Neuroscienze e dipendenze - Dipartimento per le politiche antidroga

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276 - Elementi di NEUROSCIENZE E DIPENDENZE ABSTRACT THE ADDICTED SYNAPSE: MECHANISMS OF SYNAPTIC AND STRUCTURAL PLASTICITY IN NUCLEUS ACCUMBENS Scott J Russo School and University Center of CUNY Department of Neuroscience Mount Sinai School of Medicine - New York, NY Drug addiction is marked long-lasting changes in behavior that result from altered patterns of gene expression within limbic forebrain regions, such as the nucleus accumbens (NAc). These changes in gene transcription are coordinated by a complex series of histone modifications surrounding DNA that result in either repression or activation of gene expression. Recent evidence has identified a network of gene expression regulated by the transcription factor FosB, which alters the structure and function of NAc medium spiny neurons to control addiction-like behavior. This talk will include a discussion on recent advances in our understanding of chromatin regulation by cocaine, as well as the consequences on structural plasticity and its functional relevance in driving addiction-related behavior. COMPULSIVE DRUG-SEEKING VERSUS HEDONIC BEHAVIOR MOTIVATED BY NATURAL REWARD: NEUROBEHAVIORAL MECHANISMS AND NOVEL ADDICTION TREATMENT TARGETS Friedbert Weiss Molecular and Integrative Neurosciences Department The Scripps Research Institute (TSRI) - La Jolla, CA Drug addiction is a chronically relapsing disorder characterized by compulsive drug seeking and use. A major factor contributing to the chronically relapsing and compulsive nature of addiction is the process of associative learning whereby environmental stimuli repeatedly paired with drug consumption acquire incentive-motivational value, evoking expectation of drug availability and memories of past drug euphoria. Conditioned responses to such stimuli can activate brain reward mechanisms and have been implicated both in maintaining ongoing drug use and eliciting drug desire during abstinence, precipitating relapse. Cue-induced drug seeking in animals resembles along several dimensions the compulsive character of addiction in humans. This presentation will focus on chronic vulnerability to relapse – a pivotal aspect of the addiction process – with emphasis on neural substrates responsible for the distinctly compulsive nature of drug-seeking that contrasts with normal behavior elicited by stimuli conditioned to natural rewards that is essential for survival, adaptive behavioral functioning and “healthy” hedonic pursuits. At the phenomenological level, evidence will be presented showing that the motivating effects of drugcues, as measured by conditioned reinstatement of reward seeking, are abnormally resistant to extinction, whereas the effects of stimuli conditioned to potent natural reward extinguish rapidly. Second, reinstatement by drug cues persists over months of abstinence. Even stimuli present during a single lifetime cocaine experience elicit drug seeking for up to one year, an effect not seen with stimuli conditioned to natural reward. Understanding of the mechanisms that differentiate compulsive drug seeking from normal goal-directed behavior has critical implications for understanding the neurobiological basis of maladaptive incentive motivation leading to compulsive drug-seeking and the identification of effective treatment targets for craving and relapse prevention. At the mechanistic level, therefore, data will be presented that (1) implicate the hypothalamic orexin/hypocretin system as preferentially mediating drug vs. normal reward-seeking, (2) implicate metabotropic mGlu2/3 and mGlu5 receptors in conditioned drug-seeking, but with a distinctly more selective role of mGlu2/3 receptors in reinstatement by environmental stimuli conditioned to drugs vs. natural reward. However, (3) both receptors adapt with chronic cocaine and alcohol exposure such that the efficacy of pharmacological mGlu2/3 manipulation to interfere with drug seeking increases (associated with enhanced G-protein coupling), whereas manipulations of the mGlu5 receptor loose their efficacy. (4) An additional target with a selective mediation of drug seeking that emerged in these studies is the 1 receptor. (5) Lastly, it is possible that neuroadaptation associated with histories of previous drug use prevents “unlearning” of maladaptive, or learning of new adaptive behavior, and thereby conveys “compulsive” character to behavior motivated by other stimuli including cues conditioned to natural reward. Consistent with this hypothesis, our data reveal that rats with a previous cocaine history show greater resistance to extinction of responding for cues associated with potent natural reward. More importantly, these rats showed persistent reinstatement induced by cues conditioned to potent natural reward over repeated reinstatement tests, resembling that seen in “conventional” tests of drug-seeking, thus revealing a “switch” toward compulsive-like behavior associated with stimuli conditioned to natural reinforcers in previously drug-dependent rats. Overall the results advance current understanding of mechanisms regulating behavior directed at obtaining drugs of abuse vs. natural reinforcers. (Supported by DA07348, DA08467 AA018010, AA10531).
ABSTRACT - 2° CONVEGNO NAZIONALE “NEUROSCIENZE OF ADDICTION”… - 277 USING COGNITIVE NEUROSCIENCE METHODS TO INTERROGATE THE NEUROBIOLOGY OF ADDICTION C.A. Boettiger Department of Psychology Biomedical Research Imaging Center University of North Carolina While addictive disorders are among the most common neurobehavioral disorders, treatment options remain limited. This lack is due in part to our incomplete understanding of the neurobiological bases of these disorders. One approach to this issue is to investigate the neurobiology of intermediate phenotypes of addictive disorders that capture specific aspects of these diseases, but are less etiologically complex, and more amenable to biological investigation. One promising intermediate phenotype is immediate reward bias, i.e. the strong tendency to choose smaller, sooner rewards (“Now”) over larger, delayed rewards (“Later”). This tendency can be measured and quantified in the laboratory and echoes the key characteristic of addiction: acting without regard for long-term consequences. Despite the clinical importance of such impulsive behavior, we know little about how it is promoted or curbed by the human brain. This issue was addressed in studies of individual selection bias in decisions between Now and Later. Functional magnetic resonance imaging (fMRI) shows that during Now versus Later decisions, one’s tendency to choose Now over Later is predicted by activity in specific brain areas. Activity in these areas differs based on alcohol use history, suggesting brain mechanisms for poor decisions in addiction. In addition to alcohol history, genetically predicted frontal dopamine levels predict both Now/Later preference and underlying brain activity; low frontal dopamine is associated with Now bias. We tested whether a medication indicated for treating alcoholism (Naltrexone) alters brain activity during decision-making in brain areas that predict individual immediate reward bias. Our results point to the possible importance of dopamine in regulating immediate reward bias. Neuromodulatory interventions that effectively reduce immediate reward bias hold therapeutic promise for addiction; thus, identifying ways to produce such changes and identifying the factors that influence individual response may be transformative steps in developing more effective addiction treatments. BRAIN STIMULATION IN THE STUDY AND TREATMENT OF ADDICTION Abraham Zangen The Weizmann Institute of Science, Rehovot, Israel Repeated drug administration induces neuroadaptations associated with abnormal dopaminergic activity in the brain reward system, resulting in altered cortical neurotransmission and excitability. Transcranial magnetic stimulation (TMS) can be used in human addicts to transiently stimulate or disrupt neural activity in specific cortical regions. TMS can also induce changes in cortical excitability and it is suggested that repeated stimulation can cause long lasting neuroadaptations. Therefore, TMS paradigms were used in some studies to assess the presence of altered cortical excitability associated with chronic drug consumption, while other studies have began to assess therapeutic potentials of repetitive TMS (rTMS). We have tested the neurochemical and behavioral effect of rTMS-like patterns of stimulation in animal models using implanted electrodes in specific brain regions and found that, depending on brain site and stimulation pattern, it is possible to reduce cocaine seeking behavior and glutamatergic alterations in the brain reward circuitry. We have also tested the effectiveness of rTMS over the prefrontal cortex in human addicts and confirmed the potential benefit of this approach. Currently we are testing the effectiveness of stimulation over the insular cortex in nicotine addicts, using a unique TMS coil that we have developed and preliminary data of this ongoing study will also be presented. NUOVE FRONTIERE DELL’IMAGING CON RISONANZA MAGNETICA AD ALTO CAMPO NELLA DIPENDENZA: APPLICAZIONI CLINICHE E DATI DI VERONA Franco Alessandrini Dipartimento di Neurologia Ospedale Civile Maggiore Borgo Trento - Verona La Dipendenza da sostanze è una malattia riconosciuta dall’Organizzazione Mondiale della Sanità e dalle società scientifiche. E’ descritta nell’International Classification of Diseases (ICD) (http://www.who.int) e nel Diagnostic and Statistical Manual of mental disorders. Facendo seguito alle indicazioni del Programma Regionale delle Dipendenze, Regione Veneto (http:// prd.dronet.org), alle linee d’indirizzo del Dipartimento Politiche Antidroga della Presidenza del Consiglio dei Ministri (http://www.politicheantidroga.it/) concordate con il Ministero della Salute, l’U.O. di Neuroscienze del Dipartimento delle Dipendenze Az. ULSS 20 in collaborazione con il Servizio di Neuroradiologia dell’Ospedale Civile Maggiore di Verona, si propone di utilizzare la Risonanza Magnetica (RM) encefalica ad alto campo magnetico (3.0 Tesla) per descrivere le alterazioni cerebrali in soggetti che hanno diversi profili tossicologici rispetto all’uso di sostanze non prescritte. Con le moderne apparecchiature RM ad alto campo sono possibili studi sofisticati in vivo della struttura anatomica e funzionale del cervello umano. E’ infatti possi-
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Neuroscienze e dipendenze - Dipartimento per le politiche antidroga

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