1 1088 111 COCAINE DIRECTLY IMPAIRS MEMORY EXTINCTION AND ALTERS BRAIN DNA METHYLATION DYNAMICS IN HONEY BEES. DRUG ADDICTION IS A CHRONIC RELAPSING BEHAVIORAL DISORDER. THE HIGH RELAPSE RATE HAS OFTEN BEEN ATTRIBUTED TO THE PERSEVERANCE OF DRUG-ASSOCIATED MEMORIES DUE TO HIGH INCENTIVE SALIENCE OF STIMULI LEARNT UNDER THE INFLUENCE OF DRUGS. DRUG ADDICTION HAS ALSO BEEN INTERPRETED AS A MEMORY DISORDER SINCE DRUG ASSOCIATED MEMORIES ARE UNUSUALLY ENDURING AND SOME DRUGS, SUCH AS COCAINE, INTERFERE WITH NEUROEPIGENETIC MACHINERY KNOWN TO BE INVOLVED IN MEMORY PROCESSING. HERE WE USED THE HONEY BEE (AN ESTABLISHED INVERTEBRATE MODEL FOR EPIGENOMICS AND BEHAVIORAL STUDIES) TO EXAMINE WHETHER OR NOT COCAINE AFFECTS MEMORY PROCESSING INDEPENDENTLY OF ITS EFFECT ON INCENTIVE SALIENCE. USING THE PROBOSCIS EXTENSION REFLEX TRAINING PARADIGM WE FOUND THAT COCAINE STRONGLY IMPAIRS CONSOLIDATION OF EXTINCTION MEMORY. BASED ON CORRELATION BETWEEN THE OBSERVED EFFECT OF COCAINE ON LEARNING AND EXPRESSION OF EPIGENETIC PROCESSES, WE PROPOSE THAT COCAINE INTERFERES WITH MEMORY PROCESSING INDEPENDENTLY OF INCENTIVE SALIENCE BY DIRECTLY ALTERING DNA METHYLATION DYNAMICS. OUR FINDINGS EMPHASIZE THE IMPACT OF COCAINE ON MEMORY SYSTEMS, WITH RELEVANCE FOR UNDERSTANDING HOW COCAINE CAN HAVE SUCH AN ENDURING IMPACT ON BEHAVIOR. 2018 2 636 32 BIOLOGICAL SUBSTRATES OF ADDICTION. THIS REVIEW IS AN INTRODUCTION TO ADDICTION, THE REWARD CIRCUITRY, AND LABORATORY ADDICTION MODELS. ADDICTION IS A CHRONIC DISEASE HALLMARKED BY A STATE OF COMPULSIVE DRUG SEEKING THAT PERSISTS DESPITE NEGATIVE CONSEQUENCES. MOST OF THE ADVANCES IN ADDICTION RESEARCH HAVE CENTERED ON THE CANONICAL AND CONTEMPORARY DRUGS OF ABUSE; HOWEVER, ADDICTIONS TO OTHER ACTIVITIES AND STIMULI ALSO EXIST. SUBSTANCES OF ABUSE HAVE THE POTENTIAL TO INDUCE LONG-LASTING CHANGES IN THE BRAIN AT THE BEHAVIORAL, CIRCUIT, AND SYNAPTIC LEVELS. ADDICTION-RELATED BEHAVIORAL CHANGES INVOLVE INITIATION, ESCALATION, AND OBSESSION TO DRUG SEEKING AND MUCH OF THE CURRENT RESEARCH IS FOCUSED ON MAPPING THESE MANIFESTATIONS TO SPECIFIC NEURAL PATHWAYS. DRUG ABUSE IS WELL KNOWN TO RECRUIT COMPONENTS OF THE MESOLIMBIC DOPAMINE SYSTEM, INCLUDING THE NUCLEUS ACCUMBENS AND VENTRAL TEGMENTAL AREA. IN ADDITION, ALTERED FUNCTION OF A WIDE VARIETY OF BRAIN REGIONS IS TIGHTLY ASSOCIATED WITH SPECIFIC MANIFESTATIONS OF DRUG ABUSE. THESE REGIONS PERIPHERAL TO THE MESOLIMBIC PATHWAY LIKELY PLAY A ROLE IN SPECIFIC OBSERVED COMORBIDITIES AND ENDOPHENOTYPES THAT CAN FACILITATE, OR BE CAUSED BY, SUBSTANCE ABUSE. ALTERATIONS IN SYNAPTIC STRUCTURE, FUNCTION, AND CONNECTIVITY, AS WELL AS EPIGENETIC AND GENETIC MECHANISMS ARE THOUGHT TO UNDERLIE THE PATHOLOGIES OF ADDICTION. IN PRECLINICAL MODELS, THESE PERSISTENT CHANGES ARE STUDIED AT THE LEVELS OF MOLECULAR PHARMACOLOGY AND BIOCHEMISTRY, EX VIVO AND IN VIVO ELECTROPHYSIOLOGY, RADIOGRAPHY, AND BEHAVIOR. COORDINATING RESEARCH EFFORTS ACROSS THESE DISCIPLINES AND EXAMINING CELL TYPE- AND CIRCUIT-SPECIFIC PHENOMENA ARE CRUCIAL COMPONENTS FOR TRANSLATING PRECLINICAL FINDINGS TO VIABLE MEDICAL INTERVENTIONS THAT EFFECTIVELY TREAT ADDICTION AND RELATED DISORDERS. WIRES COGN SCI 2014, 5:151-171. DOI: 10.1002/WCS.1273 CONFLICT OF INTEREST: THE AUTHORS HAVE DECLARED NO CONFLICTS OF INTEREST FOR THIS ARTICLE. FOR FURTHER RESOURCES RELATED TO THIS ARTICLE, PLEASE VISIT THE WIRES WEBSITE. 2014 3 3708 19 INFLUENCE OF PHARMACOLOGICAL AND EPIGENETIC FACTORS TO SUPPRESS NEUROTROPHIC FACTORS AND ENHANCE NEURAL PLASTICITY IN STRESS AND MOOD DISORDERS. STRESS-INDUCED MAJOR DEPRESSION AND MOOD DISORDERS ARE CHARACTERIZED BY BEHAVIOURAL ABNORMALITIES AND PSYCHIATRIC ILLNESS, LEADING TO DISABILITY AND IMMATURE MORTALITY WORLDWIDE. NEUROBIOLOGICAL MECHANISMS OF STRESS AND MOOD DISORDERS ARE DISCUSSED CONSIDERING RECENT FINDINGS, AND CHALLENGES TO ENHANCE PHARMACOLOGICAL EFFECTS OF ANTIDEPRESSANT, AND MOOD STABILIZERS. PHARMACOLOGICAL ENHANCEMENT OF KETAMINE AND SCOPOLAMINE REGULATES DEPRESSION AT THE MOLECULAR LEVEL, INCREASING SYNAPTIC PLASTICITY IN PREFRONTAL REGIONS. BLOOD-DERIVED NEUROTROPHIC FACTORS FACILITATE MOOD-DEFICIT SYMPTOMS. EPIGENETIC FACTORS MAINTAIN STRESS-RESILIENCE IN HIPPOCAMPAL REGION. REGULATION OF NEUROTROPHIC FACTORS BLOCKADES STRESS, AND ENHANCES NEURONAL SURVIVAL THOUGH IT PARALYZES LIMBIC REGIONS. MOLECULAR AGENTS AND NEUROTROPHIC FACTORS ALSO CONTROL BEHAVIORAL AND SYNAPTIC PLASTICITY IN ADDICTION AND STRESS DISORDERS. FUTURE RESEARCH ON NEURONAL DYNAMICS AND CELLULAR ACTIONS CAN BE DIRECTED TO OBTAIN THE ETIOLOGY OF SYNAPTIC DYSREGULATION IN MOOD DISORDER AND STRESS. FOR THE FIRST TIME, THE CURRENT REVIEW CONTRIBUTES TO THE LITERATURE OF SYNAPTIC PLASTICITY REPRESENTING THE ROLE OF EPIGENETIC MECHANISMS AND GLUCOCORTICOID RECEPTORS TO PREDICT DEPRESSION AND ANXIETY IN CLINICAL CONDITIONS. 2019 4 2292 23 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 5 6895 23 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION. 2009 6 3328 33 HISTONE DEACETYLASE 5 MODULATES THE EFFECTS OF SOCIAL ADVERSITY IN EARLY LIFE ON COCAINE-INDUCED BEHAVIOR. PSYCHOSTIMULANTS INDUCE STABLE CHANGES IN NEURAL PLASTICITY AND BEHAVIOR IN A TRANSCRIPTION-DEPENDENT MANNER. FURTHER, STABLE CELLULAR CHANGES REQUIRE TRANSCRIPTION THAT IS REGULATED BY EPIGENETIC MECHANISMS THAT ALTER CHROMATIN STRUCTURE, SUCH AS HISTONE ACETYLATION. THIS MECHANISM IS TYPICALLY CATALYZED BY ENZYMES WITH HISTONE ACETYLTRANSFERASE OR HISTONE DEACETYLASE (HDAC) ACTIVITY. CLASS IIA HDACS ARE NOTABLE FOR THEIR HIGH EXPRESSION IN IMPORTANT REGIONS OF THE BRAIN REWARD CIRCUITRY AND THEIR NEURAL ACTIVITY-DEPENDENT SHUTTLING IN AND OUT OF THE CELL NUCLEUS. IN PARTICULAR, HDAC5 HAS AN IMPORTANT MODULATORY FUNCTION IN COCAINE-INDUCED BEHAVIORS AND SOCIAL DEFEAT STRESS-INDUCED EFFECTS. ALTHOUGH A MUTATION IN HDAC5 HAS BEEN SHOWN TO CAUSE HYPERSENSITIVE RESPONSES TO CHRONIC COCAINE USE WHETHER THIS RESPONSE WORSENS DURING CHRONIC EARLY LIFE STRESS HAS NOT BEEN EXAMINED YET. IN THIS STUDY, WE EXPOSED MOUSE PUPS TO TWO DIFFERENT EARLY LIFE STRESS PARADIGMS (SOCIAL ISOLATION, ESI, AND SOCIAL THREAT, EST) TO DETERMINE WHETHER THE HETEROZYGOUS NULL MUTATION IN HDAC5 (HDAC5+/-) MODERATED THE EFFECTS OF EXPOSURE TO STRESS IN EARLY LIFE ON ADULT COCAINE-INDUCED CONDITIONED PLACE PREFERENCE (CPP). NOTABLY, HDAC5+/- MICE THAT HAD BEEN EXPOSED TO ESI WERE MORE SUSCEPTIBLE TO DEVELOPING COCAINE-INDUCED CPP AND MORE RESISTANT TO EXTINGUISHING THIS BEHAVIOR. THE SAME EFFECT WAS NOT OBSERVED FOR HDAC5+/- MICE EXPERIENCING EST, SUGGESTING THAT ONLY ESI INDUCES BEHAVIORAL CHANGES BY ACTING PRECISELY THROUGH HDAC5-RELATED BIOLOGICAL PATHWAYS. FINALLY, AN ANALYSIS OF C-FOS EXPRESSION PERFORMED TO DISCOVER THE NEUROBIOLOGICAL SUBSTRATES THAT MEDIATED THIS PHENOTYPE, IDENTIFIED THE DORSOLATERAL STRIATUM AS AN IMPORTANT STRUCTURE THAT MEDIATES THE INTERACTION BETWEEN HDAC5 MUTATION AND ESI. OUR DATA DEMONSTRATE THAT DECREASED HDAC5 FUNCTION IS ABLE TO EXACERBATE THE LONG-TERM BEHAVIORAL EFFECTS OF ADVERSE REARING ENVIRONMENT IN MOUSE. 2017 7 1676 33 DRUG ADDICTION: FROM BENCH TO BEDSIDE. DRUG ADDICTION IS RESPONSIBLE FOR MILLIONS OF DEATHS PER YEAR AROUND THE WORLD. STILL, ITS MANAGEMENT AS A CHRONIC DISEASE IS SHADOWED BY MISCONCEPTIONS FROM THE GENERAL PUBLIC. INDEED, DRUG CONSUMERS ARE OFTEN LABELLED AS "WEAK", "IMMORAL" OR "DEPRAVED". CONSEQUENTLY, DRUG ADDICTION IS OFTEN PERCEIVED AS AN INDIVIDUAL PROBLEM AND NOT SOCIETAL. IN TECHNICAL TERMS, DRUG ADDICTION IS DEFINED AS A CHRONIC, RELAPSING DISEASE RESULTING FROM SUSTAINED EFFECTS OF DRUGS ON THE BRAIN. THROUGH A BETTER CHARACTERISATION OF THE CEREBRAL CIRCUITS INVOLVED, AND THE LONG-TERM MODIFICATIONS OF THE BRAIN INDUCED BY ADDICTIVE DRUGS ADMINISTRATIONS, FIRST, WE MIGHT BE ABLE TO CHANGE THE WAY THE GENERAL PUBLIC SEE THE PATIENT WHO IS SUFFERING FROM DRUG ADDICTION, AND SECOND, WE MIGHT BE ABLE TO FIND NEW TREATMENTS TO NORMALISE THE ALTERED BRAIN HOMEOSTASIS. IN THIS REVIEW, WE SYNTHETISE THE CONTRIBUTION OF FUNDAMENTAL RESEARCH TO THE UNDERSTANDING DRUG ADDICTION AND ITS CONTRIBUTION TO POTENTIAL NOVEL THERAPEUTICS. MOSTLY BASED ON DRUG-INDUCED MODIFICATIONS OF SYNAPTIC PLASTICITY AND EPIGENETIC MECHANISMS (AND THEIR BEHAVIOURAL CORRELATES) AND AFTER DEMONSTRATION OF THEIR REVERSIBILITY, WE TRIED TO HIGHLIGHT PROMISING THERAPEUTICS. WE ALSO UNDERLINE THE SPECIFIC TEMPORAL DYNAMICS AND PSYCHOSOCIAL ASPECTS OF THIS COMPLEX PSYCHIATRIC DISEASE ADDING PARAMETERS TO BE CONSIDERED IN CLINICAL TRIALS AND PAVING THE WAY TO TEST NEW THERAPEUTIC VENUES. 2021 8 4630 32 NEUROEPIGENETIC REGULATION OF PATHOGENIC MEMORIES. OUR UNIQUE COLLECTION OF MEMORIES DETERMINES OUR INDIVIDUALITY AND SHAPES OUR FUTURE INTERACTIONS WITH THE WORLD. REMARKABLE ADVANCES INTO THE NEUROBIOLOGICAL BASIS OF MEMORY HAVE IDENTIFIED KEY EPIGENETIC MECHANISMS THAT SUPPORT THE STABILITY OF MEMORY. VARIOUS FORMS OF EPIGENETIC REGULATION AT THE LEVELS OF DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNAS (NCRNAS) CAN MODULATE TRANSCRIPTIONAL AND TRANSLATIONAL EVENTS REQUIRED FOR MEMORY PROCESSES. BY CHANGING THE CELLULAR PROFILE IN THE BRAIN'S EMOTIONAL, REWARD, AND MEMORY CIRCUITS, THESE EPIGENETIC MODIFICATIONS HAVE ALSO BEEN LINKED TO PERSEVERANT, PATHOGENIC MEMORIES. IN THIS REVIEW, WE WILL DELVE INTO THE RELEVANCE OF EPIGENETIC DYSREGULATION TO PATHOGENIC MEMORY MECHANISMS BY FOCUSING ON TWO NEUROPSYCHIATRIC DISORDERS PERPETUATED BY ABERRANT MEMORY ASSOCIATIONS: SUBSTANCE USE DISORDER (SUD) AND POST-TRAUMATIC STRESS DISORDER (PTSD). AS OUR UNDERSTANDING IMPROVES, NEUROEPIGENETIC MECHANISMS MAY SOMEDAY BE HARNESSED TO DEVELOP NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF THESE CHRONIC, RELAPSING DISORDERS. 2015 9 4846 25 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 10 6097 13 THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION IN THE BRAIN. STRESS LEADS TO DETRIMENTAL EFFECTS ON BRAIN FUNCTIONS AND RESULTS IN VARIOUS DISEASES. RECENT STUDIES HIGHLIGHT THE INVOLVEMENT OF GLUTAMATERGIC TRANSMISSION IN PATHOGENESIS OF DEPRESSIVE BEHAVIORS AND FEARS. ACUTE STRESS GENERATES DIFFERENT IMPACTS ON THE EXCITATORY TRANSMISSION COMPARED TO CHRONIC STRESS. DIFFERENT NEUROMODULATORS AND EPIGENETIC FACTORS ALSO PARTICIPATE IN THE ALTERATION OF SYNAPTIC TRANSMISSION AND THE REGULATION OF SYNAPTIC PLASTICITY. RESTORATION OF THE GLUTAMATERGIC TRANSMISSION IN STRESS-AFFECTED BRAIN AREAS THEREFORE PROVIDES NOVEL DIRECTIONS OF THERAPEUTIC INTERVENTIONS AGAINST STRESS. 2015 11 4631 25 NEUROGENETICS OF ACUTE AND CHRONIC OPIATE/OPIOID ABSTINENCE: TREATING SYMPTOMS AND THE CAUSE. THIS REVIEW BEGINS WITH A COMPREHENSIVE HISTORY OF OPIOID DEPENDENCE AND TREATMENT IN THE UNITED STATES. THE FOCUS IS AN EVIDENCE-BASED TREATMENT MODEL FOR OPIOID/OPIATE DEPENDENT INDIVIDUALS. THE ROLE OF REWARD GENETIC POLYMORPHISMS AND THE EPIGENETIC MODIFICATIONS THAT LEAD TO VULNERABILITY TO USE AND MISUSE OF OPIATES/OPIOID TO TREAT PAIN ARE REVIEWED. THE NEUROCHEMICAL MECHANISMS OF ACUTE OPIATE WITHDRAWAL AND OPIATE/OPIOID REWARD MECHANISMS ARE EXPLORED WITH A GOAL OF IDENTIFYING SPECIFIC TREATMENT TARGETS. ALTERATIONS IN FUNCTIONAL BRAIN CONNECTIVITY BASED ON NEUROBIOLOGICAL MECHANISMS IN HEROIN DEPENDENCE AND ABSTINENCE ARE ALSO REVIEWED. A NEW CLINICAL MODEL AN ALTERNATIVE TO MERELY BLOCKING ACUTE WITHDRAWAL SYMPTOMS AS IDENTIFIED IN THE DSM -5 IS PROPOSED. GENETIC DIAGNOSIS AT THE ONSET OF DETOXIFICATION, TO DETERMINE RISK STRATIFICATION, AND IDENTIFY POLYMORPHIC GENE TARGETS FOR PHARMACEUTICAL AND NUTRACEUTICAL INTERVENTIONS, FOLLOWED BY THE SIMULTANEOUS INITIATION OF MEDICATION ASSISTED THERAPY (MAT), TO ENABLE PSYCHOLOGICAL EXTINCTION, AND STEADY PRO-DOPAMINERGIC THERAPY WITH THE GOAL OF DEVELOPING "DOPAMINE HOMEOSTASIS" IS RECOMMENDED. THE OBJECTIVE OF THESE INTERVENTIONS IS TO PREVENT FUTURE RELAPSE BY TREATING ALL "REWARD DEFICIENCY SYNDROME" (RDS) BEHAVIORS AND EVENTUALLY MAKE AN ADDICTION-FREE LIFE POSSIBLE. 2017 12 2235 26 EPIGENETIC MODIFICATIONS, ALCOHOLIC BRAIN AND POTENTIAL DRUG TARGETS. ACUTE AND CHRONIC ALCOHOL EXPOSURE EVIDENTLY INFLUENCES EPIGENETIC CHANGES, BOTH TRANSIENTLY AND PERMANENTLY, AND THESE CHANGES IN TURN INFLUENCE A VARIETY OF CELLS AND ORGAN SYSTEMS THROUGHOUT THE BODY. MANY OF THE ALCOHOL-INDUCED EPIGENETIC MODIFICATIONS CAN CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THE PERSISTENCE OF BEHAVIORAL CHANGES DEMONSTRATES THAT LONG-LASTING CHANGES IN GENE EXPRESSION, WITHIN PARTICULAR REGIONS OF THE BRAIN, MAY CONTRIBUTE IMPORTANTLY TO THE ADDICTION PHENOTYPE. THE RESEARCH ACTIVITIES OVER THE PAST YEARS HAVE DEMONSTRATED A CRUCIAL ROLE OF EPIGENETIC MECHANISMS IN CAUSING LONG LASTING AND TRANSIENT CHANGES IN THE EXPRESSION OF SEVERAL GENES IN DIVERSE TISSUES, INCLUDING BRAIN. THIS HAS STIMULATED RECENT RESEARCH WORK THAT IS AIMED AT CHARACTERIZING THE INFLUENCE OF EPIGENETIC REGULATORY EVENTS IN MEDIATING THE LONG LASTING AND TRANSIENT EFFECTS OF ALCOHOL ABUSE ON THE BRAIN IN HUMANS AND ANIMAL MODELS OF ALCOHOL ADDICTION. IN THIS STUDY, WE UPDATE OUR CURRENT UNDERSTANDING OF THE IMPACT OF ALCOHOL EXPOSURE ON EPIGENETIC MECHANISMS IN THE BRAIN AND REFURBISH THE KNOWLEDGE OF EPIGENETICS IN THE DIRECTION OF NEW DRUGS DEVELOPMENT. 2016 13 195 25 ACF CHROMATIN-REMODELING COMPLEX MEDIATES STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIOR. IMPROVED TREATMENT FOR MAJOR DEPRESSIVE DISORDER (MDD) REMAINS ELUSIVE BECAUSE OF THE LIMITED UNDERSTANDING OF ITS UNDERLYING BIOLOGICAL MECHANISMS. IT IS LIKELY THAT STRESS-INDUCED MALADAPTIVE TRANSCRIPTIONAL REGULATION IN LIMBIC NEURAL CIRCUITS CONTRIBUTES TO THE DEVELOPMENT OF MDD, POSSIBLY THROUGH EPIGENETIC FACTORS THAT REGULATE CHROMATIN STRUCTURE. WE ESTABLISH THAT PERSISTENT UPREGULATION OF THE ACF (ATP-UTILIZING CHROMATIN ASSEMBLY AND REMODELING FACTOR) ATP-DEPENDENT CHROMATIN-REMODELING COMPLEX, OCCURRING IN THE NUCLEUS ACCUMBENS OF STRESS-SUSCEPTIBLE MICE AND DEPRESSED HUMANS, IS NECESSARY FOR STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS. WE FOUND THAT ALTERED ACF BINDING AFTER CHRONIC STRESS WAS CORRELATED WITH ALTERED NUCLEOSOME POSITIONING, PARTICULARLY AROUND THE TRANSCRIPTION START SITES OF AFFECTED GENES. THESE ALTERATIONS IN ACF BINDING AND NUCLEOSOME POSITIONING WERE ASSOCIATED WITH REPRESSED EXPRESSION OF GENES IMPLICATED IN SUSCEPTIBILITY TO STRESS. TOGETHER, OUR FINDINGS IDENTIFY THE ACF CHROMATIN-REMODELING COMPLEX AS A CRITICAL COMPONENT IN THE DEVELOPMENT OF SUSCEPTIBILITY TO DEPRESSION AND IN REGULATING STRESS-RELATED BEHAVIORS. 2015 14 980 26 CHRONIC PAIN: EMERGING EVIDENCE FOR THE INVOLVEMENT OF EPIGENETICS. EPIGENETIC PROCESSES, SUCH AS HISTONE MODIFICATIONS AND DNA METHYLATION, HAVE BEEN ASSOCIATED WITH MANY NEURAL FUNCTIONS INCLUDING SYNAPTIC PLASTICITY, LEARNING, AND MEMORY. HERE, WE CRITICALLY EXAMINE EMERGING EVIDENCE LINKING EPIGENETIC MECHANISMS TO THE DEVELOPMENT OR MAINTENANCE OF CHRONIC PAIN STATES. ALTHOUGH IN ITS INFANCY, RESEARCH IN THIS AREA POTENTIALLY UNIFIES SEVERAL PATHOPHYSIOLOGICAL PROCESSES UNDERPINNING ABNORMAL PAIN PROCESSING AND OPENS UP A DIFFERENT AVENUE FOR THE DEVELOPMENT OF NOVEL ANALGESICS. 2012 15 2000 25 EPIGENETIC AND NON-CODING REGULATION OF ALCOHOL ABUSE AND ADDICTION. ALCOHOL USE DISORDER IS A CHRONIC DEBILITATED CONDITION ADVERSELY AFFECTING THE LIVES OF MILLIONS OF INDIVIDUALS THROUGHOUT THE MODERN WORLD. INDIVIDUALS SUFFERING FROM AN ALCOHOL USE DISORDER DIAGNOSIS FREQUENTLY HAVE SERIOUS COOCCURRING CONDITIONS, WHICH OFTEN FURTHER EXACERBATES PROBLEMATIC DRINKING BEHAVIOR. COMPREHENDING THE BIOCHEMICAL PROCESSES UNDERLYING THE PROGRESSION AND PERPETUATION OF DISEASE IS ESSENTIAL FOR MITIGATING MALADAPTIVE BEHAVIOR IN ORDER TO RESTORE BOTH PHYSIOLOGICAL AND PSYCHOLOGICAL HEALTH. THE RANGE OF CELLULAR AND BIOLOGICAL SYSTEMS CONTRIBUTING TO, AND AFFECTED BY, ALCOHOL USE DISORDER AND OTHER COMORBID DISORDERS NECESSITATES A FUNDAMENTAL GRASP OF INTRICATE FUNCTIONAL RELATIONSHIPS THAT GOVERN MOLECULAR BIOLOGY. EPIGENETIC FACTORS ARE RECOGNIZED AS ESSENTIAL MEDIATORS OF CELLULAR BEHAVIOR, ORCHESTRATING A SYMPHONY OF GENE EXPRESSION CHANGES WITHIN MULTICELLULAR ENVIRONMENTS THAT ARE ULTIMATELY RESPONSIBLE FOR DIRECTING HUMAN BEHAVIOR. UNDERSTANDING THE EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISMS INVOLVED IN THE PATHOGENESIS OF DISEASE IS IMPORTANT FOR IMPROVING AVAILABLE PHARMACOTHERAPIES AND REDUCING THE INCIDENCE OF ALCOHOL ABUSE AND COOCCURRING CONDITIONS. 2021 16 800 35 CELLULAR, MOLECULAR, AND EPIGENETIC MECHANISMS IN NON-ASSOCIATIVE CONDITIONING: IMPLICATIONS FOR PAIN AND MEMORY. SENSITIZATION IS A FORM OF NON-ASSOCIATIVE CONDITIONING IN WHICH AMPLIFICATION OF BEHAVIORAL RESPONSES CAN OCCUR FOLLOWING PRESENTATION OF AN AVERSIVE OR NOXIOUS STIMULUS. UNDERSTANDING THE CELLULAR AND MOLECULAR UNDERPINNINGS OF SENSITIZATION HAS BEEN AN OVERARCHING THEME SPANNING THE FIELD OF LEARNING AND MEMORY AS WELL AS THAT OF PAIN RESEARCH. IN THIS REVIEW WE EXAMINE HOW SENSITIZATION, BOTH IN THE CONTEXT OF LEARNING AS WELL AS PAIN PROCESSING, SHARES EVOLUTIONARILY CONSERVED BEHAVIORAL, CELLULAR/SYNAPTIC, AND EPIGENETIC MECHANISMS ACROSS PHYLA. FIRST, WE CHARACTERIZE THE BEHAVIORAL PHENOMENON OF SENSITIZATION BOTH IN INVERTEBRATES AND VERTEBRATES. PARTICULAR EMPHASIS IS PLACED ON LONG-TERM SENSITIZATION (LTS) OF WITHDRAWAL REFLEXES IN APLYSIA FOLLOWING AVERSIVE STIMULATION OR INJURY, ALTHOUGH ADDITIONAL INVERTEBRATE MODELS ARE ALSO COVERED. IN THE CONTEXT OF VERTEBRATES, SENSITIZATION OF MAMMALIAN HYPERAROUSAL IN A MODEL OF POST-TRAUMATIC STRESS DISORDER (PTSD), AS WELL AS MAMMALIAN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN IS CHARACTERIZED. SECOND, WE INVESTIGATE THE CELLULAR AND SYNAPTIC MECHANISMS UNDERLYING THESE BEHAVIORS. WE FOCUS OUR DISCUSSION ON SEROTONIN-MEDIATED LONG-TERM FACILITATION (LTF) AND AXOTOMY-MEDIATED LONG-TERM HYPEREXCITABILITY (LTH) IN REDUCED APLYSIA SYSTEMS, AS WELL AS MAMMALIAN SPINAL PLASTICITY MECHANISMS OF CENTRAL SENSITIZATION. THIRD, WE EXPLORE RECENT EVIDENCE IMPLICATING EPIGENETIC MECHANISMS IN LEARNING- AND PAIN-RELATED SENSITIZATION. THIS REVIEW ILLUSTRATES THE FUNDAMENTAL AND FUNCTIONAL OVERLAY OF THE LEARNING AND MEMORY FIELD WITH THE PAIN FIELD WHICH ARGUES FOR HOMOLOGOUS PERSISTENT PLASTICITY MECHANISMS IN RESPONSE TO SENSITIZING STIMULI OR INJURY ACROSS PHYLA. 2013 17 6806 31 [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 18 4650 30 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 19 4653 22 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 20 3093 31 GENOMIC AND EPIGENOMIC RESPONSES TO CHRONIC STRESS INVOLVE MIRNA-MEDIATED PROGRAMMING. STRESS REPRESENTS A CRITICAL INFLUENCE ON MOTOR SYSTEM FUNCTION AND HAS BEEN SHOWN TO IMPAIR MOVEMENT PERFORMANCE. WE HYPOTHESIZED THAT STRESS-INDUCED MOTOR IMPAIRMENTS ARE DUE TO BRAIN-SPECIFIC CHANGES IN MIRNA AND PROTEIN-ENCODING GENE EXPRESSION. HERE WE SHOW A CAUSAL LINK BETWEEN STRESS-INDUCED MOTOR IMPAIRMENT AND ASSOCIATED GENETIC AND EPIGENETIC RESPONSES IN RELEVANT CENTRAL MOTOR AREAS IN A RAT MODEL. EXPOSURE TO TWO WEEKS OF MILD RESTRAINT STRESS ALTERED THE EXPRESSION OF 39 GENES AND NINE MIRNAS IN THE CEREBELLUM. IN LINE WITH PERSISTENT BEHAVIOURAL IMPAIRMENTS, SOME CHANGES IN GENE AND MIRNA EXPRESSION WERE RESISTANT TO RECOVERY FROM STRESS. INTERESTINGLY, STRESS UP-REGULATED THE EXPRESSION OF ADIPOQ AND PROLACTIN RECEPTOR MRNAS IN THE CEREBELLUM. STRESS ALSO ALTERED THE EXPRESSION OF PRLR, MIR-186, AND MIR-709 IN HIPPOCAMPUS AND PREFRONTAL CORTEX. IN ADDITION, OUR FINDINGS DEMONSTRATE THAT MIR-186 TARGETS THE GENE EPS15. FURTHERMORE, WE FOUND AN AGE-DEPENDENT INCREASE IN EPHRINB3 AND GABAA4 RECEPTORS. THESE DATA SHOW THAT EVEN MILD STRESS RESULTS IN SUBSTANTIAL GENOMIC AND EPIGENOMIC CHANGES INVOLVING MIRNA EXPRESSION AND ASSOCIATED GENE TARGETS IN THE MOTOR SYSTEM. THESE FINDINGS SUGGEST A CENTRAL ROLE OF MIRNA-REGULATED GENE EXPRESSION IN THE STRESS RESPONSE AND IN ASSOCIATED NEUROLOGICAL FUNCTION. 2012