DRUG ADDICTION: A Brain Disease Associated with High Risk Behavior Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health Drug Use Has Played A Major Role in HIV Transmission Convergence of HIV Seroprevalence Among IDU and Non-IDU among Selected Cities Non-injecting drug use appears to be an important factor contributing to HIV infection due to their high-risk behaviors and overlapping social and sexual networks with IDUs Strathdee and Stockman Curr HIV/AIDS Rep. 2010 7(2):99-106. Intravenous Methylphenidate Increased Sexual Desire in Cocaine Abusers and Controls a p < 0.05 b p < 0.005 c p < 0.001 Volkow ND et al., AJP 2007 164: 157-160. Key Brain Structures of the Impulsive (red) and the Controlling Systems (blue) Bechara A Nature Neuroscience 8, 1458 - 1463 (2005). Effects of Alcohol Intoxication on Brain Glucose Metabolism (Marker of Brain Function) Decreases prefrontal cortex cingulate gyrus Increases Amygdala, NAcc Alcohol decreased activity of areas involved with control and increased activity of areas involved with impulsivity Zhu et al., Alcohol Alcohol 39: 53-58 2004. • Chronic Drug Effects – Disruption of Inhibitory Control DA DA DA D2 Receptors DA DA DA DA DA signal Metabolism Dopamine D2 Receptors are Lower in Addiction DADA Cocaine DA DA DA DA DA DA DA DADA DA Reward Circuits Non-Drug Abuser Meth DA DA DA Alcohol DA DA DA Reward Circuits Drug Abuser Heroin control addicted Adapted from Volkow et al., Neurobiology of Learning and Memory 78:610-624, 2002. Impulsivity (z-score) In Methamphetamine Abusers Low Striatal DA D2/D3 Receptor Availability Is Associated with Impulsivity -3 -2 -1 0 1 2 D2/D3 Receptors BP (Z-score) Lee, B. et al. J. Neurosci. 2009. 3 PreF OFC CG Striatum umol/100g/min Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism r = 0.7, p < 0.001 35 OFC cocaine abuser umol/100gr/min 30 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 DA D2 Receptors (Ratio Index) 90 OFC control Cocaine Abusers 65 60 55 50 45 40 METH Abusers 80 70 60 50 40 r = 0.7, p < 0.005 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 DA D2 Receptors (Bmax/kd) Volkow et al., AJP 158(3):377-382, 2001. What are the Mechanisms Underlying the Relationship Between Drug Use and HIV/AIDS? • Acute Drug Effects – Drug Intoxication and Decision Making • Chronic Drug Effects – Disruption of Inhibitory Control • Interaction of Drugs and HIV Some Psychoactive Drugs Exacerbate Neurotoxic Effects of HIV Chang et al., Neuroimage, 42:869-78, 2008. Rate of Seroconversion (%) Among IDUs the Most Effective HIV/AIDS Prevention Strategy is Drug Abuse Treatment HIV Seroconversion at 18 Months By Receipt of Treatment 25 No treatment Partial treatment Continuous treatment 20 15 10 5 0 Treatment Status Source: Metzger, D. S., Woody, G. E., McLellan, A. T., O’Brien, C. P., Druley, P., Navaline, H., De Philipps, D., Stolley, P., & Abrutyn, E. (1993). Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: An 18-month prospective follow-up. Journal of Acquired Immune Deficiency Syndromes, 6, 1049-1056. Future Research Long-Acting Injectable Medications (i.e., Depot Naltrexone) Placebo: N=124 XR-NTX: N=126 IM Injection every 4 weeks for 24 weeks Krupitzky et al., unpublished Future Research Immunotherapies for Addiction Treatment (i.e., Vaccines) Antibodies Can Reduce Brain Concentrations VACCINE Binding Site Antibodies Capillary Blood Flow Brain Targeting the drugs, not the receptors Capillary Blood Flow Brain New Heroin Vaccine(s) K.D. Janda & G.F. Koob Laboratories at TSRI The Vaccine(s) Hot Plate Test Heroin 1 mg/kg, s.c. 30 min ##p<0.01, ###p<0.001, significant reduction of analgesia vs. Control/KLH group, ### p<0.001, significant reduction of analgesia vs. Control/KLH group Addicted Brain Non-Addicted Brain Control Control CG STOP Saliency Saliency Saliency NAc Drive OFC Drive Drive GO Memory Memory Memory Amygdala Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003. Medications for Relapse Prevention Addicted Brain Non-Addicted Brain Interfere with drug’s reinforcing effects Control Control Saliency Saliency GO STOP Drive Drive Memory Memory Vaccines Enzymatic degredation Naltrexone DA D3 antagonists CB1 antagonists Executive function/ Inhibitory control Biofeedback Modafinil Bupropion Stimulants Strengthen prefrontalstriatal communication Adenosine A2 antagonists DA D3 antagonists Interfere with conditioned memories (craving) Antiepileptic GVG N-acetylcysteine Teach new memories Cycloserine Counteract stress responses that lead to relapse CRF antagonists Orexin antagonists Naltrexone & Buprenorphine in the Treatment of Cocaine Dependence Rates (%) of Positive Urines for Cocaine Metabolites --Naltrexone Alone 40 --Naltrexone + Buprenorphine 41.67 36.67 33.33 18.18 9.09 Gerra G et al., J Psychopharmacol Online First January 9, 2006. Impulsive Rats Have Lower D2R in Striatum Dalley JW et al., Science 315, 1267 (2007).