The Intramural Research Program of the National Institute on Drug Abuse

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    The IRP is served by the best and brightest in the scientific community. Find out more about the scientists striving to solve the puzzles of drug addiction and its effects on the human brain.

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    The research of the Intramural Research Program is supported at the molecular, genetic, cellular, animal, and clinical levels and is conceptually integrated, highly innovative, and focused on major problems in the field of drug addiction research.

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    Intramural Research Program (IRP) of the National Institute on Drug Abuse is dedicated to innovative research on basic mechanisms that underlie drug abuse and dependence, and to develop new methods for the treatment of drug abuse and dependence.

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Featured paper of the Month!

FEBRUARY: Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area

Cell Rep. 2015 Sep 29;12(12):1997-2008

Huikun Wang, Tyler Treadway, Daniel P. Covey, Joseph F. Cheer, & Carl R. Lupica

Cocaine is a highly addictive drug that acts upon the brain’s reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine’s effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors....

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Reviews to Read

Intrinsic plasticity: an emerging player in addiction

Saïd Kourrich, Donna J. Calu and Antonello Bonci

Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability factors that are remote from the synapse). Accumulating evidence now suggests that intrinsic factors such as K+ channels are not only altered by cocaine but may also contribute to the shaping of the addiction phenotype....

Read the full review at Nature Reviews.

Comfort A. Boateng & Oluyomi M. Bakare.
Comfort A. Boateng & Oluyomi M. Bakare.
Featured paper of the Month!

JANUARY: High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout Mice

J Med Chem. 2015 Aug 13;58(15):6195-213.

Comfort A. Boateng, Oluyomi M. Bakare, Jia Zhan, Ashwini K. Banala, Caitlin Burzynski, Elie Pommier, Thomas M. Keck, Prashant Donthamsetti, Jonathan A. Javitch, Rana Rais, Barbara S. Slusher, Zheng-Xiong Xi, and Amy Hauck Newman

The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use....

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Hot off the Press!

Brief optogenetic inhibition of dopamine neurons mimics endogenous negative reward prediction errors

Nat Neurosci. 2015 Dec 7. doi: 10.1038/nn.4191.

Chun Yun Chang, Guillem R Esber, Yasmin Marrero-Garcia, Hau-Jie Yau, Antonello Bonci & Geoffrey Schoenbaum

Correlative studies have strongly linked phasic changes in dopamine activity with reward prediction error signaling. But causal evidence that these brief changes in firing actually serve as error signals to drive associative learning is more tenuous. Although there is direct evidence that brief increases can substitute for positive prediction errors, there is no comparable evidence that similarly brief pauses can substitute for negative prediction errors....

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Reviews to Read

The GPCR heterotetramer: challenging classical pharmacology

Sergi Ferre

Two concepts are gaining increasing acceptance in G protein-coupled receptor (GPCR) pharmacology: (i) pre-coupling of GPCRs with their preferred signaling molecules, and (ii) GPCR oligomerization. This is begging for the introduction of new models such as GPCR oligomer-containing signaling complexes with GPCR homodimers as functional building blocks. This model favors the formation of GPCR heterotetramers - heteromers of homodimers coupled to their cognate G protein....

Read the full review at PubMed.

The Cover from this month's paper.
The cover from this month's paper.
Featured paper of the Month!

DECEMBER: Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists

J Med Chem. 2015 Jun 25;58(12):5038-52.

Brandon R. Selfridge, Xiaohui Wang, Yingning Zhang, Hang Yin, Peter M. Grace, Linda R. Watkins, Arthur E. Jacobson, and Kenner C. Rice

Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compounds based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist....

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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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