Scientific Program

Conference Series Ltd invites all the participants across the globe to attend 3rd International Conference and Exhibition on Addiction Research & Therapy Chicago, USA.

Day 1 :

Keynote Forum

Rajendra Badgaiyan

University of Buffalo, USA

Keynote: Dopaminergic neuroimaging across the brain

Time : 08:35-09:00

OMICS International Addiction Therapy-2014 International Conference Keynote Speaker Rajendra Badgaiyan photo
Biography:

Rajendra Badgaiyan completed his MD and MA (Psychology) in India and finished postdoctoral training at University of Oregon, University of Pittsburgh and Harvard University. He completed residency training in Psychiatry at Harvard and currently directs the outpatient addiction clinic and Neuroimaging Laboratory at SUNY Buffalo. He is a member of the editorial boards of 12 journals and Chief/executive editor of 3 journals. He received several awards for research and he is recognized as the original developer of single scan dynamic molecular imaging technique that\\r\\nallows detection, mapping and measurement of dopamine released during task performance in the live human brain.

Abstract:

Converging evidence from clinical and animal studies suggests that dysregulated dopamine neurotransmission is associated\\r\\nwith addictive behavior. The precise nature of dysregulation however is unclear. It has been suggested that dysregulated\\r\\ndopamine neurotransmission alters processing of the reward and associative memory systems. These alterations lead\\r\\nto maladaptive motivational behavior leading to chemical dependency. The concepts concerning the role of dopamine in\\r\\naddiction are based mostly on the data obtained in laboratory animals. It is therefore unclear whether human addiction, which\\r\\nhas unique social and cultural influences, has similar underlying mechanism. Due to lack of a reliable technique to study\\r\\nneurotransmission in the live human brain, the role of dopamine in human addiction has not yet been completely understood.\\r\\nRecently, we developed a single scan dynamic molecular imaging technique for detection, mapping and measurement of\\r\\ndopamine released acutely in the live human brain. This technique will help us study the nature of dysregulated dopamine\\r\\nneurotransmission in addiction.

Keynote Forum

Jason Connor

The University of Queensland, Australia

Keynote: The role of the DRD2 gene, impulsivity and expectancies in severe alcohol dependence

Time : 09:00-09:25

OMICS International Addiction Therapy-2014 International Conference Keynote Speaker Jason Connor photo
Biography:

Jason P Connor is as a Principal Research Fellow in the Centre for Youth Substance Abuse Research at The University of Queensland, Australia. He also holds a National Health and Medical Research Council (NH&MRC) of Australia Fellowship. He is a clinical psychologist by training and a Fellow of the Australian Psychological Society (APS). Since moving from full-time clinical practice to academia (PhD, 2002), he has successfully combined teaching and clinical responsibilities with research, publishing over 100 peer reviewed papers. Over the past 10 years he has received $4.75 AUD million in peer reviewed research funding and $2.6 AUD million in industry and philanthropic funding as a chief investigator.

Abstract:

Parallel research in disciplines of molecular genetics and clinical psychology has contributed significantly, but independently, to our understanding of both the etiology and treatment of Alcohol Use Disorders. This presentation argues that cross-disciplinary research is essential to progress our understanding of genetics, the reward deficiency syndrome and effective alcohol use disorder treatment. A series of studies are reported that move beyond DRD2 association studies to examine phenotypes of severity in samples with severe alcohol dependence. Studies reporting robust psychological mechanisms also known to be associated with alcohol dependence are also discussed. Recent findings that combine the A1 allele of the DRD2 gene and key psychological markers are then presented. The presentation concludes that addiction scientists must embrace research design technologies and evidence-based findings from multiple disciplines to improve alcohol use disorder treatment outcomes.

Keynote Forum

Marcelo Febo

University of Florida, USA

Keynote: Brain reward functional connectivity during resting state in animal models

Time : 09:25-09:50

OMICS International Addiction Therapy-2014 International Conference Keynote Speaker Marcelo Febo photo
Biography:

Marcelo Febo completed his PhD at the University of Puerto Rico Medical School and postdoctoral studies at the University of Massachusetts Medical Center. His work focuses on measuring in vivo functional and structural changes in the rat brain following chronic drug exposure. Over the past decade he has pursued this goal through the use of high field functional magnetic resonance imaging in awake rats and mice. He has been funded early in his career by the National Institute on Drug Abuse to examine the relationship between cocaine sensitization and alterations in maternal brain activity. He is presently Program Director of Translational Research Imaging at the University of Florida Brain Institute and is also a faculty member of the Department of Psychiatry.

Abstract:

There is a growing literature supporting alterations in the functional interactions between multiple brain regions in addiction. Result from many study points beyond the mesolimbic system shows important associations between reward regions and areas of the brain regulating memory, emotions, habit formations, and cognitive functions. These areas include prefrontal cortical subregions, hippocampal and parahippocampal areas and anterior thalamic nuclei along with dorsal striatum. Our laboratory has applied a variety of experimental paradigms using functional MRI in rats to investigate putative neural circuits of drug and natural reward. Key to the strategy for examining brain function has been the use of techniques to image the unanesthetized rats. The initial work examined the direct pharmacodynamic actions of cocaine in the male and female rat brain. These studies provided an initial insight into the use of pharmacological MRI in awake rats and the regions directly activated by cocaine. In follow up experiments discussed at the conference, we explore interactions between sex and responsivity to cocaine, epigenetic modulation of cocaine-induced neuroadaptations. More recently we have used other methods to examine neuronal activity changes more directly with manganese enhanced MRI (MEMRI) and resting state functional connectivity analysis. The latter methods, along with the traditional fMRI techniques are gradually piecing together important properties of drug-induced changes in functionality in the in vivo rodent brain that can be used to guide the development of treatments.

Keynote Forum

Igor Elman

Harvard Medical School, USA

Keynote: Neuroimaging of reward deficiency syndrome: Chronic stress and behavioral addiction findings

Time : 09:50-10:15

OMICS International Addiction Therapy-2014 International Conference Keynote Speaker Igor Elman photo
Biography:

Igor Elman, MD, is an Associate Professor of Psychiatry at Harvard Medical School. He was trained at the National Institute of Mental Health and is a Diplomate of the American Board of Psychiatry with a subspecialty certification in Addiction Psychiatry. Presently, he heads a clinical research lab, focused on the role of reward and motivational systems in pathophysiology of severe neuropsychiatric disorders, including addictions, schizophrenia and post-traumatic stress disorder. He is a recipient of NIDA K23 and R01 Awards. He serves as Editor-in-Chief of the Journal of Psychology Research and Behavioral Management.

Abstract:

Based on extensive investigations of rodent and primate models, the mesoaccumbens dopamine pathway, extending from\\r\\nthe ventral tegmentum of the midbrain to the forebrain regions such as nucleus accumbens, is a crucial component of\\r\\nthe brain reward and reinforcement system that purportedly mediates pleasure, contentment, and motivation.The common\\r\\nelement of the rewarding effects of addictive chemicals relates to increases in dopamine levels in the nucleus accumbens,\\r\\nwhich is a critical event underlying the subjective pleasure or “high” (reward) that is sought by drug users. In contrast, repeated\\r\\nartificial dopamine enhancement in the neurophysiologic reward system by euphorogenic drugs leads to a dysfunctional\\r\\nhypodopaminergic state rendering it less responsive to natural reinforcers i.e., reward deficiency syndrome. Both chronic stress\\r\\nexposure in the form of post-traumatic stress disorder (PTSD) and the behavioral addiction, classified among “Substance-\\r\\nRelated and Addictive Disorders” in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, namely gambling\\r\\ndisorder (GD) are also characterized by decreased sensitivity to natural reinforcers. The purpose of this talk is to present\\r\\nfunctional magnetic resonance imaging and behavioral data, collected by our lab, demonstrating reward deficiency-type\\r\\nneuroadaptations in patients diagnosed with either PTSD or with GD. The author will highlight three lines of research\\r\\nevidence from the wheel of fortune gambling task, from visual processing of rewarding and stressful images selected from the\\r\\nInternational Affective Picture System and from the Skinner box-like computer key pressing procedurevalidated for measuring\\r\\nmotivational function in humans. Testable hypotheses and further research to unravel the primary versus secondary nature\\r\\nof the observed deficits will be highlighted along with role of the reward-enhancing behavioral and pharmacotherapeutic\\r\\ninterventions within the addictive- and stressor-related disorders’ treatment armamentarium.

Break: Coffee Break 10:15-10:30 @ Foyer

Keynote Forum

Kelvin Lim

University of Minnesota, USA

Keynote: Using brain imaging to identify new targets and strategies for addiction treatment

Time : 10:30-10:55

OMICS International Addiction Therapy-2014 International Conference Keynote Speaker Kelvin Lim photo
Biography:

Kelvin Lim received his MD from Johns Hopkins University and completed a psychiatry residency and neuroimaging fellowship at Stanford University. Since 2001, he has held the Drs. T.J. and Ellla M. Arneson Land Grant Chair in Human Behavior in the Department of Psychiatry at the University of Minnesota. His research interests are in the use of neuroimaging methods to inform the diagnosis, prognosis and treatment of psychiatric disorders including addiction and schizophrenia. He has received research funding from the NIH and Department of Veterans Affairs.

Abstract:

Treatment outcome for addiction is dismal; about 64% of those entering treatment will relapse within one year after treatment. Of those 36% able to maintain abstinence for a year, only 66% will go on to remain abstinent for 3 years (cumulative 24%). The good news is that those who make it beyond 3 years of abstinence have an 86% chance of remaining abstinent. Data collected in our laboratory in abstinent users has identified brain patterns that can predict their future relapse. These brain patterns provide possible novel approaches for relapse prevention and improved treatment outcome.

Keynote Forum

Bryan K. Yamamoto

University of Toledo, USA

Keynote: Peripheral and central mechanisms of Methamphetamine neurotoxicity: Connecting the dots

Time : 10:55-11:20

OMICS International Addiction Therapy-2014 International Conference Keynote Speaker Bryan K. Yamamoto photo
Biography:

Bryan K. Yamamoto received his PhD from Syracuse University in Neurobiology after which, he completed a postdoctoral fellowship in clinical pharmacology at the University of Colorado Medical School. He is Professor and Chair of the Department of Neurosciences at the University of Toledo College of Medicine and Life Sciences. He has been a member of NIH Study Sections since 1987 and a member of several advisory boards of NIH sponsored research centers and programs. His research has focused on how drugs of abuse affect the neurochemistry of brain and has been funded continuously over the last 27 years by the NIH.

Abstract:

Methamphetamine is a drug that is abused worldwide. Emerging clinical studies are supportive of previous preclinical findings from animals that illustrate methamphetamine injures dopamine and serotonin neurotransmitter systems. Results will be presented from animal model studies that demonstrate oxidative and excitotoxic mechanisms are involved which converge to mediate the toxic effects of methamphetamine on dopamine and serotonin neurons. Although these neurochemical findings have traditionally been attributed to the direct action of methamphetamine on the brain, new evidence will be presented indicating that the causes of the neurotoxicity are also initiated by the effects of the drug on systemic organs and circulating small molecules. Moreover, additional studies will be described that demonstrate the toxic effects of methamphetamine are not limited to neurotransmitter systems but also include protracted damage to brain endothelium that comprises the blood-brain barrier. Overall, these recent studies broaden the scope of the causes and consequences associated with the injurious effects of methamphetamine on the brain.

Keynote Forum

Subhash C Pandey

University of Illinois and Jesse Brown VA Medical Center, USA

Keynote: Neuroepigenetics and alcoholism

Time : 11:20-11:55

OMICS International Addiction Therapy-2014 International Conference Keynote Speaker Subhash C Pandey photo
Biography:

Subhash C Pandey received his PhD in 1987 from the Pharmacology division of the Central Drug Research Institute in Lucknow, India and then received his postdoctoral training in neuropsychopharmacology in the Department of Psychiatry, University of Illinois at Chicago. He is currently a Professor of Psychiatry, Anatomy and Cell Biology and the Director of Neuroscience Alcoholism Research at the University of Illinois at Chicago. He also holds a position as a VA Career Scientist at the Jesse Brown VA Medical Center, Chicago. He is well known for his scientific contributions towards the molecular and cellular neuroscience of alcoholism. He received Bowles Lectureship from the Alcohol Research Center located at University of North Carolina, Chapel Hill in 2010 and 6th SN Pradhan Lectureship from the department of pharmacology, Howard University, Washington DC in 2011 and distinguished scientist award in 2014 from the association of scientists of Indian origin in America for his outstanding contributions in the field of alcoholism research. He is serving as a Field Editor of Alcoholism: Clinical and Experimental Research Journal since 2011.

Abstract:

Epigenetic mechanisms, such as histone acetylation and DNA methylation induced changes in gene expression play an important role in brain maturation and synaptic plasticity. The effects of adolescent intermittent ethanol (AIE) treatment on epigenetically regulated synaptic plasticity associated events in the amygdala and on anxiety-like and alcohol-drinking behaviors at adulthood were investigated. Adolescent (Sprague-Dawley) rats were exposed with intermittent n-saline or ethanol [2 g/kg, intraperitoneal (IP); 2-days on/2-days off, 4 cycles (8 injections) from postnatal days 28-41]. The behavioral and epigenetic measures were performed at adulthood (postnatal day 92). It was found that histone deacetylase (HDAC) activity was increased in the amygdala of AIE adult rats as compared with adolescent intermittent saline (AIS) adult rats. This was due to increase in HDAC2, but not HDAC4, protein levels in the central (CeA) and medial nucleus of the amygdala (MeA) of AIE adult rats compared with AIS adult rats. The global histone H3-K9 acetylation was correspondingly decreased in the CeA and MeA of AIE adult rats compared with AIS adult rats. It was also found that mRNA levels of activity-regulated cytoskeleton-associated (Arc) protein and brain-derived neurotrophic factor (BDNF) exons (I & IV) and protein levels of Arc and BDNF were significantly decreased in the CeA and MeA, but not basolateral amygdala (BLA) of AIE adult rats compared with AIS adult rats. Interestingly, decreased expression of BDNF and Arc was associated with lower histone H3 acetylation levels in the promoters of these genes in the amygdala. AIE produced a reduction in dendritic spine density in the CeA and MeA of rats at adulthood. AIE also induced anxiety-like and alcohol-drinking behaviors at adulthood which were attenuated by treatment with the HDAC inhibitor, trichostatin A (TSA). Using, different model alcohol preferring and non-preferring genetic rats it was demonstrated that innately higher expression of HDAC2 in the CeA produced deficits in synaptic plasticity associated events and regulated anxiety-like and alcohol drinking behaviors. These results suggest that innately or ethanol exposure-induced abnormal chromatin architecture due to HDAC2-mediated histone modifications in the amygdala may play a crucial role in anxiety and alcoholism (Supported by the grants from NIH-NIAAA and VA Merit grant from department of Veterans Affairs).

Break: Panel Discussion 11:55-12:10
  • Molecular and Synthetic Addiction
Location: Main Hall Northbrook Hilton Chicago
Speaker

Chair

Jason Connor

The University of Queensland, Australia

Speaker

Co-Chair

F. Gerard Moeller

Virginia Commonwealth University, USA

Session Introduction

Xiaoni Zhang

Sun Yat Sen University, China

Title: MiR-155 Modulates Morphine-induced Immunosuppression by Targeting SK3

Time : 12:10-12:30

Speaker
Biography:

Xiaoni Zhang has completed her MD at Zhongshan School of Medicine, Sun Yat-Sen University, 2012. She is currently a second-year graduate student pursuing a Master's degree within the Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. Her research is focused on the molecular mechanisms of morphine-induced immunosuppressive effects.

Abstract:

Background: Opioids, especially morphine, have a diversity of effects on immune system. It is well known that morphine has been proved to have immunosuppressive properties both in vivo and in vitro, and is thought to be involved in the increased incidence of infection in heroin addicts. Evidences have shown that microglia, the main active immune defense cell in the central nervous system, plays an essential role in morphine-induced immunosuppression in central nervous system. In addition, recent studies suggest that microRNAs may play a decisive role in the regulation of gene expression during immune responses in microglia. Although numerous studies have shown that multiple factors were involved in morphine-induced immunosuppression, but the precise cellular and molecular mechanisms are still largely unknown. Objective: This study was to investigate the contribution of a specific microRNA, miR-155, in the modulation of the morphine-induced immunosuppression in microglia. Methods: We detected morphine-induced immunosuppressive effects in both heroin abused patients and morphine-treated mice primary microglia. MiR-155 expression levels were measured in morphine-treated microglia. In vitro experiments were performed to demonstrate how miR-155 influences the expression of cytokines (TNF-α,IL-6 and IL-10) in morphine-treated microglia at both mRNA and extracellular levels. Moreover, interactions between miR-155 and downstream targets were further evaluated by using western blot and luciferase reporter assay. Results: Our results showed that morphine could induce immunosuppression by interfering cytokine expression in both heroin abused patients and morphine-treated mice primary microglia cells. Expression of pro-inflammatory cytokines (TNF-α, IL-6) was decreased, while expression of anti-inflammatory cytokine (IL-10) was increased, respectively, compared to control group. We also found that miR-155 was down-regulated in morphine-treated primary microglia. Moreover, up-regulate miR-155 could reverse morphine-induced cytokines expressions by directly targeting SK3 channel in primary microglia. Conclusions: Our results demonstrated a reversal effect of miR-155 on morphine-induced immunosuppression, and suggested that SK3 channel, the direct target of miR-155, was involved in this process.

Dong Zheng

Guangzhou Brain Hospital, China

Title: The protective effect of Astaxanthin on fetal alcohol spectrum disorder in mice

Time : 12:30-12:50

Speaker
Biography:

Dong Zheng has completed his PhD at the Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 2012. He is now the director of Department of Neurology, Guangzhou Brain Hospital, Guangzhou, China. He has shown great expertise in the area of toxic encephalopathy and fetal alcohol spectrum disorder for many years, and has published a number of articles in reputed international journals.

Abstract:

Background: Astaxanthin (AST), known as a carotenoid pigment, is a strong antioxidant which protects membranous phospholipids and other lipids against peroxidation. Evidences showed that Astaxanthin had up to several-fold stronger free radical antioxidant activity than vitamin E and carotene. In double-blind, randomized controlled trial, Astaxanthin was found to lower oxidative stress in several human health conditions. Moreover, it is known that ROS up-regulate pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and IL-6. High levels of these cytokines are associated with neurotoxicity. Whereas, Astaxanthin has been found to reduce the causatives of inflammation like TNF-α. Thus, Astaxanthin has been deemed to be safe and has potential as a therapeutic antioxidant and anti-inflammation agent for further testing in human diseases.
Objective: To explore the protective effect of Astaxanthin on fetal alcohol spectrum disorder in mice, and to investigate the underlying mechanisms.
Methods: We detected the morphology, expression of neural marker genes, oxidative stress indexes, and inflammatory factors in mice model of fetal alcohol spectrum disorder with or without Astaxanthin pretreatment.
Results: Our results showed that Astaxanthin blocked maternal ethanol induced retardation of embryonic growth, and the down-regulation of neural marker genes, Otx1 and Sox2. Moreover, Astaxanthin also reversed the increases of MDA, H2O2, and the decrease of GPx in fetal alcohol spectrum disorder. In addiction, maternal ethanol induced up-regulation of TLR4, and the down-streaming MyD88, MyD88, NF-κB, TNF-α, and IL-1β in embryos, and this was inhibited by astaxanthin pretreatment.
Conclusions: Our results demonstrated a protective effect of Astaxanthin on fetal alcohol spectrum disorder, and suggested that oxidative stress and toll-like receptor signaling associated inflammatory reaction were involved in this process.

Speaker
Biography:

Ashenafi Girma Tefera earned his B.Pharm and MSc. in Pharmacology from Addis Ababa University. Now, he is a lecturer of pharmacology at undergraduate studies at Samara University. He is also working as academic dean at Universal Medical College and as a medical bulletin writer and editorial assistant at Pharma info which is a known medical bulletin in Ethiopia. He maintains an active academic role within the university teaching courses in pharmacology, mentor undergraduate students in their final year research project. He is also a member of Ethiopian pharmaceutical association. He conducted experimental researches using behavioral science techniques in rat and mice models include khat plant and anxiety, khat plant and memory. He has presented his research on substance abuse for the scientific community at the University of Minnesota-IBRO-Jimma University international symposium 2014. His main research interest is experimental researches in animal models on substance abuse including khat plant and schizophrenia, khat plant and Parkinson’s disease as well as khat plant and the level of dopamine and serotonin in rat brain.

Abstract:

Learning is a process of acquiring new information while memory is retention of the acquired information. The molecular mechanism of learning is due to the increased synaptic strength which is called long term potentiation. Khat (Catha edulis F.) is a dense evergreen shrub belonging to the family celastracea. Although comparative studies of amphetamine and khat on physiological and psychological behaviours are extensive, little is known about the effect of khat on learning and memory. The aim of this study was to evaluate the effect of acute and sub-acute exposure to crude khat (Catha edulis F.) extract on learning and memory in rodents. Crude khat extract obtained using a mixture of chloroform and diethyl ether (1:3) was administered orally in doses of 100, 200, 300 mg/kg and the control group was administered with Tween 80 2% v/v in water as a single dose and repeatedly for fourteen days. Three protocols: Morris water maze (MWM), active avoidance and multiple T-maze (MTM) tasks were used to study learning and memory. Parameters, including escape latency; time spent in the target quadrant; number of avoidances, escapes and nulls; number of wrong decisions and latency to reach the goal box were determined. The results showed that acute and sub-acute administration of khat extract at the doses used did not have a significant effect in the three learning and memory paradigms.

Speaker
Biography:

Monika Heidemarie Seltenhammer completed her VMD and PhD from VMU in Austria and Postdoctoral studies from Veterinary University of Vienna, Max Perutz Laboratories and Medical University of Vienna in Austria, where her core area of scientific work mainly consisted in cancer research (melanoma) and pathology, but also immunology, neurology and virology. She has received several honor and awards. She is a leading member of the scientific staff of Dr. Daniele Ugo Risser at the Department of Forensic Medicine of the Medical University Vienna, where she specializes in neurobiology and addiction behavior in close co-operation with Dr. Tibor Harkany, professor at the Department of Molecular Neurosciences of the Medical University of Vienna.

Abstract:

The incitation of the ~33kD Mr (molecular mass) transcription factor ΔFosB, a member of the Fos family proteins, in the acute phase and then its displacement to ~35-37kD Mr isoforms due to chronic exposure to different inducements including stress, drugs of abuse and other psychoactive substances, but also psychotherapeutic agents leads to a consistent accumulation of highly stable ΔFosB isoforms in the nucleus accumbens (NAc), the reward center of the brain. These extraordinary stable ~35-37kD ΔFosB Mr derivatives insistently persist in this brain region for several weeks or even longer following cessation of the chronic stimulus - a major fact that seems to be responsible for the development of sustained neuronal plasticity. In case of long-term drug abuse, it ultimately leads to addictive behavior by representing a source of high relapse rates at the same time. With this in mind, we demonstrate for the first time the presence of accumulated ~35-37kD Mr ΔFosB isoforms in the NAc of chronic drug-sick deceased people with pronounced long-term opioid abuse anamnesis. The detection was possible even after a postmortem interval (PMI) of 8.47± 2.61 days, enabled by a distinct modification of protein purification methods. As expected, not any ~33kD Mr ΔFosB molecule, the rather unstable Fos family member, could be detected via immunoblotting. Our current results emphasize the remarkable high resistance of this phosphorylated transcription factor. The data confirm once more the strong impact of ΔFosB and its downstream transcriptional targets with regard to long-term biological consequences for and potentially fatal adaptations of the brain leading to addictive behavior and high relapse rates in response to chronic opioid abuse. Nevertheless, our exciting results regarding the detection of these highly stable 35-37kD Mr ΔFosB isoforms under such conditions (prolonged PMIs) provide a blessing and a curse in equal measure as the impact of this phosphorylated transcription factor achieves a much higher dimension. This in turn should be taken into consideration when thinking about establishment and interpretation of sensitive biomarkers on the one hand, and development of novel therapeutic strategies in terms of psychological disorders in general and especially in (drug) addiction on the other hand.

Speaker
Biography:

Youssef Sari is an assistant professor of pharmacology. He received his doctorate in Neuroscience from Pierre and Marie Curie University, Institute of Neuroscience (Paris, France) and subsequently held postdoc and faculty research positions at Indiana University. Dr. Sari is currently holding a faculty position at the level of Assistant Professor of Pharmacology at the University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio, USA. He is the PI of R01 grant project from NIH-NIAA; the project focuses on the role of glutamate transporter 1 (GLT1) in alcohol-drinking behavior using compounds that upregulate this transporter. Dr. Sari has patents for two compounds that may have potential uses for the treatment of alcohol dependence. Dr. Sari is also testing compounds for the treatment of diseases involving oxidative stress.

Abstract:

Evidence indicates that many aspects of alcohol and drug dependence involve alterations in glutamate transmission in central reward brain regions. Studies have demonstrated that drugs of abuse, including alcohol and cocaine, alter glutamate transport. Extracellular glutamate is regulated by a number of glutamate transporters in various brain regions. Of these transporters, glutamate transporter (GLT1) is a key player in the removal of most of the extracellular glutamate. I will discuss in this presentation the uses of compounds that activate and upregulate GLT1 levels and consequently reduced alcohol consumption in alcohol-preferring (P) rats. We have recently found that ceftriaxone, an FDA-approved drug known to elevate GLT1 expression, attenuates cue-induced cocaine relapse. Moreover, we recently found that P rats treated with ceftriaxone showed a significant dose-dependent reduction in alcohol consumption and also the drug attenuated relapse-like alcohol-drinking behavior. In addition, I will present findings related to a new compound GPI-1046, which is neuroimmunophilin derivative that has therapeutic effect in reducing alcohol intake in P rats. This presentation will provide information about the potential therapeutic role of GLT1 for the treatment of alcohol abuse and dependence.

Speaker
Biography:

Marcelo Febo completed his PhD at the University of Puerto Rico Medical School and postdoctoral studies at the University of Massachusetts Medical Center. His work focuses on measuring in vivo functional and structural changes in the rat brain following chronic drug exposure. Over the past decade he has pursued this goal through the use of high field functional magnetic resonance imaging in awake rats and mice. He has been funded early in his career by the National Institute on Drug Abuse to examine the relationship between cocaine sensitization and alterations in maternal brain activity. He is presently Program Director of Translational Research Imaging at the University of Florida Brain Institute and is also a faculty member of the Department of Psychiatry.

Abstract:

Synthetic cathinones represent an emergent hazard to public health. These are marketed on the streets as ‘bath salts’, ‘plant food’ or ‘legal highs’. Bath salts are potent stimulant and hallucinogenic drugs, and their abuse has the potential to impair mental health. The various chemical constituents of bath salts share molecular features, biochemical actions, and behavioral effects with a range of other illegal stimulants such as cocaine, methamphetamine and methylenedioxymethamphetamine (MDMA, or ‘Ecstacy’). Among the bath salts, 3,4-methylenedioxypyrovalerone (MDPV) has been reported to exert powerful cocaine-like effects in rats (Baumann et al., Neuropsychopharmacology, 2012). MDPV produces strong craving and euphoria within a few minutes of intake that may last up to 4-5 hrs, or more. Importantly, MDPV consumption leads to a strong crash beginning around 6-8 hrs with varying degree of severity in terms of the negative affective outcomes. During this time, users experience hallucinations, excited delirium, severe depression, anxiety and panic attacks, and in many cases violent aggression and suicidal thoughts that may last hours, weeks, and even months. Despite the growing number of studies reporting the stimulant and reinforcing actions of bath salts there is still a knowledge gap with regard to their sites of action within the CNS and their effects on functional connectivity between brain regions. The present study was designed to investigate the dose dependent pharmacological actions of MDPV (in mg kg-1: 0.0, 0.3, 0.6 1.0, 3.0, and 6.0, ip) on BOLD activation across a number of corticostriatal, mesolimbic, frontal cortical and limbic subcortical circuits. Rats were imaged at 4.7T at the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) facility of the University of Florida. Analysis of intrinsic rsFC at 1 hr post-MDPV administration (doses in mg kg-1: 0, 0.3, 1, 3; n = 7-8 per dose) showed a dose-dependent reduction in rsFC between reward sites and memory regions. At the highest dose tested, however, we found once again that there is a significant increase in rsFC between frontal cortical areas and regions of the amygdala. The loss of synchronous BOLD activity between hippocampal and other memory regions along with greater BOLD synchrony between amygdala and prefrontal cortical sites could underlie part of the negative affective states elicited by binge consumption, especially at high dose. Similar functional connectivity changes have been reported in schizophrenia and have been linked with severity of cognitive dysfunction, hallucinations and negative affective states. This might represent an important signature of MDPV’s mechanism of action in the CNS.

Break: Panel Discussion 15:20-15:30
,br> Coffee Break 15:30-15:50 @ Foyer
  • Symposium 1 : Molecular and Epigenetic basis of Alcoholism
Location: Main Hall Northbrook Hilton Chicago
Speaker

Chair

Subhash C. Pandey

University of Illinois at Chicago, USA

Session Introduction

Subhash C. Pandey

University of Illinois at Chicago, USA

Title: Molecular and epigenetic basis of alcoholism

Time : 15:50-16:00 Introduction

Speaker
Biography:

Subhash C Pandey received his PhD in 1987 from the Pharmacology division of the Central Drug Research Institute in Lucknow, India and then received his Postdoctoral training in neuropsychopharmacology in the Department of Psychiatry, University of Illinois at Chicago. He is currently a Professor of Psychiatry, Anatomy and Cell Biology and the Director of Neuroscience Alcoholism Research at the University of Illinois at Chicago. He also holds a position as a VA Career Scientist at the Jesse Brown VA Medical Center, Chicago. He received Bowles Lectureship from the Alcohol Research Center located at University of North Carolina, Chapel Hill in 2010 and 6th SN Pradhan Lectureship from the Department of Pharmacology, Howard University, Washington DC in 2011 and distinguished scientist award in 2014 from the association of scientists of Indian origin in America for his outstanding contributions in the field of alcoholism research. He is serving as a Field Editor of Alcoholism: Clinical and Experimental Research Journal since 2011.

Abstract:

Alcohol misuse disorders are highly prevalent with as yet not fully elucidated biological underpinnings. Epigenetic mechanisms, such as histone modifications and DNA methylation, appear to be involved in changes in gene expression and synaptic plasticity associated with alcoholism. Furthermore, signaling mechanisms that regulate synaptic functions also have been shown to mediate alcohol-related behaviors. This symposium will provide a platform to bring together researchers studying the abnormal epigenetic and neuronal signaling mechanisms thought to contribute to alcoholism. A comprehensive summary of progress in these fields and overview of findings related to ethanol-induced biochemical modifications occurring in the brain will be presented. The findings from these presentations will help us identify novel epigenetic and signaling targets that can be used to develop future pharmacotherapy for alcoholism.

Speaker
Biography:

Amul J Sakharkar completed his PhD in Biochemistry from Department of Pharmaceutical Sciences, Nagpur University, India. Subsequently, he received a postdoctoral fellowship at Pennington Biomedical Research Center in Baton Rouge, Louisiana studying the effects of brain trauma on blood brain barrier integrity. He attained additional postdoctoral training at the University of Illinois at Chicago (UIC) examining the role of epigenetics in alcoholism. He is currently a Research Assistant Professor at (UIC) in the Department of Psychiatry studying the impact of adolescent alcohol exposure on drinking behaviors at adulthood and its underlying molecular substrates.

Abstract:

Binge alcohol drinking during adolescence causes molecular changes in the developing brain resulting in substance abuse and alcoholism in adulthood. DNA methylation is an important epigenetic mechanism that regulates neuronal gene expression leading to specific phenotypes. We have modeled the binge pattern of drinking by eight intraperitoneal injections of ethanol (2g/kg) or n-saline to adolescent rats during post-natal days (PND) 28-41 with a 2-day on/off paradigm. We have studied the effects of adolescent intermittent ethanol/n-saline (AIE/AIS) exposure on DNA methylation/demethylation and neuropeptide Y (NPY) expression in the amygdala and the resultant anxiety-like behaviors during adolescence and at adulthood (PND 92). AIE-exposed animals displayed anxiety-like behaviors after 24 hrs of last ethanol injection (ethanol withdrawal), which persisted until adulthood. Concomitantly, DNA methyltransferase (DNMT) activity, DNMT3b mRNA and DNA demethylating factors, i.e., GADD45a, b and g were found to be altered in the amygdala of AIE-exposed rats during adolescence and some of these changes persist in adulthood. To understand the down-stream molecular mechanisms by which DNA methylation may be regulating the anxiety-like and alcohol-drinking behaviors, we examined the DNA methylation specific to the NPY gene promoter and NPY protein levels in the amygdala. NPY protein levels were down-regulated in the central and medial amygdaloid structures of AIE-exposed rats at 24 hrs, with a persistent decrease in adulthood. Reciprocally, DNA methylation at the NPY gene promoter was increased in the amygdala of AIE adult rats, which is consistent with the increase in DNMT function and decrease in the GADD45g levels. To test if DNMT inhibition could reverse AIE-induced anxiety-like and alcohol-drinking behaviors, we treated AIS- and AIE-treated adult rats with 5’-azacytidine, a DNMT inhibitor. Treatment with 5’-azacytidine attenuated AIE exposure-induced anxiety-like behaviors and alcohol intake in adulthood. These results suggest that AIE-induced neuroadaptations alter the homeostasis between DNA methylation/demethylation pathways in the amygdala during adolescence with long-lasting changes persistent at adulthood causing anxiety-like and alcohol-drinking behaviors most likely via NPY gene expression. The novel results of the study raises the possibility of DNMT inhibitors as a promising therapeutic option to treat alcohol-abuse and co-morbid disorders (supported by NADIA grant from NIH-NIAAA to SCP).

Speaker
Biography:

Amy W. Lasek received her PhD from Cornell University and completed a postdoctoral fellowship at the University of California, Berkeley. She was an Associate Investigator at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco. She is currently an Assistant Professor of Psychiatry and Anatomy and Cell Biology at the University of Illinois at Chicago. She is also a PI on the NIH funded projects “Mechanisms of estrogen action in enhancing behavioral responses to cocaine”, “Regulation of excessive alcohol consumption by the LMO-ALK axis”, and “RNA interference core”.

Abstract:

ALK is a receptor tyrosine kinase expressed in the nervous system that we previously found to regulate behavioral responses to ethanol in mice. To further characterize the ability of ALK to control ethanol consumption, we treated mice systemically with the ALK inhibitor, TAE684, and tested them for binge-like drinking using the drinking in the dark (DID) protocol. Mice treated with TAE684 drank less ethanol than controls, indicating that ALK activity in adult mice promotes binge-like drinking. Since the ventral tegmental area (VTA) is a key brain region involved in the rewarding and reinforcing effects of ethanol, we examined whether Alk expression in the VTA might be important for ethanol consumption. A lentiviral-delivered short hairpin RNA (shRNA) targeting Alk or a non-targeting control shRNA was delivered into the VTA. Mice expressing Alk shRNA in the VTA drank less ethanol in the DID test compared to mice expressing a control shRNA. We characterized the expression of ALK in the VTA using immunohistochemistry and found that ALK is expressed on dopamine neurons, suggesting that ALK might regulate the firing properties of these neurons. Extracellular recordings of putative dopaminergic (pDA) neurons in VTA slices treated with TAE684 showed that there was no difference in the ability of dopamine to inhibit firing of pDA neurons. However, TAE684 prevented the D2 receptor desensitization of pDA neurons induced by prolonged exposure to moderate concentrations of dopamine. Together, these data suggest that ALK activity in the VTA regulates binge-like ethanol consumption and desensitization of dopamine receptors.

David P. Gavin

University of Illinois at Chicago, USA

Title: Epigenetic differences in the reward circuitry of C57BL/6J vs. DBA/2J mice

Time : 16:50-17:15

Speaker
Biography:

David P Gavin completed his MD from University of Illinois at Chicago (UIC) College of Medicine, and then participated in the Adult Psychiatry Residency Neuroscience Research Track at UIC. Following residency he remained at UIC as an Assistant Professor. In the last year, he has been awarded a NARSAD Young Investigator Grant for his continued studies in schizophrenia, and a VA Career Development Award to study the potential contribution of DNA demethylation pathways to alcoholism.

Abstract:

The enduring nature of addiction suggests molecular mechanisms in the brain that are durable yet sensitive to environmental factors. Neuronal DNA methylation is perhaps the longest lasting form of gene regulation in the body with essentially no required turnover. However, recently it has been shown that environmental stimuli including drugs of abuse, such as ethanol, can alter DNA methylation at gene promoters. To date, very little is known about the relationship between DNA demethylation factors and drugs of abuse. DNA demethylation is thought to occur via a base excision repair pathway whereby Gadd45 proteins serve a key role in focusing the demethylation machinery at specific genomic loci. In the current study we examined the role of these proteins in two mouse strains known to differ in their preference for ethanol consumption, C57BL/6J (C57) and DBA/2J (DBA). C57 and DBA mice were administered normal saline or 2 g/kg ethanol and brains were dissected out after 1 hour of injections. Subsequently measured Gadd45a, b, g via qRT-PCR, Gadd45b protein using immunohistochemistry, and a gene repeatedly shown to have a role in addiction and regulated by epigenetic mechanisms Brain-derived neurotrophic factor (Bdnf IXa) via in situ RT-PCR. Using chromatin immunoprecipitation and methylated DNA immunoprecipitation measured acetylated lysines 9 and 14 at histone 3 (H3K9, K14ac) and 5-methylcytosine and 5-hydroxymethylcytosine, respectively, at the Bdnf IXa promoter. At baseline in the NAc it was found that C57 mice have reduced levels of Gadd45b and Gadd45g mRNA compared to DBA mice, but do not differ in levels of Gadd45a. Gadd45b protein and Bdnf IXa mRNA is also reduced in the NAc shell but not the core. Further, H3K9, K14ac is reduced, 5MC is increased, and 5HMC does not differ at the Bdnf IXa promoter in C57 mice compared to the DBA strain at baseline. It was found that acute ethanol significantly increases Gadd45b protein and Bdnf IXa mRNA expression in the NAc, as well as changing H3K9,K14ac binding to the Bdnf IXa promoter. These data suggest that a deficit in a key factor in DNA demethylation, Gadd45b, contributes to the Bdnf deficit and potentially increased ethanol preference of the C57 mice compared to the DBA strain.

Speaker
Biography:

Mark S Brodie completed his PhD from the University of Illinois at Chicago in the Department of Pharmacology and postdoctoral studies with Thomas Dunwiddie at the University of Colorado Health Sciences Center, where he and Dr. Dunwiddie developed a brain slice preparation of the ventral tegmental area. He is currently a Professor of Physiology and Biophysics, in the College of Medicine of the University of Illinois at Chicago. In addition to being an award-winning teacher, he has actively studied the effects of alcohol on brain reward neurons of the ventral tegmental area for almost 30 years. His work has been fundamental in examining the direct actions of alcohol on neurons of the ventral tegmental area, and in exploring the effects of chronic alcohol on the responses of those neurons to acutely administered alcohol and neurotransmitters.

Abstract:

Among the brain areas affected by acute and chronic administration of alcohol is the ventral tegmental area (VTA). Salience related to reward and reinforcement in alcohol addiction is dictated by the functioning of dopaminergic (DAergic) neurons of the VTA. Acute alcohol increases the rate of spontaneous action potential generation of VTA DAergic neurons in vivo and in vitro. Chronic alcohol has been shown to alter the effects of gamma-aminobutyric acid (GABA) in a number of brain areas. Repeated ethanol administration to mice produces a decreased sensitivity of DAergic VTA neurons to GABA, as measured in extracellular recordings from brain slices; it has been observed that hyposensitivity to GABA induced by chronic alcohol exposure in a number of animal models employing different ethanol treatment regimens. One mechanism by which alcohol could induce this GABAergic hyposensitivity is alteration of the enzyme histone deacetylase (HDAC), which in turn could change the acetylation of histone proteins, which would alter the expression of GABA receptors. It was investigated how HDAC inhibitors affect GABAergic sensitivity of DA VTA neurons after chronic alcohol exposure, and also examined changes in HDAC2 and histone H3-K9 acetylation in the VTA during alcohol withdrawal. Mice were treated with either ethanol (3.5 g/kg, i.p.) or saline twice daily for 3 weeks, and recordings were made at least 14 h after the last injection. In recordings from DA VTA neurons from ethanol-withdrawn mice, sensitivity to GABA (50-500 µM) was reduced. In DA VTA neurons from ethanol-withdrawn mice that were incubated with the HDAC inhibitor SAHA (vorinostat) or trichostatin A (TSA) for two hours, the hyposensitivity of DA VTA neurons to GABA was significantly attenuated. TSA or SAHA treatment did not affect sensitivity to GABA of DA VTA neurons from saline-treated mice. Withdrawal from repeated ethanol was associated with an increase in HDAC2 and a decrease in acetylated H3-K9. Similar findings were observed when we studied the effect of a chronic ethanol-containing diet on GABA sensitivity in the VTA of Sprague-Dawley rats. Significant GABA hyposensitivity was observed in DAergic VTA neurons from rats given access to ethanol-containing diet for two weeks. This GABA hyposensitivity was accompanied by an increase in HDAC2 and a decrease in acetylated H3-K9 in the VTA, and the GABA hyposensitivity was reversed by an acute incubation with SAHA. Therefore, the blockade of HDAC2 by HDAC inhibitors normalizes GABA hyposensitivity of DAergic neurons during withdrawal from chronic ethanol in different paradigms, suggesting that HDAC inhibition can reverse alcohol-induced changes in reward circuitry induced by ethanol exposure.

Break: Panel Discussion 17:40-17:55

18:00-19:00 Cocktails sponsored by Journal of Addiction Research & Therapy @ Oaks