1 6125 97 THE EPIGENETIC MECHANISMS OF AMPHETAMINE. AMPHETAMINE (AMPH) IS A PSYCHOSTIMULANT AND THE MOST PRESCRIBED DRUG TO TREAT ATTENTION DEFICIT HYPERACTIVE DISORDER (ADHD). ALTHOUGH THERAPEUTICALLY USED DOSES ARE GENERALLY WELL TOLERATED, NUMEROUS SIDE EFFECTS ARE STILL KNOWN TO OCCUR, SUCH AS JITTERINESS, LOSS OF APPETITE AND PSYCHOSIS. MOREOVER, AMPH IS LIABLE TO BE ABUSED BY USERS LOOKING FOR INCREASED ALERTNESS, WEIGHT LOSS OR ATHLETIC PERFORMANCE. A GROWING BODY OF EVIDENCE INDICATES THAT DRUGS OF ABUSE, INCLUDING AMPH, CONTROL GENE EXPRESSION THROUGH CHROMATIN MODIFICATIONS. HOWEVER, WHILE NUMEROUS STUDIES HAVE INVESTIGATED THE MOLECULAR MECHANISMS OF AMPH ACTION, ONLY A SMALL NUMBER OF STUDIES HAVE EXPLORED CHANGES IN GENE EXPRESSION CAUSED BY AMPH. THIS REVIEW EXAMINES THE EPIGENETIC CHANGES INDUCED BY CHRONIC AND ACUTE TREATMENTS WITH AMPH AND INCLUDES, WHERE RELEVANT, DATA OBTAINED WITH OTHER PSYCHOSTIMULANTS SUCH AS METHAMPHETAMINE AND COCAINE. 2015 2 4418 28 MOLECULAR AND EPIGENETIC ASPECTS OF OPIOID RECEPTORS IN DRUG ADDICTION AND PAIN MANAGEMENT IN SPORT. OPIOIDS ARE SUBSTANCES DERIVED FROM OPIUM (NATURAL OPIOIDS). IN ITS RAW STATE, OPIUM IS A GUMMY LATEX EXTRACTED FROM PAPAVER SOMNIFERUM. THE USE OF OPIOIDS AND THEIR NEGATIVE HEALTH CONSEQUENCES AMONG PEOPLE WHO USE DRUGS HAVE BEEN STUDIED. TODAY, OPIOIDS ARE STILL THE MOST COMMONLY USED AND EFFECTIVE ANALGESIC TREATMENTS FOR SEVERE PAIN, BUT THEIR USE AND ABUSE CAUSES DETRIMENTAL SIDE EFFECTS FOR HEALTH, INCLUDING ADDICTION, THUS IMPACTING THE USER'S QUALITY OF LIFE AND CAUSING OVERDOSE. THE MESOCORTICOLIMBIC DOPAMINERGIC CIRCUITRY REPRESENTS THE BRAIN CIRCUIT MEDIATING BOTH NATURAL REWARDS AND THE REWARDING ASPECTS OF NEARLY ALL DRUGS OF ABUSE, INCLUDING OPIOIDS. HENCE, UNDERSTANDING HOW OPIOIDS AFFECT THE FUNCTION OF DOPAMINERGIC CIRCUITRY MAY BE USEFUL FOR BETTER KNOWLEDGE OF THE PROCESS AND TO DEVELOP EFFECTIVE THERAPEUTIC STRATEGIES IN ADDICTION. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE MAIN FEATURES OF OPIOIDS AND OPIOID RECEPTORS AND FOCUS ON THE MOLECULAR AND UPCOMING EPIGENETIC MECHANISMS LEADING TO OPIOID ADDICTION. SINCE SYNTHETIC OPIOIDS CAN BE EFFECTIVE FOR PAIN MANAGEMENT, THEIR ABILITY TO INDUCE ADDICTION IN ATHLETES, WITH THE RISK OF INCURRING DOPING, IS ALSO DISCUSSED. 2023 3 4424 31 MOLECULAR AND NEUROLOGIC RESPONSES TO CHRONIC ALCOHOL USE. THIS CHAPTER PROVIDES AN OVERVIEW OF CURRENT KNOWLEDGE ON THE MOLECULAR AND CLINICAL ASPECTS OF CHRONIC ALCOHOL EFFECTS ON THE CENTRAL NERVOUS SYSTEM. THIS DRUG IS ALMOST UBIQUITOUS, WIDELY ENJOYED SOCIALLY, BUT PRODUCES A DIVERSE SPECTRUM OF NEUROLOGIC DISEASE WHEN ABUSED. ACUTELY, ALCOHOL INTERACTS PREDOMINANTLY WITH GAMMA-AMINOBUTYRIC ACID-A (GABA-A) AND N-METHYL-D-ASPARTATE (NMDA) RECEPTORS, BUT TRIGGERS DIVERSE SIGNALING EVENTS WITHIN WELL-DEFINED NEURAL PATHWAYS. THESE EVENTS RESULT IN ADAPTIVE CHANGES IN GENE EXPRESSION THAT ULTIMATELY PRODUCE TWO MAJOR STATES: ADDICTION AND TOXICITY. EPIGENETIC MODIFICATIONS OF CHROMATIN COULD LEAD TO LONG-LIVED OR EVEN TRANSGENERATIONAL CHANGES IN GENE EXPRESSION, THUS PRODUCING ASPECTS OF THE HERITABILITY OF ALCOHOL USE DISORDERS (AUD) AND LONG-TERM BEHAVIORS SUCH AS RECIDIVISM. THE DIVERSE CLINICAL SYNDROMES PRODUCED BY CHRONIC ALCOHOL ACTIONS IN THE CENTRAL NERVOUS SYSTEM REFLECT THE MOLECULAR PATHOLOGY AND PREDOMINANTLY INVOLVE ASPECTS OF TOLERANCE/WITHDRAWAL, SELECTIVE VULNERABILITY (MANIFEST AS CENTRAL PONTINE MYELINOLYSIS, MARCHIAFAVA-BIGNAMI DISEASE), AND ADDITIONAL ENVIRONMENTAL FACTORS (E.G., THIAMINE DEFICIENCY IN WERNICKE-KORSAKOFF'S SYNDROME). ADDITIONALLY, DELETERIOUS ASPECTS OF CHRONIC ALCOHOL ON SIGNALING, SYNAPTIC TRANSMISSION, AND CELL TOXICITY LEAD TO PRIMARY ALCOHOLIC DEMENTIA. GENETICALLY DETERMINED ASPECTS OF MYELIN STRUCTURE AND ALCOHOL ACTIONS ON MYELIN GENE EXPRESSION MAY BE A PROMINENT MOLECULAR MECHANISM RESULTING IN A PREDISPOSITION TO, OR CAUSATION OF, AUD AND MULTIPLE OTHER NEUROLOGIC COMPLICATIONS OF CHRONIC ALCOHOL. THE DRAMATIC PROGRESS MADE IN UNDERSTANDING MOLECULAR ACTIONS OF ALCOHOL HOLDS GREAT PROMISE FOR OUR EVENTUAL TREATMENT OR PREVENTION OF AUD AND NEUROLOGIC COMPLICATIONS RESULTING FROM CHRONIC ALCOHOL ABUSE. 2014 4 4846 23 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 5 2580 30 EPIGENETICS OF MICRO-OPIOID RECEPTORS: INTERSECTION WITH HIV-1 INFECTION OF THE CENTRAL NERVOUS SYSTEM. THE ABUSE OF INTRAVENOUS DRUGS, SUCH AS HEROIN, HAS BECOME A MAJOR PUBLIC HEALTH CONCERN DUE TO THE INCREASED RISK OF HIV-1 INFECTION. OPIOIDS SUCH AS HEROIN WERE ORIGINALLY IDENTIFIED AND SUBSEQUENTLY ABUSED FOR THEIR ANALGESIC EFFECTS. HOWEVER, MANY INVESTIGATIONS HAVE FOUND ADDITIONAL EFFECTS OF OPIOIDS, INCLUDING REGULATION OF THE IMMUNE SYSTEM. AS SUCH, CHRONIC OPIOID ABUSE HAS BEEN SHOWN TO PROMOTE HIV-1 PATHOGENESIS AND FACILITATE HIV-1-ASSOCIATED NEUROCOGNITIVE DYSFUNCTION. CLINICAL OPIOIDS, SUCH AS MORPHINE AND METHADONE, AS WELL AS ILLICIT OPIOIDS, SUCH AS HEROIN, EXERT THEIR EFFECTS PRIMARILY THROUGH INTERACTIONS WITH THE MICRO-OPIOID RECEPTOR (MOR). HOWEVER, THE MECHANISMS BY WHICH OPIOIDS ENHANCE NEUROCOGNITIVE DYSFUNCTION THROUGH MOR-MEDIATED SIGNALING PATHWAYS ARE NOT COMPLETELY UNDERSTOOD. NEW FINDINGS IN THE REGULATION OF MOR EXPRESSION, PARTICULARLY EPIGENETIC AND TRANSCRIPTIONAL REGULATION AS WELL AS ALTERNATIVE SPLICING, SHEDS NEW INSIGHTS INTO POSSIBLE MECHANISMS OF HIV-1 AND OPIATE SYNERGY. IN THIS REVIEW, WE IDENTIFY MECHANISMS REGULATING MOR EXPRESSION AND PROPOSE NOVEL MECHANISMS BY WHICH OPIOIDS AND HIV-1 MAY MODULATE THIS REGULATION. ADDITIONALLY, WE SUGGEST THAT DIFFERENTIAL REGULATION OF NEWLY IDENTIFIED MOR ISOFORMS BY OPIOIDS AND HIV-1 HAS FUNCTIONAL CONSEQUENCE IN ENHANCING HIV-1 NEUROCOGNITIVE DYSFUNCTION. 2012 6 3774 22 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 7 636 34 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 8 847 23 CHILDHOOD MALTREATMENT AND HEADACHE DISORDERS. CHILDHOOD MALTREATMENT IS SUBSTANTIATED IN 12 % OF CHILDREN, BUT NEARLY 50 % ADULTS RECALL HAVING BEEN NEGLECTED OR ABUSED AS CHILDREN. MALTREATMENT, ESPECIALLY EMOTIONAL ABUSE, IS ASSOCIATED WITH MIGRAINE. DYSREGULATION OF THE HPA AXIS, AUTONOMIC, IMMUNE, AND METABOLIC SYSTEMS APPEARS TO BE A CONSEQUENCE OF MALTREATMENT, AND IS ALSO REPORTED IN MIGRAINE. AREAS OF THE BRAIN STRUCTURALLY AND FUNCTIONALLY AFFECTED BY CHILDHOOD ABUSE AND BY MIGRAINE ARE ALSO SIMILAR, AND INCLUDE THE LIMBIC SYSTEM STRUCTURES, WHICH CONNECT TO PAIN REGIONS IN THE BRAINSTEM. PUTATIVE MECHANISMS BY WHICH EARLY LIFE STRESS INCREASES THE LIKELIHOOD OF DEVELOPING MIGRAINE INCLUDE GENE X ENVIRONMENT INTERACTIONS, IN ADDITION TO EPIGENETIC MODIFICATIONS VIA DNA METHYLATION. THESE MODIFICATIONS ARE STABLE AND MAY BE TRANSFERRED ACROSS GENERATIONS, BUT THEY MAY ALSO BE REVERSED BY SOME MEDICATIONS COMMONLY USED IN MIGRAINE, INCLUDING VALPROIC ACID AND TOPIRAMATE. 2016 9 6155 32 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 10 2292 27 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 11 4639 34 NEURONAL EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) ACTIVITY AS MARKER AND MEDIATOR OF ALCOHOL AND OPIOID DEPENDENCE. EARLY PIONEERING WORK IN THE FIELD OF BIOCHEMISTRY IDENTIFIED PHOSPHORYLATION AS A CRUCIAL POST-TRANSLATIONAL MODIFICATION OF PROTEINS WITH THE ABILITY TO BOTH INDICATE AND ARBITRATE COMPLEX PHYSIOLOGICAL PROCESSES. MORE RECENT INVESTIGATIONS HAVE FUNCTIONALLY LINKED PHOSPHORYLATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) TO A VARIETY OF NEUROPHYSIOLOGICAL MECHANISMS RANGING FROM ACUTE NEUROTRANSMITTER ACTION TO LONG-TERM GENE EXPRESSION. ERK PHOSPHORYLATION SERVES AS AN INTRACELLULAR BRIDGING MECHANISM THAT FACILITATES NEURONAL COMMUNICATION AND PLASTICITY. DRUGS OF ABUSE, INCLUDING ALCOHOL AND OPIOIDS, ACT AS ARTIFICIAL YET POWERFUL REWARDS THAT IMPINGE UPON NATURAL REINFORCEMENT PROCESSES CRITICAL FOR SURVIVAL. THE GRADED PROGRESSION FROM INITIAL EXPOSURE TO ADDICTION (OR SUBSTANCE DEPENDENCE) IS BELIEVED TO RESULT FROM DRUG- AND DRUG CONTEXT-INDUCED ADAPTATIONS IN NEURONAL SIGNALING PROCESSES ACROSS BRAIN REWARD AND STRESS CIRCUITS FOLLOWING EXCESSIVE DRUG USE. IN THIS REGARD, COMMONLY ABUSED DRUGS AS WELL AS DRUG-ASSOCIATED EXPERIENCES ARE CAPABLE OF MODIFYING THE PHOSPHORYLATION OF ERK WITHIN CENTRAL REINFORCEMENT SYSTEMS. IN ADDITION, CHRONIC DRUG AND ALCOHOL EXPOSURE MAY DRIVE ERK-REGULATED EPIGENETIC AND STRUCTURAL ALTERATIONS THAT UNDERLIE A LONG-TERM PROPENSITY FOR ESCALATING DRUG USE. UNDER THE INFLUENCE OF SUCH A NEUROBIOLOGICAL VULNERABILITY, ENCOUNTERING DRUG-ASSOCIATED CUES AND CONTEXTS CAN PRODUCE SUBSEQUENT ALTERATIONS IN ERK SIGNALING THAT DRIVE RELAPSE TO DRUG AND ALCOHOL SEEKING. CURRENT STUDIES ARE DETERMINING PRECISELY WHICH MOLECULAR AND REGIONAL ERK PHOSPHORYLATION-ASSOCIATED EVENTS CONTRIBUTE TO THE ADDICTION PROCESS, AS WELL AS WHICH NEUROADAPTATIONS NEED TO BE TARGETED IN ORDER TO RETURN DEPENDENT INDIVIDUALS TO A HEALTHY STATE. 2014 12 1677 24 DRUG ADDICTION: HYPERKATIFEIA/NEGATIVE REINFORCEMENT AS A FRAMEWORK FOR MEDICATIONS DEVELOPMENT. COMPULSIVE DRUG SEEKING THAT IS ASSOCIATED WITH ADDICTION IS HYPOTHESIZED TO FOLLOW A HEURISTIC FRAMEWORK THAT INVOLVES THREE STAGES (BINGE/INTOXICATION, WITHDRAWAL/NEGATIVE AFFECT, AND PREOCCUPATION/ANTICIPATION) AND THREE DOMAINS OF DYSFUNCTION (INCENTIVE SALIENCE/PATHOLOGIC HABITS, NEGATIVE EMOTIONAL STATES, AND EXECUTIVE FUNCTION, RESPECTIVELY) VIA CHANGES IN THE BASAL GANGLIA, EXTENDED AMYGDALA/HABENULA, AND FRONTAL CORTEX, RESPECTIVELY. THIS REVIEW FOCUSES ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE ADDICTION CYCLE. HYPERKATIFEIA PROVIDES AN ADDITIONAL SOURCE OF MOTIVATION FOR COMPULSIVE DRUG SEEKING VIA NEGATIVE REINFORCEMENT. NEGATIVE REINFORCEMENT REFLECTS AN INCREASE IN THE PROBABILITY OF A RESPONSE TO REMOVE AN AVERSIVE STIMULUS OR DRUG SEEKING TO REMOVE HYPERKATIFEIA THAT IS AUGMENTED BY GENETIC/EPIGENETIC VULNERABILITY, ENVIRONMENTAL TRAUMA, AND PSYCHIATRIC COMORBIDITY. NEUROBIOLOGICAL TARGETS FOR HYPERKATIFEIA IN ADDICTION INVOLVE NEUROCIRCUITRY OF THE EXTENDED AMYGDALA AND ITS CONNECTIONS VIA WITHIN-SYSTEM NEUROADAPTATIONS IN DOPAMINE, ENKEPHALIN/ENDORPHIN OPIOID PEPTIDE, AND GAMMA-AMINOBUTYRIC ACID/GLUTAMATE SYSTEMS AND BETWEEN-SYSTEM NEUROADAPTATIONS IN PROSTRESS CORTICOTROPIN-RELEASING FACTOR, NOREPINEPHRINE, GLUCOCORTICOID, DYNORPHIN, HYPOCRETIN, AND NEUROIMMUNE SYSTEMS AND ANTISTRESS NEUROPEPTIDE Y, NOCICEPTIN, ENDOCANNABINOID, AND OXYTOCIN SYSTEMS. SUCH NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS ARE HYPOTHESIZED TO MEDIATE A NEGATIVE HEDONIC SET POINT THAT GRADUALLY GAINS ALLOSTATIC LOAD AND SHIFTS FROM A HOMEOSTATIC HEDONIC STATE TO AN ALLOSTATIC HEDONIC STATE. BASED ON PRECLINICAL STUDIES AND TRANSLATIONAL STUDIES TO DATE, MEDICATIONS AND BEHAVIORAL THERAPIES THAT RESET BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURN THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. SIGNIFICANCE STATEMENT: THE FOCUS OF THIS REVIEW IS ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE DRUG ADDICTION CYCLE AND A DRIVING FORCE FOR NEGATIVE REINFORCEMENT IN ADDICTION. MEDICATIONS AND BEHAVIORAL THERAPIES THAT REVERSE HYPERKATIFEIA BY RESETTING BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURNING THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. 2021 13 3970 30 LONG-LASTING EPIGENETIC CHANGES IN THE DOPAMINE TRANSPORTER IN ADULT ANIMALS EXPOSED TO AMPHETAMINE DURING EMBRYOGENESIS: INVESTIGATING BEHAVIORAL EFFECTS. THE DOPAMINE TRANSPORTER (DAT) IS AN INTEGRAL MEMBER OF THE DOPAMINERGIC SYSTEM AND IS RESPONSIBLE FOR THE RELEASE AND REUPTAKE OF DOPAMINE FROM THE SYNAPTIC SPACE INTO THE DOPAMINERGIC NEURONS. DAT IS ALSO THE MAJOR TARGET OF AMPHETAMINE (AMPH). THE EFFECTS OF AMPH ON DAT HAVE BEEN INTENSIVELY STUDIED; HOWEVER, THE MECHANISMS UNDERLYING THE LONG-TERM EFFECTS CAUSED BY EMBRYONAL EXPOSURE TO ADDICTIVE DOSES OF AMPH REMAIN LARGELY UNEXPLORED. AS IN MAMMALS, IN THE NEMATODE C. ELEGANS AMPH CAUSES CHANGES IN LOCOMOTION WHICH ARE LARGELY MEDIATED BY THE C. ELEGANS DAT HOMOLOGUE, DAT-1. HERE, WE SHOW THAT CHRONIC EMBRYONIC EXPOSURES TO AMPH ALTER THE EXPRESSION OF DAT-1 IN ADULT C. ELEGANS VIA LONG-LASTING EPIGENETIC MODIFICATIONS. THESE CHANGES ARE CORRELATED WITH AN ENHANCED BEHAVIORAL RESPONSE TO AMPH IN ADULT ANIMALS. IMPORTANTLY, PHARMACOLOGICAL AND GENETIC INTERVENTION DIRECTED AT PREVENTING THE AMPH-INDUCED EPIGENETIC MODIFICATIONS OCCURRING DURING EMBRYOGENESIS INHIBITED THE LONG-LASTING BEHAVIORAL EFFECTS OBSERVED IN ADULT ANIMALS. BECAUSE MANY COMPONENTS OF THE DOPAMINERGIC SYSTEM, AS WELL AS EPIGENETIC MECHANISMS, ARE HIGHLY CONSERVED BETWEEN C. ELEGANS AND MAMMALS, THESE RESULTS COULD BE CRITICAL FOR OUR UNDERSTANDING OF HOW DRUGS OF ABUSE INITIATE PREDISPOSITION TO ADDICTION. 2023 14 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 15 1088 28 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 16 1091 31 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 17 2259 29 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 18 4469 25 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 19 4849 23 OPIOID-MEDIATED HIV-1 IMMUNOPATHOGENESIS. DESPITE THE ABILITY OF COMBINATION ANTIRETROVIRAL THERAPY TO DRAMATICALLY SUPPRESS VIREMIA, THE BRAIN CONTINUES TO BE A RESERVOIR OF HIV-1 LOW-LEVEL REPLICATION. ADDING FURTHER COMPLEXITY TO THIS IS THE COMORBIDITY OF DRUG ABUSE WITH HIV-1 ASSOCIATED NEUROCOGNITIVE DISORDERS AND NEUROHIV. AMONG SEVERAL ABUSED DRUGS, THE USE OF OPIATES IS HIGHLY PREVALENT IN HIV-1 INFECTED INDIVIDUALS, BOTH AS AN ABUSED DRUG AS WELL AS FOR PAIN MANAGEMENT. OPIOIDS AND THEIR RECEPTORS HAVE ATTAINED NOTABLE ATTENTION OWING TO THEIR ABILITY TO MODULATE IMMUNE FUNCTIONS, IN TURN, IMPACTING DISEASE PROGRESSION. VARIOUS CELL CULTURE, ANIMAL AND HUMAN STUDIES HAVE IMPLICATED THE ROLE OF OPIOIDS AND THEIR RECEPTORS IN MODULATING VIRAL REPLICATION AND VIRUS-MEDIATED PATHOLOGY BOTH POSITIVELY AND NEGATIVELY. FURTHER, THE COMBINATORIAL EFFECTS OF HIV-1/HIV-1 PROTEINS AND MORPHINE HAVE DEMONSTRATED ACTIVATION OF INFLAMMATORY SIGNALING IN THE HOST SYSTEM. HEREIN, WE SUMMARIZED THE CURRENT KNOWLEDGE ON THE ROLE OF OPIOIDS ON PERIPHERAL IMMUNOPATHOGENESIS, VIRAL IMMUNOPATHOGENESIS, EPIGENETIC PROFILES OF THE HOST AND VIRAL GENOME, NEUROPATHOGENESIS OF SIV/SHIV-INFECTED NON-HUMAN PRIMATES, BLOOD-BRAIN-BARRIER, HIV-1 VIRAL LATENCY, AND VIRAL REBOUND. OVERALL, THIS REVIEW PROVIDES RECENT INSIGHTS INTO THE ROLE OF OPIOIDS IN HIV-1 IMMUNOPATHOGENESIS. GRAPHICAL ABSTRACT. 2020 20 2841 30 FREQUENCY OF THE DOPAMINE RECEPTOR D3 (RS6280) VS. OPIOID RECEPTOR MICRO1 (RS1799971) POLYMORPHIC RISK ALLELES IN PATIENTS WITH OPIOID USE DISORDER: A PREPONDERANCE OF DOPAMINERGIC MECHANISMS? WHILE OPIOIDS ARE A POWERFUL CLASS OF DRUGS THAT INHIBIT TRANSMISSION OF PAIN SIGNALS, THEIR USE IS TARNISHED BY THE CURRENT EPIDEMIC OF OPIOID USE DISORDER (OUD) AND OVERDOSE DEATHS. NOTWITHSTANDING PUBLISHED REPORTS, THERE REMAIN GAPS IN OUR KNOWLEDGE OF OPIOID RECEPTOR MECHANISMS AND THEIR ROLE IN OPIOID SEEKING BEHAVIOR. THUS, NOVEL INSIGHTS INTO MOLECULAR, NEUROGENETIC AND NEUROPHARMACOLOGICAL BASES OF OUD ARE NEEDED. WE PROPOSE THAT AN ADDICTIVE ENDOPHENOTYPE MAY NOT BE ENTIRELY SPECIFIC TO THE DRUG OF CHOICE BUT RATHER MAY BE GENERALIZABLE TO ALTERED BRAIN REWARD CIRCUITS IMPACTING NET MESOCORTICOLIMBIC DOPAMINE RELEASE. WE SUGGEST THAT GENETIC OR EPIGENETIC ALTERATIONS ACROSS DOPAMINERGIC REWARD SYSTEMS LEAD TO UNCONTROLLABLE SELF-ADMINISTRATION OF OPIOIDS AND OTHER DRUGS. FOR INSTANCE, DIMINISHED AVAILABILITY VIA KNOCKOUT OF DOPAMINE D3 RECEPTOR (DRD3) INCREASES VULNERABILITY TO OPIOIDS. BUILDING UPON THIS CONCEPT VIA THE USE OF A SOPHISTICATED POLYMORPHIC RISK ANALYSIS IN A HUMAN COHORT OF CHRONIC OPIOID USERS, WE FOUND EVIDENCE FOR A HIGHER FREQUENCY OF POLYMORPHIC DRD3 RISK ALLELE (RS6280) THAN OPIOID RECEPTOR MICRO1 (RS1799971). IN CONCLUSION, WHILE OPIOIDERGIC MECHANISMS ARE INVOLVED IN OUD, DOPAMINE-RELATED RECEPTORS MAY HAVE PRIMARY INFLUENCE ON OPIOID-SEEKING BEHAVIOR IN AFRICAN AMERICANS. THESE FINDINGS SUGGEST OUD-TARGETED NOVEL AND IMPROVED NEUROPHARMACOLOGICAL THERAPIES MAY REQUIRE FOCUS ON DRD3-MEDIATED REGULATION OF DOPAMINERGIC HOMEOSTASIS. 2022