# Presentation: 469102

## Slide 1

## Slide 2

## Different Brain Circuitry Involved in

**Different Brain Circuitry Involved in**
**Drug Reward and Drug Persistence Behavior**

***Source:  Adapted from McFarland, K. and Kalivas, P.W.  Journal of Neuroscience, 21(21), pp. 8655-8663, November 1, 2001.***

**Notes:**
Through NIDA funded research we have learned a great deal about the neural circuits involved in drug addiction....As you can see, we’ve moved beyond just dopamine to other circuits, such as glutamate

## NIDA’s Neuroscience Program

***NIDA’s Neuroscience Program***

***Defining the Problems...***

***Developing the Tools...***

## Genetics Research at NIDA

## Genetics Research at NIDA40-50% of the vulnerability to addiction is genetic

## Genetic Variation Predicts Naltrexone Treatment Response for Alcohol Dependence

**Cumulative Survival (Time to Relapse)**

**Days**

***Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003***

**Notes:**
Pharmacogenomics:  Genetic variation can predict treatment response.
The Effectiveness of Your Medication May Depend on Your Genes
Background: Drug and alcohol abuse in America create staggering societal costs and prevent millions of people from reaching their full potential at school, on the job, and in their communities. Consequently, there have been substantial efforts to better understand addiction and to develop treatments that can be successfully used to help people eliminate their alcohol and/or drug addiction. It has been hypothesized that while there are commonalities in addiction, there are also unique features of individuals that may make some treatments effective for a subset of people, but not for everyone. This may be due, in part, to differences in genetic make-up, which could affect an individual=s susceptibility to particular medications or to other treatment approaches. By identifying the genes that are involved in addiction, we are one step closer to determining whether they may influence treatment effectiveness.
Advance: Prior research studies in animals have identified the mu-opioid receptor as a promising gene candidate for understanding addiction and targeting medication development. This is a receptor in the brain where opiate drugs, such as morphine and heroin, attach to exert their behavioral effects. The medication naltrexone is currently used to treat people addicted to opiates, such as morphine, and it has been found to also successfully treat individuals dependent on alcohol. Naltrexone binds to this particular receptor, but as an antagonist. Meaning, naltrexone has no behavioral effects of its own and, it can interfere with the actions of other opiate drugs. Also, naltrexone has not been found to be effective in all people. In the present study, researchers examined whether different forms of the gene for the mu opioid receptor result in differences in response to treatment with naltrexone for alcoholism. They found that people with a particular form of the mu opioid receptor gene responded very well to treatment with naltrexone, whereas people with a different form of the gene responded poorly to naltrexone. 
Implications: These results show that variations in the gene for the mu opioid receptor can determine whether or not a person is likely to be successfully treated with the opioid antagonist, naltrexone. This has important implications not only for treating people who are addicted to alcohol, but also for treating people who are addicted to a variety of other drugs. The results demonstrate that genes can determine whether or not individuals will respond to treatment with a particular medication. This suggests that, when possible, that understanding an individual=s genetic make-up may be an efficient mechanism for identifying people who will respond to specific treatments for addiction, and possibly, for other diseases as well. 
Oslin DW, Berrettini W., Kranzler HR, Pettinati H., Gelernter J., Volpicelli JR, and O=Brien CP: A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546-1552, 2003.

## Amphetamine and the Hallucinogen DOI Produce Different Protein Profiles in Brain

- Vehicle

- AMPH

- DOI

**Amphetamine and the Hallucinogen DOI Produce Different Protein Profiles in Brain**

**Notes:**
Going beyond the genes to the protein:
This shows different protein profiles following amphetamine vs DOI (5-hydroxytryptamine (5-HT)2 agonist (+/- )-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)) Source: Ariel Deutsch 

Note: the number on the lower right shows the number of the protein – note protein changes with slide transition

## High-Throughput Genome-Wide Scan for Addiction Loci

- High-Throughput Genome-Wide Scan for Addiction Loci

**NIDA plans to work with Perlegen Sciences **
**    ****to utilize their resource of 1.5 million single **
**    ****nucleotide polymorphisms in a whole**
**    ****genome scan to identify drug addiction loci**
**Three groups from the NIDA Genetics **
**    ****Consortium competed for access to the **
**    ****Perlegen resource -- A group studying nicotine **
**    ****genetics, headed by Dr. Laura Bierut, has been granted access**

***40-50% of the vulnerability to addiction is genetic***

## Adolescent Brain Development

##  ADDICTION IS A DEVELOPMENTAL DISEASE 

***It starts in adolescence and childhood***

***NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003***

**% in each age group who develop first-time cannabis use disorder**

**0.0%**

**0.2%**

**0.4%**

**0.6%**

**0.8%**

**1.0%**

**1.2%**

**1.4%**

**1.6%**

**5**

**10**

**15**

**18**

**25**

**30**

**35**

**40**

**45**

**50**

**55**

**60**

**65**

**70**

**Age**

**Age at cannabis use disorder as per DSM IV**

## Brain Maturation from Ages 5 to 20

- Copyright ©2004 by the National Academy of Sciences

**Gogtay, Giedd, et al. (2004) Proc. Natl. Acad. Sci. USA 101, 8174-8179**

**Brain Maturation from Ages 5 to 20**

**Notes:**
Fig. 3. Right lateral and top views of the dynamic sequence of GM maturation over the 
cortical surface
Red = more gray matter, blue = less

## Imaging and Other Innovative Technologies

## Slide 14

**Notes:**
Structural Abnormalities in the Brains of Human Subjects Who Use Methamphetamine 
Using structural magnetic resonance imaging and new computational brain mapping techniques, the current study revealed severe decreases in gray-matter density in brain regions of chronic methamphetamine abusers that are associated with cognition and emotion. The normal asymmetry between brain hemispheres found in one of these regions, the anterior cingulate gyrus, was erased in methamphetamine abusers. Interestingly, this finding is similar to that observed in the brains of patients with schizophrenia. In addition, methamphetamine abusers showed smaller hippocampal volumes, a region of the brain associated with learning and memory, than controls, which was correlated with decreased memory performance on a word-recall test. 

The structural deficits observed in this study may help account for many of the emotional and cognitive problems observed in chronic methamphetamine abusers. Future studies are needed to clarify how these deficits relate to clinical prognosis. 

Citation: Thompson PM, Hayashi KM, Simon SL, Geaga JA, Hong MS, Sui Y, Lee JY, Toga AW, Ling W, London ED (2004) J Neurosci 24: 6028-36. 

Figure legend:  Gray-matter differences on the medial brain surface. Group difference maps show mean percentage differences in gray-matter volumes between the control group average and the methamphetamine group average, with significant deficits in red and spared regions in blue. The cingulate gyrus shows highly significant gray-matter deficits (red colors; p < 0.034, corrected), whereas other brain regions are comparatively spared (blue colors). 

## Partial Recovery of Brain Metabolism and Function in Methamphetamine Abusers After Protracted Abstinence

**Partial Recovery of Brain Metabolism and Function in Methamphetamine Abusers After Protracted Abstinence**

***Short Abstinence***

***Protracted Abstinence***

**% Metabolic Change**

**Improved memory correlates with thalamic recovery**

- Adapted from Wang, Volkow, et al, (2004) American Journal of Psychiatry 161: 242-8 (scans unpublished)

**Notes:**
Partial Recovery of Brain Metabolism in Methamphetamine Abusers After Protracted Abstinence 

Decreased metabolism in METH abusers after short interval of abstinence in caudate, NAc, insula and thalamus. 
Decreased metabolism in METH abusers after protracted abstinence only in caudate, NAc and insula; thalamus recovers (arrows). 

Recovery of function following protracted abstinence - Correlation Between Changes in Thalamic Activity and Neuropsychological Test Performance in METH Abusers Evaluated After Short and Protracted Intervals of Abstinence

Advance: Brain glucose metabolism (FDG PET) was measured in methamphetamine abusers after short-term (less than 6 months) and long-term (12-17 months) abstinence and compared to non-drug users. Short-term abstinence did not improve brain glucose metabolism in any of the regions studied. However, following long-term abstinence, activity in the thalamus returned to levels similar to those in non-drug users. This increased activity with prolonged abstinence, which may reflect adaptive changes to compensate for other persistent deficits, was associated with improved performance in motor and verbal memory tests. In contrast, there was no recovery of function in the striatum, which may reflect long-lasting changes in dopamine cell activity in this region. Such changes could account for the persistent lack of motivation and inability to experience pleasure observed in detoxified methamphetamine abusers. 

Implications: Therefore, while protracted abstinence may reverse some of the drug-induced alterations in brain function, other deficits persist. These findings have implications in the treatment of methamphetamine abusers, suggesting that protracted abstinence and proper rehabilitation may reverse some methamphetamine-induced alterations in brain function. 

Citation: Unpublished images from Volkow Lab, BNL related to Wang GJ, Volkow ND, Chang L, Miller E, Sedler M, Hitzemann R, Zhu W, Logan J, Ma, Y and Fowler JS (2004) American Journal of Psychiatry 161: 242-8 (graphs from Figure 2). 

## We Are Using Science to

**We Are Using Science to**
**Develop Even Better Treatment **

## NIDA Has Numerous Mechanisms To Fund Innovative Drug Abuse Research

## Some Recent RFAs and PAs

- _RFA-DA-05-003_ Developmental Centers for Translational Research on the Clinical Neurobiology of Drug Addiction
- _PA-04-152_ MDMA: Research Areas Needing More Interest
- _PA-04-110_ Prescription Drug Abuse
- _PA-03-175_ Fine Mapping Genes and Gene Variants for Drug Addiction Susceptibility
- _PA-03-155_ Molecular Genetics of Drug Addiction Vulnerability
- _PAR-03-146_ (B/START) Behavioral Science Track Award for Rapid Transition
- _PAR-03-017_ Cutting-Edge Basic Research Awards (CEBRA)
**Find out more at: ****	****	****	****	****                 ****http://www.drugabuse.gov/funding/resfundslist.html**

## NIDA CEBRA PROGRAM

**Foster highly innovative, novel or conceptually creative research** that advances our understanding of drug abuse and addiction
**Support research that is high-risk and potentially high-impact** and that is underrepresented or not included in NIDA's current portfolio

- PURPOSE

## Micro-optical probes

**CEBRA: Two-photon endoscopy****(Mark Schnitzer)**

**Notes:**
Can do in vivo studies in awake behaving animals to look at synaptic activity – This is just a glimpse of what CEBRA grantee, Mark Schnitzer will be presenting later today.

Micorendoscopy development for imaging deep brain structures

Probes are 350-1000 microns in diameter no larger than an micodialysis probes and much smaller the miniature endoscopes of 1-8mm in dia.

The probes use multiple gradient refractive index micro-lenses  that can provide micron-scale resolution 
These probes can go as deeper (350-1000 microns) than conventional surface probes.   

Looking a 8 micron diameter red blood cells traveling at a speed of 30-350 microns/sec

## NIH ROADMAP

- Building Blocks, Biological Pathways and Networks
- Molecular Library and Imaging

- Structural Biology
- Nanomedicine
- Bioinformatics and Computational Biology

**NEW PATHWAYS TO DISCOVERY**

-     To accelerate the discovery and translation of biomedical research into new and effective prevention and treatment strategies.

**RESEARCH TEAMS OF THE FUTURE**
-    High-Risk Research
-    Interdisciplinary Research

**RE-ENGINEERING THE CLINICAL RESEARCH ENTERPRISE**

-   Public-Private Partnerships

## Current and Future Roadmap Funding Opportunities 

**NEW PATHWAYS TO DISCOVERY**
- _Molecular Libraries and Imaging_
- Novel Preclinical Tools for Predictive ADME-Toxicology
- Cheminformatics Research Centers
- Assay Technology Development         (Re-issuance)

- Pilot Scale Libraries for High Throughput Screening
- New Methodologies for Natural Products Chemistry

- _Building Blocks, Biological Pathways _
- National Technology Centers for Networks & Pathways (Re-issuance)
- _Bioinformatics and Computational Biology_
- National Centers for Biomedical Computing (Re-issuance)
- _Structural Biology_
- Membrane Protein Production and Structure Determination
- _Nanomedicine:_      Nanomedicine Development Centers

## Neurosciences Blueprint 

***Neurosciences Blueprint ***

**Sunday, October 24, 1:00 p.m.–3:00 p.m.**
**Convention Center, Room 3**

## Funding Opportunities: http://www.drugabuse.gov/funding/resfundslist.html
Training Opportunities: www.drugabuse.gov/researchtraining/traininghome.html
Roadmap activities: http://www.drugabuse.gov/about/roadmap/index.html

**Training Opportunities:** _[www.drugabuse.gov/researchtraining/traininghome.html](http://www.drugabuse.gov/researchtraining/traininghome.html)_
**Roadmap activities:** _[http://](http://www.drugabuse.gov/about/roadmap/index.html)__[www.drugabuse.gov/about/roadmap/index.html](http://www.drugabuse.gov/about/roadmap/index.html)_

**www.drugabuse.gov**

## Slide 25