour.

You can read more about this paper on PubMed.

Reviews to Read Archives

Study authors Agustin Zapata and Eun-Kyung Hwang

Study authors 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 excited a majority of LHb neurons in in vitro electrophysiology experiments. These results indicate that the LHb participates in the suppression of impulsive responding for cocaine through the activation of a cholinergic circuit, and they suggest that LHb dysfunction may contribute to impaired impulse control associated with drug addiction.

You can read more about this paper on PubMed.

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Melissa J Sharpe

Hot off the Press paper!

Dopamine transients are sufficient and necessary for
acquisition of model-based associations

Nat Neurosci. 2017 Apr 3. doi: 10.1038/nn.4538. [Epub ahead of print]

Melissa J Sharpe, Chun Yun Chang, Melissa A Liu, Hannah M Batchelor, Lauren E Mueller, Joshua L Jones, Yael Niv & Geoffrey Schoenbaum

Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.

Read more about this paper on PubMed.

Hot off the Press Archives


Barry Hoffer
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 Hoffer
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.

Full Story Here.

Women Scientist Advisors Committee Logo

This year's winners at the NIDA IRP are Lindsay De Biase (Postdoctoral Fellow), Jayanthi Sankar (Staff Scientist) and Marisela Morales (Investigator). The winners were presented with trophies at the Biomedical Research Center this month.

Learn more about the Women Scientist Advisors Committee here.

Tsung-Ping Su

2016 Award for Sustainable Acquisitions - Individual
Dr. Da-Ting Lin has prioritized energy conservation, financial savings, and protecting both human and environmental health through his work.

Full Story Here.


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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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