1 2513 88 EPIGENETICS AND PSYCHOSTIMULANT ADDICTION. CHRONIC DRUG EXPOSURE ALTERS GENE EXPRESSION IN THE BRAIN AND PRODUCES LONG-TERM CHANGES IN NEURAL NETWORKS THAT UNDERLIE COMPULSIVE DRUG TAKING AND SEEKING. EXACTLY HOW DRUG-INDUCED CHANGES IN SYNAPTIC PLASTICITY AND SUBSEQUENT GENE EXPRESSION ARE TRANSLATED INTO PERSISTENT NEUROADAPTATIONS REMAINS UNCLEAR. EMERGING EVIDENCE SUGGESTS THAT COMPLEX DRUG-INDUCED NEUROADAPTATIONS IN THE BRAIN ARE MEDIATED BY HIGHLY SYNCHRONIZED AND DYNAMIC PATTERNS OF GENE REGULATION. RECENTLY, IT HAS BECOME CLEAR THAT EPIGENETIC MECHANISMS CONTRIBUTE TO DRUG-INDUCED STRUCTURAL, SYNAPTIC, AND BEHAVIORAL PLASTICITY BY REGULATING EXPRESSION OF GENE NETWORKS. HERE WE REVIEW HOW ALTERATIONS IN HISTONE MODIFICATIONS, DNA METHYLATION, AND MICRORNAS REGULATE GENE EXPRESSION AND CONTRIBUTE TO PSYCHOSTIMULANT ADDICTION WITH A FOCUS ON THE EPIGENETIC MECHANISMS THAT REGULATE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION FOLLOWING CHRONIC COCAINE EXPOSURE. IDENTIFYING EPIGENETIC SIGNATURES THAT DEFINE PSYCHOSTIMULANT ADDICTION MAY LEAD TO NOVEL, EFFICACIOUS TREATMENTS FOR DRUG CRAVING AND RELAPSE. 2013 2 6806 51 [EPIGENETICS AND DRUG ADDICTION: A FOCUS ON MECP2 AND ON HISTONE ACETYLATION]. CHRONIC DRUG EXPOSURE ALTERS GENE EXPRESSION IN THE BRAIN, WHICH IS BELIEVED TO UNDERLIE COMPULSIVE DRUG SEEKING AND DRUG TAKING BEHAVIOR. RECENT EVIDENCE SHOWS THAT DRUG-INDUCED LONG-TERM NEUROADAPTATIONS IN THE BRAIN ARE MEDIATED IN PART BY EPIGENETIC MECHANISMS. BY REMODELING CHROMATIN, THIS TYPE OF REGULATION CONTRIBUTES TO DRUG-INDUCED SYNAPTIC PLASTICITY THAT TRANSLATES INTO BEHAVIORAL MODIFICATIONS. HOW DRUG-INDUCED ALTERATIONS IN DNA METHYLATION REGULATE GENE EXPRESSION IS REVIEWED HERE, WITH A FOCUS ON MECP2, A PROTEIN BINDING METHYLATED DNA. THE IMPORTANCE OF HISTONE MODIFICATIONS, ESPECIALLY ACETYLATION IS ALSO DISCUSSED, WITH AN EMPHASIS ON THE EFFECTS OF INHIBITORS OF HISTONE DEACETYLASES ON DRUG-INDUCED BEHAVIORAL CHANGES. THE PRECISE IDENTIFICATION OF THE EPIGENETIC MECHANISMS THAT ARE UNDER THE CONTROL OF DRUGS OF ABUSE MAY HELP TO UNCOVER NOVEL TARGETS FOR THE TREATMENT OF DRUG SEEKING AND RELAPSE. 2015 3 4650 36 NEUROPLASTICITY IN ADDICTION: CELLULAR AND TRANSCRIPTIONAL PERSPECTIVES. DRUG ADDICTION IS A CHRONIC, RELAPSING BRAIN DISORDER WHICH CONSISTS OF COMPULSIVE PATTERNS OF DRUG-SEEKING AND TAKING THAT OCCURS AT THE EXPENSE OF OTHER ACTIVITIES. THE TRANSITION FROM CASUAL TO COMPULSIVE DRUG USE AND THE ENDURING PROPENSITY TO RELAPSE IS THOUGHT TO BE UNDERPINNED BY LONG-LASTING NEUROADAPTATIONS IN SPECIFIC BRAIN CIRCUITRY, ANALOGOUS TO THOSE THAT UNDERLIE LONG-TERM MEMORY FORMATION. RESEARCH SPANNING THE LAST TWO DECADES HAS MADE GREAT PROGRESS IN IDENTIFYING CELLULAR AND MOLECULAR MECHANISMS THAT CONTRIBUTE TO DRUG-INDUCED CHANGES IN PLASTICITY AND BEHAVIOR. ALTERATIONS IN SYNAPTIC TRANSMISSION WITHIN THE MESOCORTICOLIMBIC AND CORTICOSTRIATAL PATHWAYS, AND CHANGES IN THE TRANSCRIPTIONAL POTENTIAL OF CELLS BY EPIGENETIC MECHANISMS ARE TWO IMPORTANT MEANS BY WHICH DRUGS OF ABUSE CAN INDUCE LASTING CHANGES IN BEHAVIOR. IN THIS REVIEW WE PROVIDE A SUMMARY OF MORE RECENT RESEARCH THAT HAS FURTHERED OUR UNDERSTANDING OF DRUG-INDUCED NEUROPLASTIC CHANGES BOTH AT THE LEVEL OF THE SYNAPSE, AND ON A TRANSCRIPTIONAL LEVEL, AND HOW THESE CHANGES MAY RELATE TO THE HUMAN DISEASE OF ADDICTION. 2012 4 2259 33 EPIGENETIC PRIMING IN DRUG ADDICTION. DRUG ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND CONTINUED USE DESPITE NEGATIVE OUTCOMES. CURRENT PHARMACOLOGICAL THERAPIES TARGET NEURONAL RECEPTORS OR TRANSPORTERS UPON WHICH DRUGS OF ABUSE ACT INITIALLY, YET THESE TREATMENTS REMAIN INEFFECTIVE FOR MOST INDIVIDUALS AND DO NOT PREVENT DISEASE RELAPSE AFTER ABSTINENCE. DRUGS OF ABUSE, IN ADDITION TO THEIR ACUTE EFFECTS, CAUSE PERSISTENT PLASTICITY AFTER REPEATED USE, INVOLVING DYSREGULATED GENE EXPRESSION IN THE BRAIN'S REWARD REGIONS, WHICH ARE THOUGHT TO MEDIATE THE PERSISTENT BEHAVIORAL ABNORMALITIES THAT CHARACTERIZE ADDICTION. EMERGING EVIDENCE IMPLICATES EPIGENETIC PRIMING AS A KEY MECHANISM THAT UNDERLIES THE LONG-LASTING ALTERATIONS IN NEURONAL GENE REGULATION, WHICH CAN REMAIN LATENT UNTIL TRIGGERED BY RE-EXPOSURE TO DRUG-ASSOCIATED STIMULI OR THE DRUG ITSELF. THUS, TO EFFECTIVELY TREAT DRUG ADDICTION, WE MUST IDENTIFY THE PRECISE EPIGENETIC MECHANISMS THAT ESTABLISH AND PRESERVE THE DRUG-INDUCED PATHOLOGY OF THE BRAIN REWARD CIRCUITRY. 2018 5 2058 30 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE ALCOHOLIC BRAIN. CHRONIC ALCOHOL EXPOSURE CAUSES WIDESPREAD CHANGES IN BRAIN GENE EXPRESSION IN HUMANS AND ANIMAL MODELS. MANY OF THESE CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THERE IS AN EMERGING APPRECIATION FOR THE ROLE OF EPIGENETIC PROCESSES IN ALCOHOL-INDUCED CHANGES IN BRAIN GENE EXPRESSION AND BEHAVIOR. FOR EXAMPLE, CHRONIC ALCOHOL EXPOSURE PRODUCES CHANGES IN DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION THAT AFFECT EXPRESSION OF MULTIPLE GENES IN VARIOUS TYPES OF BRAIN CELLS (I.E., NEURONS AND GLIA) AND CONTRIBUTE TO BRAIN PATHOLOGY AND BRAIN PLASTICITY ASSOCIATED WITH ALCOHOL ABUSE AND DEPENDENCE. DRUGS TARGETING THE EPIGENETIC "MASTER REGULATORS" ARE EMERGING AS POTENTIAL THERAPEUTICS FOR NEURODEGENERATIVE DISORDERS AND DRUG ADDICTION. 2013 6 4327 37 MICRORNAS MODULATE INTERACTIONS BETWEEN STRESS AND RISK FOR COCAINE ADDICTION. EXPOSURE TO STRESS INCREASES VULNERABILITY TO DRUG ABUSE, AS WELL AS RELAPSE LIABILITY IN ADDICTED INDIVIDUALS. CHRONIC DRUG USE ALTERS STRESS RESPONSE IN A MANNER THAT INCREASES DRUG SEEKING BEHAVIORS AND RELAPSE. DRUG EXPOSURE AND WITHDRAWAL HAVE BEEN SHOWN TO ALTER STRESS RESPONSES, AND CORTICOSTEROID MEDIATORS OF STRESS HAVE BEEN SHOWN TO IMPACT ADDICTION-RELATED BRAIN FUNCTION AND DRUG-SEEKING BEHAVIOR. DESPITE THE DOCUMENTED INTERPLAY BETWEEN STRESS AND SUBSTANCE ABUSE, THE MECHANISMS BY WHICH STRESS EXPOSURE AND DRUG SEEKING INTERACT REMAIN LARGELY UNKNOWN. RECENT STUDIES INDICATE THAT MICRORNAS (MIRNA) PLAY A SIGNIFICANT ROLE IN STRESS MODULATION AS WELL AS ADDICTION-RELATED PROCESSES INCLUDING NEUROGENESIS, SYNAPSE DEVELOPMENT, PLASTICITY, DRUG ACQUISITION, WITHDRAWAL AND RELAPSE. MIRNAS ARE SHORT NON-CODING RNAS THAT FUNCTION AS BIDIRECTIONAL EPIGENETIC MODULATORS OF GENE EXPRESSION THROUGH IMPERFECT SEQUENCE TARGETED DEGRADATION AND/OR TRANSLATIONAL REPRESSION OF MRNAS. THEY SERVE AS DYNAMIC REGULATORS OF CNS PHYSIOLOGY AND PATHOPHYSIOLOGY, AND FACILITATE RAPID AND LONG-LASTING CHANGES TO COMPLEX SYSTEMS AND BEHAVIORS. MIRNAS FUNCTION IN GLUCOCORTICOID SIGNALING AND THE MESOLIMBIC DOPAMINE REWARD SYSTEM, AS WELL AS MOOD DISORDERS RELATED TO DRUG WITHDRAWAL. THE LITERATURE SUGGESTS MIRNAS PLAY A PIVOTAL ROLE IN THE INTERACTION BETWEEN EXPOSURES TO STRESS, ADDICTION-RELATED PROCESSES, AND NEGATIVE AFFECTIVE STATES RESULTING FROM EXTENDED DRUG WITHDRAWAL. THIS MANUSCRIPT REVIEWS RECENT EVIDENCE FOR THE ROLE OF MIRNAS IN THE MODULATION OF STRESS AND COCAINE RESPONSES, AND DISCUSSES POTENTIAL MEDIATION OF THE INTERACTION OF THESE SYSTEMS BY MIRNAS. UNCOVERING THE MECHANISM BEHIND THE ASSOCIATION OF STRESS AND DRUG TAKING HAS THE POTENTIAL TO IMPACT THE TREATMENT OF DRUG ABUSE AND PREVENTION OF RELAPSE. FURTHER COMPREHENSION OF THESE COMPLEX INTERACTIONS MAY PROVIDE PROMISING NEW TARGETS FOR THE TREATMENT OF DRUG ADDICTION. 2016 7 4653 28 NEUROSCIENCE OF ALCOHOLISM: MOLECULAR AND CELLULAR MECHANISMS. ALCOHOL USE AND ABUSE APPEAR TO BE RELATED TO NEUROADAPTIVE CHANGES AT FUNCTIONAL, NEUROCHEMICAL, AND STRUCTURAL LEVELS. ACUTE AND CHRONIC ETHANOL EXPOSURE HAVE BEEN SHOWN TO MODULATE FUNCTION OF THE ACTIVITY-DEPENDENT GENE TRANSCRIPTION FACTOR, CAMP-RESPONSIVE ELEMENT BINDING (CREB) PROTEIN IN THE BRAIN, WHICH MAY BE ASSOCIATED WITH THE DEVELOPMENT OF ALCOHOLISM. STUDY OF THE DOWNSTREAM EFFECTORS OF CREB HAVE IDENTIFIED SEVERAL IMPORTANT CREB-RELATED GENES, SUCH AS NEUROPEPTIDE Y, BRAIN-DERIVED NEUROTROPHIC FACTOR, ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN, AND CORTICOTROPHIN-RELEASING FACTOR, THAT MAY PLAY A CRUCIAL ROLE IN THE BEHAVIORAL EFFECTS OF ETHANOL AND MOLECULAR CHANGES IN THE SPECIFIC NEUROCIRCUITRY THAT UNDERLIE BOTH ALCOHOL ADDICTION AND A GENETIC PREDISPOSITION TO ALCOHOLISM. BRAIN CHROMATIN REMODELING DUE TO HISTONE COVALENT MODIFICATIONS MAY ALSO BE INVOLVED IN MEDIATING THE BEHAVIORAL EFFECTS AND NEUROADAPTIVE CHANGES THAT OCCUR DURING ETHANOL EXPOSURE. THIS REVIEW OUTLINES PROGRESSIVE NEUROSCIENCE RESEARCH INTO MOLECULAR AND EPIGENETIC MECHANISMS OF ALCOHOLISM. 2010 8 2292 39 EPIGENETIC REGULATION IN SUBSTANCE USE DISORDERS. SUBSTANCE USE DISORDER IS A CHRONIC CONDITION OF COMPULSIVE DRUG SEEKING AND USE THAT IS MEDIATED BY STABLE CHANGES IN CENTRAL REWARD PATHWAYS. REPEATED USE OF ABUSED DRUGS CAUSES PERSISTENT ALTERATIONS IN GENE EXPRESSION RESPONSIBLE FOR THE LONG-TERM BEHAVIORAL AND STRUCTURAL CHANGES. RECENTLY, IT HAS BEEN SUGGESTED THAT EPIGENETIC MECHANISMS ARE RESPONSIBLE IN PART FOR THESE DRUG-INDUCED CHANGES IN GENE EXPRESSION. ONE OF THE ALLURING ASPECTS OF EPIGENETIC REGULATION OF GENE EXPRESSION IS THAT EPIGENETIC MECHANISMS MAY PROVIDE TRANSIENT AND POTENTIALLY STABLE CONDITIONS THAT IN TURN MAY ULTIMATELY PARTICIPATE IN THE MOLECULAR MECHANISMS REQUIRED FOR NEURONAL CHANGES SUBSERVING LONG-LASTING CHANGES IN BEHAVIOR. THIS REVIEW DESCRIBES EPIGENETIC MECHANISMS OF GENE REGULATION AND THEN DISCUSSES THE EMERGING ROLE OF EPIGENETICS IN DRUG-INDUCED PLASTICITY AND BEHAVIOR. UNDERSTANDING THESE MECHANISMS THAT ESTABLISH AND MAINTAIN DRUG-DEPENDENT PLASTICITY CHANGES MAY LEAD TO DEEPER UNDERSTANDING OF SUBSTANCE USE DISORDERS AS WELL AS NOVEL APPROACHES TO TREATMENT. 2010 9 1252 36 CURRENT PERSPECTIVES ON THE NEUROBIOLOGY OF DRUG ADDICTION: A FOCUS ON GENETICS AND FACTORS REGULATING GENE EXPRESSION. DRUG ADDICTION IS A CHRONIC, RELAPSING DISORDER DEFINED BY CYCLIC PATTERNS OF COMPULSIVE DRUG SEEKING AND TAKING INTERSPERSED WITH EPISODES OF ABSTINENCE. WHILE GENETIC VARIABILITY MAY INCREASE THE RISK OF ADDICTIVE BEHAVIOURS IN AN INDIVIDUAL, EXPOSURE TO A DRUG RESULTS IN NEUROADAPTATIONS IN INTERCONNECTED BRAIN CIRCUITS WHICH, IN SUSCEPTIBLE INDIVIDUALS, ARE BELIEVED TO UNDERLIE THE TRANSITION TO, AND MAINTENANCE OF, AN ADDICTED STATE. THESE ADAPTATIONS CAN OCCUR AT THE CELLULAR, MOLECULAR, OR (EPI)GENETIC LEVEL AND ARE ASSOCIATED WITH SYNAPTIC PLASTICITY AND ALTERED GENE EXPRESSION, THE LATTER BEING MEDIATED VIA BOTH FACTORS AFFECTING TRANSLATION (EPIGENETICS) AND TRANSCRIPTION (NON CODING MICRORNAS) OF THE DNA OR RNA ITSELF. NEW ADVANCES USING TECHNIQUES SUCH AS OPTOGENETICS HAVE THE POTENTIAL TO INCREASE OUR UNDERSTANDING OF THE MICROCIRCUITRY MEDIATING ADDICTIVE BEHAVIOURS. HOWEVER, THE PROCESSES LEADING TO ADDICTION ARE COMPLEX AND MULTIFACTORIAL AND THUS WE FACE A MAJOR CONTEMPORARY CHALLENGE TO ELUCIDATE THE FACTORS IMPLICATED IN THE DEVELOPMENT AND MAINTENANCE OF AN ADDICTED STATE. 2012 10 2250 33 EPIGENETIC MODULATION OF OPIOID RECEPTORS BY DRUGS OF ABUSE. CHRONIC EXPOSURE TO DRUGS OF ABUSE PRODUCES PROFOUND CHANGES IN GENE EXPRESSION AND NEURAL ACTIVITY ASSOCIATED WITH DRUG-SEEKING AND TAKING BEHAVIOR. DYSREGULATION OF OPIOID RECEPTOR GENE EXPRESSION IS COMMONLY OBSERVED ACROSS A VARIETY OF ABUSED SUBSTANCES INCLUDING OPIOIDS, COCAINE, AND ALCOHOL. EARLY STUDIES IN CULTURED CELLS SHOWED THAT THE SPATIAL AND TEMPORAL GENE EXPRESSION OF OPIOID RECEPTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA AND HISTONE MODIFICATIONS AND NON-CODING RNAS. ACCUMULATING EVIDENCE INDICATE THAT DRUGS OF ABUSE CAN MODULATE OPIOID RECEPTOR GENE EXPRESSION BY TARGETING VARIOUS EPIGENETIC REGULATORY NETWORKS. BASED ON CURRENT CELLULAR AND ANIMAL MODELS OF SUBSTANCE USE DISORDER AND CLINICAL EVIDENCE, THIS REVIEW SUMMARIZES HOW CHRONIC DRUG EXPOSURE ALTERS THE GENE EXPRESSION OF MU, DELTA, KAPPA, AND NOCICEPTIN RECEPTORS VIA DNA AND HISTONE MODIFICATIONS. THE INFLUENCE OF DRUGS OF ABUSE ON EPIGENETIC MODULATORS, SUCH AS NON-CODING RNAS AND TRANSCRIPTION FACTORS, IS ALSO PRESENTED. FINALLY, THE THERAPEUTIC POTENTIAL OF MANIPULATING EPIGENETIC PROCESSES AS AN AVENUE TO TREAT SUBSTANCE USE DISORDER IS DISCUSSED. 2022 11 3952 30 LOCUS-SPECIFIC EPIGENETIC REMODELING CONTROLS ADDICTION- AND DEPRESSION-RELATED BEHAVIORS. CHRONIC EXPOSURE TO DRUGS OF ABUSE OR STRESS REGULATES TRANSCRIPTION FACTORS, CHROMATIN-MODIFYING ENZYMES AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN DISCRETE BRAIN REGIONS. GIVEN THE PROMISCUITY OF THE ENZYMES INVOLVED, IT HAS NOT YET BEEN POSSIBLE TO OBTAIN DIRECT CAUSAL EVIDENCE TO IMPLICATE THE REGULATION OF TRANSCRIPTION AND CONSEQUENT BEHAVIORAL PLASTICITY BY CHROMATIN REMODELING THAT OCCURS AT A SINGLE GENE. WE INVESTIGATED THE MECHANISM LINKING CHROMATIN DYNAMICS TO NEUROBIOLOGICAL PHENOMENA BY APPLYING ENGINEERED TRANSCRIPTION FACTORS TO SELECTIVELY MODIFY CHROMATIN AT A SPECIFIC MOUSE GENE IN VIVO. WE FOUND THAT HISTONE METHYLATION OR ACETYLATION AT THE FOSB LOCUS IN NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, WAS SUFFICIENT TO CONTROL DRUG- AND STRESS-EVOKED TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES VIA INTERACTIONS WITH THE ENDOGENOUS TRANSCRIPTIONAL MACHINERY. THIS APPROACH ALLOWED US TO RELATE THE EPIGENETIC LANDSCAPE AT A GIVEN GENE DIRECTLY TO REGULATION OF ITS EXPRESSION AND TO ITS SUBSEQUENT EFFECTS ON REWARD BEHAVIOR. 2014 12 1532 25 DNA METHYLATION DYNAMICS AND COCAINE IN THE BRAIN: PROGRESS AND PROSPECTS. CYTOSINE MODIFICATIONS, INCLUDING DNA METHYLATION, ARE STABLE EPIGENETIC MARKS THAT MAY TRANSLATE ENVIRONMENTAL CHANGE INTO TRANSCRIPTIONAL REGULATION. RESEARCH HAS BEGUN TO INVESTIGATE DNA METHYLATION DYNAMICS IN RELATION TO COCAINE USE DISORDERS. SPECIFICALLY, DNA METHYLATION MACHINERY, INCLUDING METHYLTRANSFERASES AND BINDING PROTEINS, ARE DYSREGULATED IN BRAIN REWARD PATHWAYS AFTER CHRONIC COCAINE EXPOSURE. IN ADDITION, NUMEROUS METHYLOME-WIDE AND CANDIDATE PROMOTER STUDIES HAVE IDENTIFIED DIFFERENTIAL METHYLATION, AT THE NUCLEOTIDE LEVEL, IN RODENT MODELS OF COCAINE ABUSE AND DRUG SEEKING BEHAVIOR. THIS REVIEW HIGHLIGHTS THE CURRENT PROGRESS IN THE FIELD OF COCAINE-RELATED METHYLATION, AND OFFERS CONSIDERATIONS FOR FUTURE RESEARCH. 2017 13 2598 31 EPIGENETICS OF THE DEPRESSED BRAIN: ROLE OF HISTONE ACETYLATION AND METHYLATION. MAJOR DEPRESSIVE DISORDER IS A CHRONIC, REMITTING SYNDROME INVOLVING WIDELY DISTRIBUTED CIRCUITS IN THE BRAIN. STABLE ALTERATIONS IN GENE EXPRESSION THAT CONTRIBUTE TO STRUCTURAL AND FUNCTIONAL CHANGES IN MULTIPLE BRAIN REGIONS ARE IMPLICATED IN THE HETEROGENEITY AND PATHOGENESIS OF THE ILLNESS. EPIGENETIC EVENTS THAT ALTER CHROMATIN STRUCTURE TO REGULATE PROGRAMS OF GENE EXPRESSION HAVE BEEN ASSOCIATED WITH DEPRESSION-RELATED BEHAVIOR, ANTIDEPRESSANT ACTION, AND RESISTANCE TO DEPRESSION OR 'RESILIENCE' IN ANIMAL MODELS, WITH INCREASING EVIDENCE FOR SIMILAR MECHANISMS OCCURRING IN POSTMORTEM BRAINS OF DEPRESSED HUMANS. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETIC CONTRIBUTIONS TO DEPRESSION, IN PARTICULAR THE ROLE OF HISTONE ACETYLATION AND METHYLATION, WHICH ARE REVEALING NOVEL MECHANISTIC INSIGHT INTO THE SYNDROME THAT MAY AID IN THE DEVELOPMENT OF NOVEL TARGETS FOR DEPRESSION TREATMENT. 2013 14 3376 31 HISTONE-MEDIATED EPIGENETICS IN ADDICTION. MANY OF THE BRAIN REGIONS, NEUROTRANSMITTER SYSTEMS, AND BEHAVIORAL CHANGES THAT OCCUR AFTER OCCASIONAL DRUG USE IN HEALTHY SUBJECTS AND AFTER CHRONIC DRUG ABUSE IN ADDICTED PATIENTS ARE WELL CHARACTERIZED. AN EMERGING LITERATURE SUGGESTS THAT EPIGENETIC PROCESSES, THOSE PROCESSES THAT REGULATE THE ACCESSIBILITY OF DNA TO REGULATORY PROTEINS WITHIN THE NUCLEUS, ARE KEYS TO HOW ADDICTION DEVELOPS AND HOW IT MAY BE TREATED. INVESTIGATIONS OF THE REGULATION OF CHROMATIN, THE ORGANIZATIONAL SYSTEM OF DNA, BY HISTONE MODIFICATION ARE LEADING TO A NEW UNDERSTANDING OF THE CELLULAR AND BEHAVIORAL ALTERATIONS THAT OCCUR AFTER DRUG USE. WE WILL DESCRIBE HOW, WHEN, AND WHERE HISTONE TAILS ARE MODIFIED AND HOW SOME OF THE MOST RECOGNIZED HISTONE REGULATION PATTERNS ARE INVOLVED IN THE CYCLE OF ADDICTION, INCLUDING INITIAL AND CHRONIC DRUG INTAKE, WITHDRAWAL, ABSTINENCE, AND RELAPSE. FINALLY, WE CONSIDER HOW AN APPROACH THAT TARGETS HISTONE MODIFICATIONS MAY PROMOTE SUCCESSFUL TREATMENT. 2014 15 584 36 BEHAVIORAL NEUROADAPTATION TO ALCOHOL: FROM GLUCOCORTICOIDS TO HISTONE ACETYLATION. A PRIME MECHANISM THAT CONTRIBUTES TO THE DEVELOPMENT AND MAINTENANCE OF ALCOHOLISM IS THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVITY AND THE RELEASE OF GLUCOCORTICOIDS (CORTISOL IN HUMANS AND PRIMATES, CORTICOSTERONE IN RODENTS) FROM THE ADRENAL GLANDS. IN THE BRAIN, SUSTAINED, LOCAL ELEVATION OF GLUCOCORTICOID CONCENTRATION EVEN LONG AFTER CESSATION OF CHRONIC ALCOHOL CONSUMPTION COMPROMISES FUNCTIONAL INTEGRITY OF A CIRCUIT, INCLUDING THE PREFRONTAL CORTEX (PFC), THE HIPPOCAMPUS (HPC), AND THE AMYGDALA (AMG). THESE STRUCTURES ARE IMPLICATED IN LEARNING AND MEMORY PROCESSES AS WELL AS IN ORCHESTRATING NEUROADAPTIVE RESPONSES TO STRESS AND ANXIETY RESPONSES. THUS, POTENTIATION OF ANXIETY-RELATED NEUROADAPTATION BY ALCOHOL IS CHARACTERIZED BY AN ABNORMALLY AMG HYPERACTIVITY COUPLED WITH A HYPOFUNCTION OF THE PFC AND THE HPC. THIS REVIEW DESCRIBES RESEARCH ON MOLECULAR AND EPIGENETIC MECHANISMS BY WHICH ALCOHOL CAUSES DISTINCT REGION-SPECIFIC ADAPTIVE CHANGES IN GENE EXPRESSION PATTERNS AND ULTIMATELY LEADS TO A VARIETY OF COGNITIVE AND BEHAVIORAL IMPAIRMENTS ON PREFRONTAL- AND HIPPOCAMPAL-BASED TASKS. ALCOHOL-INDUCED NEUROADAPTATIONS INVOLVE THE DYSREGULATION OF NUMEROUS SIGNALING CASCADES, LEADING TO LONG-TERM CHANGES IN TRANSCRIPTIONAL PROFILES OF GENES, THROUGH THE ACTIONS OF TRANSCRIPTION FACTORS SUCH AS [CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB)] AND CHROMATIN REMODELING DUE TO POSTTRANSLATIONAL MODIFICATIONS OF HISTONE PROTEINS. WE DESCRIBE THE ROLE OF PREFRONTAL-HPC-AMG CIRCUIT IN MEDIATING THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL ON LEARNING AND MEMORY, AND REGION-SPECIFIC MOLECULAR AND EPIGENETIC MECHANISMS INVOLVED IN THIS PROCESS. THIS REVIEW FIRST DISCUSSES THE IMPORTANCE OF BRAIN REGION-SPECIFIC DYSREGULATION OF GLUCOCORTICOID CONCENTRATION IN THE DEVELOPMENT OF ALCOHOL DEPENDENCE AND DESCRIBES HOW PERSISTENTLY INCREASED GLUCOCORTICOID LEVELS IN PFC MAY BE INVOLVED IN MEDIATING WORKING MEMORY IMPAIRMENTS AND NEUROADAPTIVE CHANGES DURING WITHDRAWAL FROM CHRONIC ALCOHOL INTAKE. IT THEN HIGHLIGHTS THE ROLE OF CAMP-PKA-CREB SIGNALING CASCADE AND HISTONE ACETYLATION WITHIN THE PFC AND LIMBIC STRUCTURES IN ALCOHOL-INDUCED ANXIETY AND BEHAVIORAL IMPAIRMENTS, AND HOW AN UNDERSTANDING OF FUNCTIONAL ALTERATIONS OF THESE PATHWAYS MIGHT LEAD TO BETTER TREATMENTS FOR NEUROPSYCHIATRIC DISORDERS. 2016 16 2013 34 EPIGENETIC BASIS OF THE DARK SIDE OF ALCOHOL ADDICTION. ALCOHOLISM IS A COMPLEX BRAIN DISEASE CHARACTERIZED BY THREE DISTINCT STAGES OF THE ADDICTION CYCLE THAT MANIFEST AS NEUROADAPTIVE CHANGES IN THE BRAIN. ONE SUCH STAGE OF THE ADDICTION CYCLE IS ALCOHOL WITHDRAWAL AND THE NEGATIVE AFFECTIVE STATES THAT PROMOTE DRINKING AND MAINTAIN ADDICTION. REPEATED ALCOHOL USE, GENETIC PREDISPOSITION TO ALCOHOLISM AND ANXIETY, AND ALCOHOL EXPOSURE DURING CRUCIAL DEVELOPMENTAL PERIODS ALL CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-INDUCED WITHDRAWAL AND NEGATIVE AFFECTIVE SYMPTOMS. EPIGENETIC MODIFICATIONS WITHIN THE AMYGDALA HAVE PROVIDED A MOLECULAR BASIS OF THESE NEGATIVE AFFECTIVE SYMPTOMS, ALSO KNOWN AS THE DARK SIDE OF ADDICTION. HERE, WE PROPOSE THAT ALLOSTATIC CHANGE WITHIN THE EPIGENOME IN THE AMYGDALA IS A PRIME MECHANISM OF THE BIOLOGICAL BASIS OF NEGATIVE AFFECTIVE STATES RESULTING FROM, AND CONTRIBUTING TO, ALCOHOLISM. ACUTE ALCOHOL EXPOSURE PRODUCES AN ANXIOLYTIC RESPONSE WHICH IS ASSOCIATED WITH THE OPENING OF CHROMATIN DUE TO INCREASED HISTONE ACETYLATION, INCREASED CREB BINDING PROTEIN (CBP) LEVELS, AND HISTONE DEACETYLASE (HDAC) INHIBITION. AFTER CHRONIC ETHANOL EXPOSURE, THESE CHANGES RETURN TO BASELINE ALONG WITH ANXIETY-LIKE BEHAVIORS. HOWEVER, DURING WITHDRAWAL, HISTONE ACETYLATION DECREASES DUE TO INCREASED HDAC ACTIVITY AND DECREASED CBP LEVELS IN THE AMYGDALA CIRCUITRY LEADING TO THE DEVELOPMENT OF ANXIETY-LIKE BEHAVIORS. ADDITIONALLY, INNATELY HIGHER EXPRESSION OF THE HDAC2 ISOFORM LEADS TO A DEFICIT IN GLOBAL AND GENE-SPECIFIC HISTONE ACETYLATION IN THE AMYGDALA THAT IS ASSOCIATED WITH A DECREASE IN THE EXPRESSION OF SEVERAL SYNAPTIC PLASTICITY-ASSOCIATED GENES AND MAINTAINING HEIGHTENED ANXIETY-LIKE BEHAVIOR AND EXCESSIVE ALCOHOL INTAKE. ADOLESCENT ALCOHOL EXPOSURE ALSO LEADS TO HIGHER EXPRESSION OF HDAC2 AND A DEFICIT IN HISTONE ACETYLATION LEADING TO DECREASED EXPRESSION OF SYNAPTIC PLASTICITY-ASSOCIATED GENES AND HIGH ANXIETY AND DRINKING BEHAVIOR IN ADULTHOOD. ALL THESE STUDIES INDICATE THAT THE EPIGENOME CAN UNDERGO ALLOSTATIC REPROGRAMMING IN THE AMYGDALOID CIRCUITRY DURING VARIOUS STAGES OF ALCOHOL EXPOSURE. FURTHERMORE, OPENING THE CHROMATIN BY INHIBITING HDACS USING PHARMACOLOGICAL OR GENETIC MANIPULATIONS CAN LEAD TO THE ATTENUATION OF ANXIETY AS WELL AS ALCOHOL INTAKE. CHROMATIN REMODELING PROVIDES A CLEAR BIOLOGICAL BASIS FOR THE NEGATIVE AFFECTIVE STATES SEEN DURING ALCOHOL ADDICTION AND PRESENTS OPPORTUNITIES FOR NOVEL DRUG DEVELOPMENT AND TREATMENT OPTIONS. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED "ALCOHOLISM". 2017 17 4846 24 OPIATE ADDICTION AND COCAINE ADDICTION: UNDERLYING MOLECULAR NEUROBIOLOGY AND GENETICS. ADDICTIVE DISEASES, INCLUDING ADDICTION TO HEROIN, PRESCRIPTION OPIOIDS, OR COCAINE, POSE MASSIVE PERSONAL AND PUBLIC HEALTH COSTS. ADDICTIONS ARE CHRONIC RELAPSING DISEASES OF THE BRAIN CAUSED BY DRUG-INDUCED DIRECT EFFECTS AND PERSISTING NEUROADAPTATIONS AT THE EPIGENETIC, MRNA, NEUROPEPTIDE, NEUROTRANSMITTER, OR PROTEIN LEVELS. THESE NEUROADAPTATIONS, WHICH CAN BE SPECIFIC TO DRUG TYPE, AND THEIR RESULTANT BEHAVIORS ARE MODIFIED BY VARIOUS INTERNAL AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING STRESS RESPONSIVITY, ADDICT MINDSET, AND SOCIAL SETTING. SPECIFIC GENE VARIANTS, INCLUDING VARIANTS ENCODING PHARMACOLOGICAL TARGET PROTEINS OR GENES MEDIATING NEUROADAPTATIONS, ALSO MODIFY VULNERABILITY AT PARTICULAR STAGES OF ADDICTION. GREATER UNDERSTANDING OF THESE INTERACTING FACTORS THROUGH LABORATORY-BASED AND TRANSLATIONAL STUDIES HAVE THE POTENTIAL TO OPTIMIZE EARLY INTERVENTIONS FOR THE THERAPY OF CHRONIC ADDICTIVE DISEASES AND TO REDUCE THE BURDEN OF RELAPSE. HERE, WE REVIEW THE MOLECULAR NEUROBIOLOGY AND GENETICS OF OPIATE ADDICTION, INCLUDING HEROIN AND PRESCRIPTION OPIOIDS, AND COCAINE ADDICTION. 2012 18 2773 33 EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASES 1 AND 2 ACTIVATION BY ADDICTIVE DRUGS: A SIGNAL TOWARD PATHOLOGICAL ADAPTATION. ADDICTION IS A CHRONIC AND RELAPSING PSYCHIATRIC DISORDER THAT IS THOUGHT TO OCCUR IN VULNERABLE INDIVIDUALS. SYNAPTIC PLASTICITY EVOKED BY DRUGS OF ABUSE IN THE SO-CALLED NEURONAL CIRCUITS OF REWARD HAS BEEN PROPOSED TO UNDERLIE BEHAVIORAL ADAPTATIONS THAT CHARACTERIZE ADDICTION. BY INCREASING DOPAMINE IN THE STRIATUM, ADDICTIVE DRUGS ALTER THE BALANCE OF DOPAMINE AND GLUTAMATE SIGNALS CONVERGING ONTO STRIATAL MEDIUM-SIZED SPINY NEURONS (MSNS) AND ACTIVATE INTRACELLULAR EVENTS INVOLVED IN LONG-TERM BEHAVIORAL ALTERATIONS. OUR LABORATORY CONTRIBUTED TO THE IDENTIFICATION OF SALIENT MOLECULAR CHANGES INDUCED BY ADMINISTRATION OF ADDICTIVE DRUGS TO RODENTS. WE PIONEERED THE OBSERVATION THAT A COMMON FEATURE OF ADDICTIVE DRUGS IS TO ACTIVATE, BY A DOUBLE TYROSINE/THREONINE PHOSPHORYLATION, THE EXTRACELLULAR SIGNAL-REGULATED KINASES 1 AND 2 (ERK1/2) IN THE STRIATUM, WHICH CONTROL A PLETHORA OF SUBSTRATES, SOME OF THEM BEING CRITICALLY INVOLVED IN COCAINE-MEDIATED MOLECULAR AND BEHAVIORAL ADAPTATIONS. HEREIN, WE REVIEW HOW THE INTERPLAY BETWEEN DOPAMINE AND GLUTAMATE SIGNALING CONTROLS COCAINE-INDUCED ERK1/2 ACTIVATION IN MSNS. WE EMPHASIZE THE KEY ROLE OF N-METHYL-D-ASPARTATE RECEPTOR POTENTIATION BY D1 RECEPTOR TO TRIGGER ERK1/2 ACTIVATION AND ITS SUBSEQUENT NUCLEAR TRANSLOCATION WHERE IT MODULATES BOTH EPIGENETIC AND GENETIC PROCESSES ENGAGED BY COCAINE. WE DISCUSS HOW COCAINE-INDUCED LONG-TERM SYNAPTIC AND STRUCTURAL PLASTICITY OF MSNS, AS WELL AS BEHAVIORAL ADAPTATIONS, ARE INFLUENCED BY ERK1/2-CONTROLLED TARGETS. WE CONCLUDE THAT A BETTER KNOWLEDGE OF MOLECULAR MECHANISMS UNDERLYING ERK1/2 ACTIVATION BY DRUGS OF ABUSE AND/OR ITS ROLE IN LONG-TERM NEURONAL PLASTICITY IN THE STRIATUM MAY PROVIDE A NEW ROUTE FOR THERAPEUTIC TREATMENT IN ADDICTION. 2014 19 1870 38 EMERGING ROLE OF EPIGENETIC MECHANISMS IN ALCOHOL ADDICTION. ALCOHOL USE DISORDER (AUD) IS A COMPLEX BRAIN DISORDER WITH AN ARRAY OF PERSISTENT BEHAVIORAL AND NEUROCHEMICAL MANIFESTATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF AUD, AND RECENT STUDIES ON ALCOHOL EXPOSURE AND SUBSEQUENT CHANGES IN GENE EXPRESSION SUGGEST THE IMPORTANCE OF EPIGENETIC MECHANISMS. IN PARTICULAR, HISTONE MODIFICATIONS AND DNA METHYLATION HAVE EMERGED AS IMPORTANT REGULATORS OF GENE EXPRESSION AND ASSOCIATED PHENOTYPES OF AUD. GIVEN THE THERAPEUTIC POTENTIAL OF EPIGENETIC TARGETS, THIS REVIEW AIMS TO SUMMARIZE THE ROLE OF EPIGENETIC REGULATION IN OUR CURRENT UNDERSTANDING OF AUD BY EVALUATING KNOWN EPIGENETIC SIGNATURES OF BRAIN REGIONS CRITICAL TO ADDICTIVE BEHAVIORS IN BOTH ANIMAL AND HUMAN STUDIES THROUGHOUT VARIOUS STAGES OF AUD. MORE SPECIFICALLY, THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL EXPOSURE, TOLERANCE, AND POSTEXPOSURE WITHDRAWAL ON EPIGENETICALLY INDUCED CHANGES TO GENE EXPRESSION AND SYNAPTIC PLASTICITY WITHIN KEY BRAIN REGIONS AND THE ASSOCIATED BEHAVIORAL PHENOTYPES HAVE BEEN DISCUSSED. UNDERSTANDING THE CONTRIBUTION OF EPIGENETIC REGULATION TO CRUCIAL SIGNALING PATHWAYS MAY PROVE VITAL FOR FUTURE DEVELOPMENT OF NOVEL BIOMARKERS AND TREATMENT AGENTS IN AMELIORATING OR PREVENTING AUD. 2017 20 2606 31 EPIGENETICS-BEYOND THE GENOME IN ALCOHOLISM. GENETIC AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF ALCOHOLISM. WHOLE-GENOME EXPRESSION PROFILING HAS HIGHLIGHTED THE IMPORTANCE OF SEVERAL GENES THAT MAY CONTRIBUTE TO ALCOHOL ABUSE DISORDERS. IN ADDITION, MORE RECENT FINDINGS HAVE ADDED YET ANOTHER LAYER OF COMPLEXITY TO THE OVERALL MOLECULAR MECHANISMS INVOLVED IN A PREDISPOSITION TO ALCOHOLISM AND ADDICTION BY DEMONSTRATING THAT PROCESSES RELATED TO GENETIC FACTORS THAT DO NOT MANIFEST AS DNA SEQUENCE CHANGES (I.E., EPIGENETIC PROCESSES) PLAY A ROLE. BOTH ACUTE AND CHRONIC ETHANOL EXPOSURE CAN ALTER GENE EXPRESSION LEVELS IN SPECIFIC NEURONAL CIRCUITS THAT GOVERN THE BEHAVIORAL CONSEQUENCES RELATED TO TOLERANCE AND DEPENDENCE. THE UNREMITTING CYCLE OF ALCOHOL CONSUMPTION OFTEN INCLUDES SATIATION AND SELF-MEDICATION WITH ALCOHOL, FOLLOWED BY EXCRUCIATING WITHDRAWAL SYMPTOMS AND THE RESULTANT RELAPSE, WHICH REFLECTS BOTH THE POSITIVE AND NEGATIVE AFFECTIVE STATES OF ALCOHOL ADDICTION. RECENT STUDIES HAVE INDICATED THAT BEHAVIORAL CHANGES INDUCED BY ACUTE AND CHRONIC ETHANOL EXPOSURE MAY INVOLVE CHROMATIN REMODELING RESULTING FROM COVALENT HISTONE MODIFICATIONS AND DNA METHYLATION IN THE NEURONAL CIRCUITS INVOLVING A BRAIN REGION CALLED THE AMYGDALA. THESE FINDINGS HAVE HELPED IDENTIFY ENZYMES INVOLVED IN EPIGENETIC MECHANISMS, SUCH AS THE HISTONE DEACETYLASE, HISTONE ACETYLTRANSFERASE, AND DNA METHYLTRANSFERASE ENZYMES, AS NOVEL THERAPEUTIC TARGETS FOR THE DEVELOPMENT OF FUTURE PHARMACOTHERAPIES FOR THE TREATMENT OF ALCOHOLISM. 2012