NA shell NA shell vPFC mVP VTA NA core NA core dPFC SN dVP Blockade in these regions blocks relapse or reinstatement Drug Seeking Behavior – Motor Subcircuit glutamate Reward – Limbic Subcircuit dopamine Blockade in these regions blocks initiation of drug use, but not relapse Different Brain Circuitry Involved in Drug Reward and Drug Persistence Behavior 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 , November 1, 2001.

NIDA’s Neuroscience Program Defining the Problems... Developing the Tools...

Genetics Research at NIDA

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 Naltrexone/ Asp40 Allele (A/G, G/G) (n=23) Naltrexone/ Asn40 Allele (A/A) (n=48) Placebo/ Asn40 Allele (A/A) (n=41) Placebo/ Asp40 Allele (A/G, G/G) (n=18) Oslin, Berrettini, Volpicelli, Kranzler, O’Brien, et al., 2003

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

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 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% Age Age at cannabis use disorder as per DSM IV

Copyright ©2004 by the National Academy of Sciences Gogtay, Giedd, et al. (2004) Proc. Natl. Acad. Sci. USA 101, Brain Maturation from Ages 5 to 20

Imaging and Other Innovative Technologies

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: (scans unpublished)

Genetics Mechanisms Treatments We Are Using Science to Develop Even Better Treatment 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 Developmental Centers for Translational Research on the Clinical Neurobiology of Drug Addiction  PA MDMA: Research Areas Needing More Interest  PA Prescription Drug Abuse  PA Fine Mapping Genes and Gene Variants for Drug Addiction Susceptibility  PA Molecular Genetics of Drug Addiction Vulnerability  PAR (B/START) Behavioral Science Track Award for Rapid Transition  PAR Cutting-Edge Basic Research Awards (CEBRA) Find out more at:

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)

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

Funding Opportunities:Funding Opportunities: Training Opportunities:Training Opportunities: Roadmap activities:Roadmap activities: