1 3774 99 INTERACTION OF GONADAL HORMONES, DOPAMINERGIC SYSTEM, AND EPIGENETIC REGULATION IN THE GENERATION OF SEX DIFFERENCES IN SUBSTANCE USE DISORDERS: A SYSTEMATIC REVIEW. SUBSTANCE USE DISORDER (SUD) IS A CHRONIC CONDITION CHARACTERIZED BY PATHOLOGICAL DRUG-TAKING AND SEEKING BEHAVIORS. REMARKABLY DIFFERENT BETWEEN MALES AND FEMALES, SUGGESTING THAT DRUG ADDICTION IS A SEXUALLY DIFFERENTIATED DISORDER. THE NEUROBIOLOGICAL BASES OF SEX DIFFERENCES IN SUD INCLUDE SEX-SPECIFIC REWARD SYSTEM ACTIVATION, INFLUENCED BY INTERACTIONS BETWEEN GONADAL HORMONE LEVEL CHANGES, DOPAMINERGIC REWARD CIRCUITS, AND EPIGENETIC MODIFICATIONS OF KEY REWARD SYSTEM GENES. THIS SYSTEMATIC REVIEW, ADHERING TO PICOS AND PRISMA-P 2015 GUIDELINES, HIGHLIGHTS THE SEX-DEPENDENT ROLES OF ESTROGENS, PROGESTERONE, AND TESTOSTERONE IN SUD. IN PARTICULAR, ESTRADIOL ELEVATES AND PROGESTERONE REDUCES DOPAMINERGIC ACTIVITY IN SUD FEMALES, WHILST TESTOSTERONE AND PROGESTERONE AUGMENT SUD BEHAVIOR IN MALES. FINALLY, SUD IS ASSOCIATED WITH A SEX-SPECIFIC INCREASE IN THE RATE OF OPIOID AND MONOAMINERGIC GENE METHYLATION. THE STUDY REVEALS THE NEED FOR DETAILED RESEARCH ON GONADAL HORMONE LEVELS, DOPAMINERGIC OR REWARD SYSTEM ACTIVITY, AND EPIGENETIC LANDSCAPES IN BOTH SEXES FOR EFFICIENT SUD THERAPY DEVELOPMENT. 2023 2 6155 35 THE GENETIC EPIDEMIOLOGY OF SUBSTANCE USE DISORDER: A REVIEW. BACKGROUND: SUBSTANCE USE DISORDER (SUD) REMAINS A SIGNIFICANT PUBLIC HEALTH ISSUE. A GREATER UNDERSTANDING OF HOW GENES AND ENVIRONMENT INTERACT TO REGULATE PHENOTYPES COMPRISING SUD WILL FACILITATE DIRECTED TREATMENTS AND PREVENTION. METHODS: THE LITERATURE STUDYING THE NEUROBIOLOGICAL CORRELATES OF SUD WITH A FOCUS ON THE GENETIC AND ENVIRONMENTAL INFLUENCES UNDERLYING THESE MECHANISMS WAS REVIEWED. RESULTS FROM TWIN/FAMILY, HUMAN GENETIC ASSOCIATION, GENE-ENVIRONMENT INTERACTION, EPIGENETIC LITERATURE, PHENOME-WIDE ASSOCIATION STUDIES ARE SUMMARIZED FOR ALCOHOL, NICOTINE, CANNABINOIDS, COCAINE, AND OPIOIDS. RESULTS: THERE ARE SUBSTANTIAL GENETIC INFLUENCES ON SUD THAT ARE EXPECTED TO INFLUENCE MULTIPLE NEUROTRANSMISSION PATHWAYS, AND THESE INFLUENCES ARE PARTICULARLY IMPORTANT WITHIN THE DOPAMINERGIC SYSTEM. GENETIC INFLUENCES INVOLVED IN OTHER ASPECTS OF SUD ETIOLOGY INCLUDING DRUG PROCESSING AND METABOLISM ARE ALSO IDENTIFIED. STUDIES OF GENE-ENVIRONMENT INTERACTION EMPHASIZE THE IMPORTANCE OF ENVIRONMENTAL CONTEXT IN SUD. EPIGENETIC STUDIES INDICATE DRUG-SPECIFIC CHANGES IN GENE EXPRESSION AS WELL AS DIFFERENCES IN GENE EXPRESSION RELATED TO THE USE OF MULTIPLE SUBSTANCES. FURTHER, GENE EXPRESSION IS EXPECTED TO DIFFER BY STAGE OF SUD SUCH AS SUBSTANCE INITIATION VERSUS CHRONIC SUBSTANCE USE. WHILE A SUBSTANTIAL LITERATURE HAS DEVELOPED FOR ALCOHOL AND NICOTINE USE DISORDERS, THERE IS COMPARATIVELY LESS INFORMATION FOR OTHER COMMONLY ABUSED SUBSTANCES. CONCLUSIONS: A BETTER UNDERSTANDING OF GENETICALLY-MEDIATED MECHANISMS INVOLVED IN THE NEUROBIOLOGY OF SUD PROVIDES INCREASED OPPORTUNITY TO DEVELOP BEHAVIORAL AND BIOLOGICALLY BASED TREATMENT AND PREVENTION OF SUD. 2017 3 5855 27 SUBSTANCE USE DISORDER A BIO-DIRECTIONAL SUBSET OF REWARD DEFICIENCY SYNDROME. THIS COMMENTARY IS TO INFORM CLINICIANS CHALLENGED WITH AN INCREASE IN PEOPLE SEEKING TREATMENT FOR SUBSTANCE USE DISORDER (SUD), THAT THE NINETY PERCENT REVOLVING DOOR, IS, IN PART, DUE TO POST-WITHDRAWAL, UNTREATED NEUROTOXICITY. THIS IMPAIRMENT ATTENUATES NEUROTRANSMITTER SIGNALING AND COMPROMISES RESTING STATE FUNCTIONAL CONNECTIVITY, LEADING TO UNWANTED SEQUELAE INCLUDING DEPRESSION, SLEEP DISTURBANCES, SENSATION SEEKING, LACK OF SATISFACTION AND IMPULSIVITY. NEUROIMAGING STUDIES INDICATE THAT NEUROBIOLOGICAL RECOVERY CAN TAKE YEARS. LIKE A "DOUBLE EDGE SWORD" SUD HAS A BIOLOGICAL BI -DIRECTIONAL (BIO-DIRECTIONAL) EFFECT ON THE BRAIN REWARD CIRCUITRY. THE ACUTE INTAKE OF PSYCHOACTIVE DRUGS RESULTS IN HEIGHTENED DOPAMINERGIC ACTIVITY, WHILE, THE OPPOSITE, HYPODOPAMINERGIA OCCURS FOLLOWING CHRONIC ABUSE. INDIVIDUALS WITH SUD CAN HAVE A GENETIC PREDISPOSITION, COMPOUNDED BY STRESS AND NEUROTOXICALLY INDUCED, EPIGENETIC INSULTS THAT IMPACT RECOVERY FROM PROTRACTED ABSTINENCE. FOLLOW-UP POST -SHORT-TERM RECOVERY USUALLY INCLUDES SUPPORTIVE THERAPIES AND PROGRAMS LIKE 12 -STEPS AND OTHER FELLOWSHIPS. HOWEVER, RELAPSE WILL USUALLY OCCUR IF POST -SHORT-TERM RECOVERY HYPODOPAMINERGIA IS NOT TREATED WITH ATTEMPTS AT EPIGENETIC MANIPULATION OF COMPROMISED BRAIN NEUROCHEMISTRY USING SOME MANNER OF PRO-DOPAMINE REGULATION. 2017 4 3094 35 GENOMIC AND PERSONALIZED MEDICINE APPROACHES FOR SUBSTANCE USE DISORDERS (SUDS) LOOKING AT GENOME-WIDE ASSOCIATION STUDIES. DRUG ADDICTION, OR SUBSTANCE USE DISORDER (SUD), IS A CHRONIC, RELAPSING DISORDER IN WHICH COMPULSIVE DRUG-SEEKING AND DRUG-TAKING BEHAVIOUR PERSIST DESPITE SERIOUS NEGATIVE CONSEQUENCES. DRUG ABUSE REPRESENTS A PROBLEM THAT DESERVES GREAT ATTENTION FROM A SOCIAL POINT OF VIEW, AND FOCUSES ON THE IMPORTANCE OF GENETIC STUDIES TO HELP IN UNDERSTANDING THE GENETIC BASIS OF ADDICTION AND ITS MEDICAL TREATMENT. DESPITE THE COMPLEXITY OF DRUG ADDICTION DISORDERS, AND THE HIGH NUMBER OF ENVIRONMENTAL VARIABLES PLAYING A ROLE IN THE ONSET, RECURRENCE, AND DURATION OF THE SYMPTOMS, SEVERAL STUDIES HAVE HIGHLIGHTED THE NON-NEGLIGIBLE ROLE OF GENETICS, AS DEMONSTRATED BY HERITABILITY AND GENOME-WIDE ASSOCIATION STUDIES. A CORRELATION BETWEEN THE RELATIVE RISK OF ADDICTION TO SPECIFIC SUBSTANCES AND HERITABILITY HAS BEEN RECENTLY OBSERVED, SUGGESTING THAT NEUROBIOLOGICAL MECHANISMS MAY BE, AT LEAST IN PART, INHERITED. ALL THESE OBSERVATIONS POINT TOWARDS A SCENARIO WHERE THE CORE NEUROBIOLOGICAL FACTORS OF ADDICTION, INVOLVING THE REWARD SYSTEM, IMPULSIVITY, COMPULSIVITY, STRESS, AND ANXIETY RESPONSE, ARE TRANSMITTED, AND THEREFORE, GENES AND MUTATIONS UNDERLYING THEIR VARIATION MIGHT BE DETECTED. IN THE LAST FEW YEARS, THE DEVELOPMENT OF NEW AND MORE EFFICIENT SEQUENCING TECHNOLOGIES HAS PAVED THE WAY FOR LARGE-SCALE STUDIES IN SEARCHING FOR GENETIC AND EPIGENETIC FACTORS AFFECTING DRUG ADDICTION DISORDERS AND THEIR TREATMENTS. THESE STUDIES HAVE BEEN CRUCIAL TO PINPOINT SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN GENES THAT AFFECT THE REACTION TO MEDICAL TREATMENTS. THIS IS CRITICALLY IMPORTANT TO IDENTIFY PHARMACOGENOMIC APPROACHES FOR SUBSTANCE USE DISORDER, SUCH AS OPRM1 SNPS AND METHADONE REQUIRED DOSES FOR MAINTENANCE TREATMENT (MMT). NEVERTHELESS, DESPITE THE PROMISING RESULTS OBTAINED BY GENOME-WIDE ASSOCIATION AND PHARMACOGENOMIC STUDIES, SPECIFIC STUDIES RELATED TO POPULATION GENETICS DIVERSITY ARE LACKING, UNDERMINING THE OVERALL APPLICABILITY OF THE PRELIMINARY FINDINGS, AND THUS POTENTIALLY AFFECTING THE PORTABILITY AND THE ACCURACY OF THE GENETIC STUDIES. IN THIS REVIEW, FOCUSING ON CANNABIS, COCAINE AND HEROIN USE, WE REPORT THE STATE-OF-THE-ART GENOMICS AND PHARMACOGENOMICS OF SUDS, AND THE POSSIBLE FUTURE PERSPECTIVES RELATED TO MEDICAL TREATMENT RESPONSE IN PEOPLE THAT ASK FOR ASSISTANCE IN SOLVING DRUG-RELATED PROBLEMS. 2021 5 4630 30 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 6 6266 19 THE NEUROBIOLOGY OF SUICIDE. THE STRESS-DIATHESIS MODEL POSITS THAT SUICIDE IS THE RESULT OF AN INTERACTION BETWEEN STATE-DEPENDENT (ENVIRONMENTAL) STRESSORS AND A TRAIT-LIKE DIATHESIS OR SUSCEPTIBILITY TO SUICIDAL BEHAVIOUR, INDEPENDENT OF PSYCHIATRIC DISORDERS. FINDINGS FROM POST-MORTEM STUDIES OF THE BRAIN AND FROM GENOMIC AND IN-VIVO NEUROIMAGING STUDIES INDICATE A BIOLOGICAL BASIS FOR THIS DIATHESIS, INDICATING THE IMPORTANCE OF NEUROBIOLOGICAL SCREENING AND INTERVENTIONS, IN ADDITION TO COGNITIVE AND MOOD INTERVENTIONS, IN THE PREVENTION OF SUICIDE. EARLY-LIFE ADVERSITY AND EPIGENETIC MECHANISMS MIGHT EXPLAIN SOME OF THE LINK BETWEEN SUICIDE RISK AND BRAIN CIRCUITRY AND NEUROCHEMISTRY ABNORMALITIES. RESULTS FROM A RANGE OF STUDIES USING DIVERSE DESIGNS AND POST-MORTEM AND IN-VIVO TECHNIQUES SHOW IMPAIRMENTS OF THE SEROTONIN NEUROTRANSMITTER SYSTEM AND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS STRESS-RESPONSE SYSTEM IN THE DIATHESIS FOR SUICIDAL BEHAVIOUR. THESE IMPAIRMENTS MANIFEST AS IMPAIRED COGNITIVE CONTROL OF MOOD, PESSIMISM, REACTIVE AGGRESSIVE TRAITS, IMPAIRED PROBLEM SOLVING, OVER-REACTIVITY TO NEGATIVE SOCIAL SIGNS, EXCESSIVE EMOTIONAL PAIN, AND SUICIDAL IDEATION, LEADING TO SUICIDAL BEHAVIOUR. BIOMARKERS RELATED TO THE DIATHESIS MIGHT HELP TO INFORM RISK-ASSESSMENT PROCEDURES AND TREATMENT CHOICE IN THE PREVENTION OF SUICIDE. 2014 7 4469 27 MOLECULAR NEUROLOGICAL CORRELATES OF ENDORPHINERGIC/DOPAMINERGIC MECHANISMS IN REWARD CIRCUITRY LINKED TO ENDORPHINERGIC DEFICIENCY SYNDROME (EDS). THE CONSENSUS OF THE CURRENT LITERATURE STRONGLY SUPPORTS THE CONCEPT THAT BRAIN NEUROTRANSMITTERS, AND SECOND MESSENGERS INVOLVED IN THE NET RELEASE OF DOPAMINE IN THE MESOLIMBIC REGION, ESPECIALLY THE NUCLEUS ACCUMBENS (NAC), IS DIRECTLY LINKED TO MOTIVATION, ANTI-STRESS, INCENTIVE SALIENCE (WANTING), AND WELL-BEING. THE ROLE OF DOPAMINE IN TERMS OF ALCOHOL WITHDRAWAL SYMPTOMOLOGY, COCAINE CRAVING BEHAVIOR, DOPAMINE -CONDENSATION PRODUCTS (TIQS), AND MORE RECENTLY, THE GENETIC ASPECTS OF DRUG-SEEKING AND PRO-DOPAMINE REGULATION, PROVIDE COMPELLING EVIDENCE OF THE RELEVANT MOLECULAR NEUROLOGICAL CORRELATES OF DOPAMINERGIC /ENDORPHINERGIC MECHANISMS IN REWARD CIRCUITRY DUE TO GENETIC POLYMORPHISMS AND EPIGENETIC INSULTS. IN THE FACE OF AN AMERICANS OPIOID EPIDEMIC, THE CLINICAL CONSENSUS IS TO TREAT OPIOID USE DISORDER (OUD) WITH LIFE-LONG OPIOID SUBSTITUTION THERAPY. HOWEVER, THE AUTHORS SUGGEST A PARADIGM SHIFT INVOLVING NOVEL MODALITIES LIKE TARGETING THE ENDORPHINERGIC SYSTEM LINKED TO DOPAMINE RELEASE AT THE NAC, IN TERMS OF THE INDUCTION OF REQUIRED "DOPAMINE HOMEOSTASIS." UTILIZING THE KNOWN GENETIC - ENVIRONMENTAL INTERACTION THEOREM P = G +E, THE AUTHORS PROVIDE A CLEAR RATIONALE FOR THE ADOPTION OF GENETIC RISK TESTING COUPLED WITH ENDORPHINERGIC/DOPAMINE REGULATION TO ADDRESS DYSFUNCTION ACROSS THE BRAIN REWARD CIRCUITRY. THE GOAL OF ALTERING RESTING-STATE, FUNCTIONAL CONNECTIVITY MAY REQUIRE A GENTLE "NEUROTRANSMITTER FIX" VIS ENKEPHALINASE INHIBITION TO OVERCOME OR COMBAT - SELF-INDUCTION OF ACUTE DOPAMINE RELEASE VIA PSYCHOACTIVE SUBSTANCE MISUSE RESULTING IN CHRONIC DOPAMINE DOWN-REGULATION. AS SUBSETS OF REWARD DEFICIENCY, WE ARE POISED TO PROVIDE NOVEL, GENETICALLY GUIDED THERAPY FOR ENDORPHINERGIC, OPIOIDERGIC, AND DOPAMINERGIC DEFICIENCIES AND RELATED SYNDROMES, UTILIZING "PRECISION ADDICTION MANAGEMENT. 2020 8 2574 26 EPIGENETICS OF DRUG ADDICTION. SUBSTANCE USE DISORDERS (SUDS) ARE CHRONIC BRAIN DISEASES CHARACTERIZED BY TRANSITIONS FROM RECREATIONAL TO COMPULSIVE DRUG USE AND ABERRANT DRUG CRAVING THAT PERSISTS FOR MONTHS TO YEARS AFTER ABSTINENCE IS ACHIEVED. THE TRANSITION TO COMPULSIVE DRUG USE IMPLIES THAT PLASTICITY IS OCCURRING, ALTERING THE PHYSIOLOGY OF THE BRAIN TO PRECIPITATE ADDICTED STATES. EPIGENETIC PHENOMENA REPRESENT A VARIED ORCHESTRA OF TRANSCRIPTIONAL TUNING MECHANISMS THAT, IN RESPONSE TO ENVIRONMENTAL STIMULI, CREATE AND MAINTAIN GENE EXPRESSION-MEDIATED PHYSIOLOGICAL OUTCOMES. THEREFORE, EPIGENETIC MECHANISMS REPRESENT A CONVERGENT REGULATORY FRAMEWORK THROUGH WHICH THE PLASTICITY REQUIRED TO ACHIEVE AN ADDICTED STATE CAN ARISE AND THEN PERSIST LONG AFTER DRUG USE HAS ENDED. IN THE FIRST SECTION, WE WILL INTRODUCE BASIC CONCEPTS IN EPIGENETICS, SUCH AS CHROMATIN ARCHITECTURE, HISTONES AND THEIR POSTTRANSLATIONAL MODIFICATIONS, DNA METHYLATION, NONCODING RNAS, AND TRANSCRIPTION FACTORS, ALONG WITH METHODS FOR THEIR INVESTIGATION. WE WILL THEN EXAMINE THE IMPLICATIONS OF THESE MECHANISMS IN SUDS, WITH A PARTICULAR FOCUS ON COCAINE-MEDIATED NEUROEPIGENETIC PLASTICITY ACROSS MULTIPLE BEHAVIORAL MODELS OF ADDICTION. 2021 9 4846 20 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 10 747 24 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE. 2021 11 1091 29 COGNITIVE ENHANCERS AS A TREATMENT FOR HEROIN RELAPSE AND ADDICTION. HEROIN ADDICTION IS A DISORDER THAT STEMS FROM MALADAPTIVE PLASTICITY WITHIN NEURAL CIRCUITS AND PRODUCES BROAD COGNITIVE DEFICITS. DESPITE CONSIDERABLE ADVANCES IN PSYCHOTHERAPY AND PHARMACOTHERAPY FOR HEROIN RELAPSE AND ADDICTION, EFFECTIVE TREATMENTS FOR HEROIN USE DISORDER ARE STILL LACKING. INCREASING PRECLINICAL EVIDENCE INDICATES THAT HEROIN SEEKING BEHAVIOR IS PERSISTENT AFTER WITHDRAWAL, WHILE COGNITIVE DYSFUNCTIONS ASSOCIATED WITH CHRONIC HEROIN USE ARE AN IMPORTANT CONTRIBUTING FACTOR TO RISK OF HEROIN RELAPSE AND ADDICTION. COGNITIVE ENHANCERS MAY BE USED TO STIMULATE TREATMENT SUCCESS AND ENHANCE TREATMENT EFFICACY. THE PURPOSE OF THIS REVIEW IS TO OUTLINE THE LITERATURE THAT DEMONSTRATES THE COGNITIVE DEFICITS DURING THE DEVELOPMENT OF HEROIN ADDICTION AND WITHDRAWAL PROCESS, AND SEVERAL FACTORS THAT UNDERLINE THE EFFICACY OF COGNITIVE ENHANCERS FOR HEROIN USE DISORDERS. THE REVIEW, THEN, EXAMINES THE POTENTIAL USE AND PHARMACOLOGICAL MECHANISMS OF COGNITIVE ENHANCERS THAT ACT ON CHOLINERGIC, GLUTAMATERGIC, DOPAMINERGIC OR ADRENERGIC PATHWAYS. IT ALSO EXAMINES THE EFFECTS OF COMPOUNDS THAT ALTER CREB SIGNALING AND EPIGENETIC MECHANISMS IN ANIMAL MODEL OF HEROIN RELAPSE. THE CURRENT BODY OF RESEARCH REVEALS THE NEW INSIGHTS INTO THE PHARMACOLOGICAL MECHANISMS UNDERLYING HEROIN ADDICTION AND HOLDS A SIGNIFICANT PROMISE FOR COGNITIVE ENHANCERS AS AN IMPROVED APPROACH TO TREAT HEROIN USE DISORDER IN A MORE EFFICIENT AND PERSISTENT WAY. 2019 12 4632 24 NEUROIMAGING GENETIC APPROACHES TO POSTTRAUMATIC STRESS DISORDER. NEUROIMAGING GENETIC STUDIES THAT ASSOCIATE GENETIC AND EPIGENETIC VARIATION WITH NEURAL ACTIVITY OR STRUCTURE PROVIDE AN OPPORTUNITY TO LINK GENES TO PSYCHIATRIC DISORDERS, OFTEN BEFORE PSYCHOPATHOLOGY IS DISCERNABLE IN BEHAVIOR. HERE WE REVIEW NEUROIMAGING GENETICS STUDIES WITH PARTICIPANTS WHO HAVE POSTTRAUMATIC STRESS DISORDER (PTSD). RESULTS SHOW THAT GENES RELATED TO THE PHYSIOLOGICAL STRESS RESPONSE (E.G., GLUCOCORTICOID RECEPTOR AND ACTIVITY, NEUROENDOCRINE RELEASE), LEARNING AND MEMORY (E.G., PLASTICITY), MOOD, AND PAIN PERCEPTION ARE TIED TO NEURAL INTERMEDIATE PHENOTYPES ASSOCIATED WITH PTSD. THESE GENES ARE ASSOCIATED WITH AND SOMETIMES PREDICT NEURAL STRUCTURE AND FUNCTION IN AREAS INVOLVED IN ATTENTION, EXECUTIVE FUNCTION, MEMORY, DECISION-MAKING, EMOTION REGULATION, SALIENCE OF POTENTIAL THREATS, AND PAIN PERCEPTION. EVIDENCE SUGGESTS THESE RISK POLYMORPHISMS AND NEURAL INTERMEDIATE PHENOTYPES ARE VULNERABILITIES TOWARD DEVELOPING PTSD IN THE AFTERMATH OF TRAUMA, OR VULNERABILITIES TOWARD PARTICULAR SYMPTOMS ONCE PTSD HAS DEVELOPED. WORK DISTINGUISHING BETWEEN THE RE-EXPERIENCING AND DISSOCIATIVE SUB-TYPES OF PTSD, AND EXAMINING OTHER PTSD SYMPTOM CLUSTERS IN ADDITION TO THE RE-EXPERIENCING AND HYPERAROUSAL SYMPTOMS, WILL FURTHER CLARIFY NEUROBIOLOGICAL MECHANISMS AND INCONSISTENT FINDINGS. FURTHERMORE, AN EXCITING POSSIBILITY IS THAT GENETIC ASSOCIATIONS WITH PTSD MAY EVENTUALLY BE UNDERSTOOD THROUGH DIFFERENTIAL INTERMEDIATE PHENOTYPES OF NEURAL CIRCUIT STRUCTURE AND FUNCTION, POSSIBLY UNDERLYING THE DIFFERENT SYMPTOM CLUSTERS SEEN WITHIN PTSD. 2016 13 2934 25 GENETIC ADDICTION RISK SCORE (GARS) , A PREDICTOR OF VULNERABILITY TO OPIOID DEPENDENCE. THE INTERACTION OF NEUROTRANSMITTERS AND GENES THAT CONTROL THE RELEASE OF DOPAMINE IS THE BRAIN REWARD CASCADE (BRC). VARIATIONS WITHIN THE BRC, WHETHER GENETIC OR EPIGENETIC, MAY PREDISPOSE INDIVIDUALS TO ADDICTIVE BEHAVIORS AND ALTERED PAIN TOLERANCE. THIS DISCUSSION AUTHORED BY A GROUP OF CONCERNED SCIENTISTS AND CLINICIANS EXAMINES THE GENETIC ADDICTION RISK SCORE (GARS), THE FIRST TEST TO ACCURATELY PREDICT VULNERABILITY TO PAIN, ADDICTION, AND OTHER COMPULSIVE BEHAVIORS, DEFINED AS REWARD DEFICIENCY SYNDROME (RDS). INNOVATIVE STRATEGIES TO COMBAT EPIDEMIC OPIOID, IATROGENIC PRESCRIPTION DRUG ABUSE AND DEATH, BASED ON THE ROLE OF DOPAMINERGIC TONE IN PAIN PATHWAYS, ARE PROPOSED. SENSITIVITY TO PAIN MAY RESIDE IN THE MESOLIMBIC PROJECTION SYSTEM, WHERE GENETIC POLYMORPHISMS ASSOCIATE WITH A PREDISPOSITION TO PAIN VULNERABILITY OR TOLERANCE. THEY PROVIDE UNIQUE THERAPEUTIC TARGETS THAT COULD ASSIST IN THE TREATMENT OF PAIN, AND IDENTIFY RISK FOR SUBSEQUENT ADDICTION. PHARMACOGENOMIC TESTING OF CANDIDATE GENES LIKE CB1, MU RECEPTORS, AND PENK MIGHT RESULT IN PHARMACOGENOMIC, PERSONALIZED SOLUTIONS, AND IMPROVED CLINICAL OUTCOMES. GENETICALLY IDENTIFYING RISK FOR ALL RDS BEHAVIORS, ESPECIALLY IN COMPROMISED POPULATIONS, MAY BE A FRONTLINE TOOL TO ASSIST MUNICIPALITIES TO PROVIDE BETTER RESOURCE ALLOCATION. 2018 14 3606 23 IMPROVING TREATMENT OF NEURODEVELOPMENTAL DISORDERS: RECOMMENDATIONS BASED ON PRECLINICAL STUDIES. INTRODUCTION: NEURODEVELOPMENTAL DISORDERS (NDDS) ARE COMMON AND SEVERELY DEBILITATING. THEIR CHRONIC NATURE AND RELIANCE ON BOTH GENETIC AND ENVIRONMENTAL FACTORS MAKES STUDYING NDDS AND THEIR TREATMENT A CHALLENGING TASK. AREAS COVERED: HEREIN, THE AUTHORS DISCUSS THE NEUROBIOLOGICAL MECHANISMS OF NDDS, AND PRESENT RECOMMENDATIONS ON THEIR TRANSLATIONAL RESEARCH AND THERAPY, OUTLINED BY THE INTERNATIONAL STRESS AND BEHAVIOR SOCIETY. VARIOUS DRUGS CURRENTLY PRESCRIBED TO TREAT NDDS ALSO REPRESENT A HIGHLY DIVERSE GROUP. ACTING ON VARIOUS NEUROTRANSMITTER AND PHYSIOLOGICAL SYSTEMS, THESE DRUGS OFTEN LACK SPECIFICITY OF ACTION, AND ARE COMMONLY USED TO TREAT MULTIPLE OTHER PSYCHIATRIC CONDITIONS. THERE HAS ALSO BEEN RELATIVELY LITTLE PROGRESS IN THE DEVELOPMENT OF NOVEL MEDICATIONS TO TREAT NDDS. BASED ON CLINICAL, PRECLINICAL AND TRANSLATIONAL MODELS OF NDDS, OUR RECOMMENDATIONS COVER A WIDE RANGE OF METHODOLOGICAL APPROACHES AND CONCEPTUAL STRATEGIES. EXPERT OPINION: TO IMPROVE PHARMACOTHERAPY AND DRUG DISCOVERY FOR NDDS, WE NEED A STRONGER EMPHASIS ON TARGETING MULTIPLE ENDOPHENOTYPES, A BETTER DISSECTION OF GENETIC/EPIGENETIC FACTORS OR "HIDDEN HERITABILITY," AND A CAREFUL CONSIDERATION OF POTENTIAL DEVELOPMENTAL/TROPHIC ROLES OF BRAIN NEUROTRANSMITTERS. THE VALIDITY OF ANIMAL NDD MODELS CAN BE IMPROVED THROUGH DISCOVERY OF NOVEL (BEHAVIORAL, PHYSIOLOGICAL AND NEUROIMAGING) BIOMARKERS, APPLYING PROPER ENVIRONMENTAL ENRICHMENT, WIDENING THE SPECTRUM OF MODEL ORGANISMS, TARGETING DEVELOPMENTAL TRAJECTORIES OF NDD-RELATED BEHAVIORS AND COMORBID CONDITIONS BEYOND TRADITIONAL NDDS. WHILE THESE RECOMMENDATIONS CANNOT BE ADDRESSED ALL IN ONCE, OUR INCREASED UNDERSTANDING OF NDD PATHOBIOLOGY MAY TRIGGER INNOVATIVE CROSS-DISCIPLINARY RESEARCH EXPANDING BEYOND TRADITIONAL METHODS AND CONCEPTS. 2016 15 6577 21 TREATMENT STRATEGIES FOR COMPLEX BEHAVIORAL INSOMNIA IN CHILDREN WITH NEURODEVELOPMENTAL DISORDERS. PURPOSE OF REVIEW: THIS REVIEW DESCRIBES RECENT RESEARCH IN PEDIATRIC BEHAVIORAL INSOMNIAS IN NEURODEVELOPMENTAL DISORDERS AND THEIR TREATMENT. RECENT FINDINGS: INSOMNIA IN CHILDREN WITH AUTISM SPECTRUM DISORDER (ASD) AND OTHER NEURODEVELOPMENTAL DISORDERS (NDDS) IS TYPICALLY COMPLEX, CHRONIC, AND DIFFICULT TO ADEQUATELY CONTROL. ABNORMALITIES IN GENETIC AND/OR EPIGENETIC REGULATION OF SLEEP/WAKEFULNESS AND ITS TIMING PREDISPOSE PATIENTS WITH NDD TO INSOMNIA, ALTHOUGH POOR SLEEP HYGIENE, MALADAPTIVE ASSOCIATIONS, AND LIMIT-SETTING ARE LIKELY TO CONTRIBUTE. PARENTS ARE AGENTS FOR CHANGE IN PROBLEMATIC SLEEP BEHAVIORS IN PATIENTS WITH NDD. WE REVIEW THE BENEFITS OF BEHAVIORAL THERAPIES AND MELATONIN TO TREAT SLEEP PROBLEMS IN CHILDREN WITH NDD. PROBLEMATIC SLEEP IS SO PREVALENT IN SOME NEURODEVELOPMENTAL SYNDROMES (RETT, ANGELMAN, WILLIAMS, AND SMITH-MAGENIS) THAT IT IS PART OF THEIR DIAGNOSTIC CRITERIA. SUMMARY: CHILDREN AND ADOLESCENTS WITH NEUROLOGICAL DISORDERS FREQUENTLY HAVE COMPLEX SLEEP DISORDERS THAT REQUIRE TREATMENT. UNDERSTANDING THE BASIC PATHOLOGY AND TREATMENT STRATEGIES PROVIDES AN OPPORTUNITY TO IMPROVE WELL BEING AND QUALITY OF LIFE IN THOSE AFFECTED BY NDD AND THEIR FAMILIES. 2013 16 4441 37 MOLECULAR GENETICS OF COCAINE USE DISORDERS IN HUMANS. DRUG ADDICTION, ONE OF THE MAJOR HEALTH PROBLEMS WORLDWIDE, IS CHARACTERIZED BY THE LOSS OF CONTROL IN DRUG INTAKE, CRAVING, AND WITHDRAWAL. AT THE INDIVIDUAL LEVEL, DRUGS OF ABUSE PRODUCE SERIOUS CONSEQUENCES ON HEALTH AND HAVE A NEGATIVE IMPACT ON THE FAMILY ENVIRONMENT AND ON INTERPERSONAL AND WORK RELATIONSHIPS. AT A WIDER SCALE, THEY HAVE SIGNIFICANT SOCIO-ECONOMIC AND PUBLIC HEALTH CONSEQUENCES AND THEY CAUSE DELINQUENCY AND CITIZEN INSECURITY. COCAINE, A PSYCHOSTIMULANT SUBSTANCE, IS ONE OF THE MOST USED ILLICIT DRUGS, ESPECIALLY IN AMERICA, WESTERN EUROPE, AND AUSTRALIA. COCAINE USE DISORDERS (CUD) ARE COMPLEX MULTIFACTORIAL CONDITIONS DRIVEN BY BOTH GENETIC AND ENVIRONMENTAL INFLUENCES. IMPORTANTLY, NOT ALL PEOPLE WHO USE COCAINE DEVELOP CUD, AND THIS IS DUE, AT LEAST IN PART, TO BIOLOGICAL FACTORS THAT ARE ENCODED IN THE GENOME OF INDIVIDUALS. ACUTE AND REPEATED USE OF COCAINE INDUCES EPIGENETIC AND GENE EXPRESSION CHANGES RESPONSIBLE FOR THE NEURONAL ADAPTATIONS AND THE REMODELING OF BRAIN CIRCUITS THAT LEAD TO THE TRANSITION FROM USE TO ABUSE OR DEPENDENCE. THE PURPOSE OF THIS REVIEW IS TO DELINEATE SUCH FACTORS, WHICH SHOULD EVENTUALLY HELP TO UNDERSTAND THE INTER-INDIVIDUAL VARIABILITY IN THE SUSCEPTIBILITY TO COCAINE ADDICTION. HERITABILITY ESTIMATES FOR CUD ARE HIGH AND GENETIC RISK FACTORS FOR COCAINE ADDICTION HAVE BEEN INVESTIGATED BY CANDIDATE GENE ASSOCIATION STUDIES (CGAS) AND GENOME-WIDE ASSOCIATION STUDIES (GWAS), REVIEWED HERE. ALSO, THE HIGH COMORBIDITY THAT EXISTS BETWEEN CUD AND SEVERAL OTHER PSYCHIATRIC DISORDERS IS WELL KNOWN AND INCLUDES PHENOTYPES LIKE SCHIZOPHRENIA, AGGRESSION, ANTISOCIAL OR RISK-TAKING BEHAVIORS. SUCH COMORBIDITIES ARE ASSOCIATED WITH A WORSE LIFETIME TRAJECTORY, AND HERE WE REPORT SHARED GENETIC FACTORS THAT MAY CONTRIBUTE TO THEM. GENE EXPRESSION CHANGES AND EPIGENETIC MODIFICATIONS INDUCED BY COCAINE USE AND CHRONIC ABUSE IN HUMANS ARE ADDRESSED BY REVIEWING TRANSCRIPTOMIC STUDIES PERFORMED ON NEURONAL CELLS AND ON POSTMORTEM BRAINS. WE REPORT SOME GENES WHICH EXPRESSION IS ALTERED BY COCAINE THAT ALSO BEAR GENETIC RISK VARIANTS FOR THE DISORDER. FINALLY, WE HAVE A GLANCE TO THE PHARMACOGENETICS OF CUD TREATMENTS, STILL IN EARLY STAGES. A BETTER UNDERSTANDING OF THE GENETIC UNDERPINNINGS OF CUD WILL FOSTER THE SEARCH OF EFFECTIVE TREATMENTS AND HELP TO MOVE FORWARD TO PERSONALIZED MEDICINE. 2022 17 1490 27 DNA DIRECTED PRO-DOPAMINE REGULATION COUPLING SUBLUXATION REPAIR, H-WAVE((R)) AND OTHER NEUROBIOLOGICALLY BASED MODALITIES TO ADDRESS COMPLEXITIES OF CHRONIC PAIN IN A FEMALE DIAGNOSED WITH REWARD DEFICIENCY SYNDROME (RDS): EMERGENCE OF INDUCTION OF "DOPAMINE HOMEOSTASIS" IN THE FACE OF THE OPIOID CRISIS. ADDICTION IS A COMPLEX MULTIFACTORIAL CONDITION. ESTABLISHED GENETIC FACTORS CAN PROVIDE CLEAR GUIDANCE IN ASSESSING THE RISK OF ADDICTION TO SUBSTANCES AND BEHAVIORS. CHRONIC STRESS CAN ACCUMULATE, FORMING DIFFICULT TO RECOGNIZE ADDICTION PATTERNS FROM BOTH GENETIC AND EPIGENETIC (ENVIRONMENTAL) FACTORS. FURTHERMORE, PSYCHOLOGICAL/PHYSICAL/CHEMICAL STRESSORS ARE TYPICALLY CATEGORIZED LINEARLY, DELAYING IDENTIFICATION AND TREATMENT. THE PATIENT IN THIS CASE REPORT IS A CAUCASIAN FEMALE, AGED 36, WHO PRESENTED WITH CHRONIC PAIN AND PARTIAL DISABILITY FOLLOWING A SURGICALLY REPAIRED TRIMALLEOLAR FRACTURE. THE PATIENT HAD A HISTORY OF UNRESOLVED ATTENTION DEFICIT DISORDER AND AN MRI SCAN OF HER BRAIN REVEALED ATROPHY AND FUNCTIONAL ASYMMETRY. IN 2018, THE PATIENT ENTERED THE BAJAJ CHIROPRACTIC CLINIC, WHERE INITIAL TREATMENT FOCUSED ON RE-ESTABLISHING INTEGRITY OF THE SPINE AND LOWER EXTREMITY BIOMECHANICS AND GRADUATED INTO COGNITIVE BEHAVIOR STABILIZATION ASSISTED BY DNA PRO-DOPAMINE REGULATION GUIDED BY GENETIC ADDICTION RISK SEVERITY TESTING. DURING TREATMENT (2018-2021), PROGRESS ACHIEVED INCLUDED: IMPROVED COGNITIVE CLARITY, FOCUS, SLEEP, ANXIETY, AND EMOTIONAL STABILITY IN ADDITION TO PAIN REDUCTION (75%); ELIMINATION OF POWERFUL ANALGESICS; AND REDUCED INTAKE OF PREVIOUSLY UNADDRESSED ALCOHOLISM. TO HELP REDUCE HEDONIC ADDICTIVE BEHAVIORS AND PAIN, COUPLING OF H-WAVE WITH CORRECTIVE CHIROPRACTIC CARE SEEMS PRUDENT. WE EMPHASIZE THE IMPORTANCE OF GENETIC ASSESSMENT ALONG WITH ATTEMPTS AT INDUCING REQUIRED DOPAMINERGIC HOMEOSTASIS VIA PRECISION KB220PAM. IT IS HYPOTHESIZED THAT FROM PREVENTIVE CARE MODELS, A NEW STANDARD IS EMERGING INCLUDING SELF-AWARENESS AND ACCOUNTABILITY FOR REWARD DEFICIENCY AS A FUNCTION OF HYPODOPAMINERGIA. THIS CASE STUDY DOCUMENTS THE PROGRESSION OF A PATIENT DEALING WITH THE COMPLEXITIES OF AN INJURY, PAIN MANAGEMENT, COGNITIVE IMPAIRMENT, ANXIETY, DEPRESSION, AND THE APPLICATION OF UNIVERSAL HEALTH PRINCIPLES TOWARDS CORRECTION VERSUS PALLIATIVE CARE. 2022 18 5310 19 PSYCHOBIOLOGY AND MOLECULAR GENETICS OF RESILIENCE. EVERY INDIVIDUAL EXPERIENCES STRESSFUL LIFE EVENTS. IN SOME CASES ACUTE OR CHRONIC STRESS LEADS TO DEPRESSION AND OTHER PSYCHIATRIC DISORDERS, BUT MOST PEOPLE ARE RESILIENT TO SUCH EFFECTS. RECENT RESEARCH HAS BEGUN TO IDENTIFY THE ENVIRONMENTAL, GENETIC, EPIGENETIC AND NEURAL MECHANISMS THAT UNDERLIE RESILIENCE, AND HAS SHOWN THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES IN SEVERAL NEURAL CIRCUITS INVOLVING NUMEROUS NEUROTRANSMITTER AND MOLECULAR PATHWAYS. THESE CHANGES SHAPE THE FUNCTIONING OF THE NEURAL CIRCUITS THAT REGULATE REWARD, FEAR, EMOTION REACTIVITY AND SOCIAL BEHAVIOUR, WHICH TOGETHER ARE THOUGHT TO MEDIATE SUCCESSFUL COPING WITH STRESS. 2009 19 6917 17 [WHOSE BORDERLINE IS IT? HYPOTHESIZED ETIOLOGIES OF BORDERLINE PERSONALITY]. BORDERLINE PERSONALITY IS A WELL KNOWN CONCEPT IN PSYCHIATRIC LITERATURE, HOWEVER, NOT FULLY UNDERSTOOD AS TO ITS VERY NATURE. THIS ARTICLE PRESENTS A SHORT REVIEW OF HYPOTHESIZED ETIOLOGIES OF THE BORDERLINE PERSONALITY, STARTING WITH SO CALLED TRADITIONAL THEORIES, NAMELY, BORDERLINE PERSONALITY AS A CONSOLIDATED PERSONALITY ORGANIZATION, IN WHICH THE PATIENT PATHOLOGICALLY DEALS WITH HIS OR HER INNER AGGRESSION, OR WITH AN ENDURING DEVELOPMENTAL FAILURE. MORE MODERN HYPOTHESES FOCUS ON POSSIBLE CHILDHOOD SEXUAL ABUSE AS THE ORIGIN OF THE BORDERLINE, VIEWING THE ADULT PERSONALITY AS A CHRONIC, UNRESOLVED, POST-TRAUMATIC DISORDER. ADDITIONALLY, A NEURO-EPIGENETIC VIEW HYPOTHESIZED THAT A UNIQUE CONGENITAL NEUROLOGICAL STRUCTURE INTERACTS WITH CONSEQUENTIAL EVENTS IN EARLY CHILDHOOD TO CREATE THE BORDERLINE PERSONALITY. 2008 20 6626 19 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013