1 1651 199 DOPAMINE AND GLUCOSE, OBESITY, AND REWARD DEFICIENCY SYNDROME. OBESITY AS A RESULT OF OVEREATING AS WELL AS A NUMBER OF WELL DESCRIBED EATING DISORDERS HAS BEEN ACCURATELY CONSIDERED TO BE A WORLD-WIDE EPIDEMIC. RECENTLY A NUMBER OF THEORIES BACKED BY A PLETHORA OF SCIENTIFICALLY SOUND NEUROCHEMICAL AND GENETIC STUDIES PROVIDE STRONG EVIDENCE THAT FOOD ADDICTION IS SIMILAR TO PSYCHOACTIVE DRUG ADDICTION. OUR LABORATORY HAS PUBLISHED ON THE CONCEPT KNOWN AS REWARD DEFICIENCY SYNDROME (RDS) WHICH IS A GENETIC AND EPIGENETIC PHENOMENA LEADING TO IMPAIRMENT OF THE BRAIN REWARD CIRCUITRY RESULTING IN A HYPO-DOPAMINERGIC FUNCTION. RDS INVOLVES THE INTERACTIONS OF POWERFUL NEUROTRANSMITTERS AND RESULTS IN ABNORMAL CRAVING BEHAVIOR. A NUMBER OF IMPORTANT FACTS WHICH COULD HELP TRANSLATE TO POTENTIAL THERAPEUTIC TARGETS ESPOUSED IN THIS FOCUSED REVIEW INCLUDE: (1) CONSUMPTION OF ALCOHOL IN LARGE QUANTITIES OR CARBOHYDRATES BINGING STIMULATES THE BRAIN'S PRODUCTION OF AND UTILIZATION OF DOPAMINE; (2) IN THE MESO-LIMBIC SYSTEM THE ENKEPHALINERGIC NEURONS ARE IN CLOSE PROXIMITY, TO GLUCOSE RECEPTORS; (3) HIGHLY CONCENTRATED GLUCOSE ACTIVATES THE CALCIUM CHANNEL TO STIMULATE DOPAMINE RELEASE FROM P12 CELLS; (4) A SIGNIFICANT CORRELATION BETWEEN BLOOD GLUCOSE AND CEREBROSPINAL FLUID CONCENTRATIONS OF HOMOVANILLIC ACID THE DOPAMINE METABOLITE; (5) 2-DEOXYGLUCOSE (2DG), THE GLUCOSE ANALOG, IN PHARMACOLOGICAL DOSES IS ASSOCIATED WITH ENHANCED DOPAMINE TURNOVER AND CAUSES ACUTE GLUCOPRIVATION. EVIDENCE FROM ANIMAL STUDIES AND FMRI IN HUMANS SUPPORT THE HYPOTHESIS THAT MULTIPLE, BUT SIMILAR BRAIN CIRCUITS ARE DISRUPTED IN OBESITY AND DRUG DEPENDENCE AND FOR THE MOST PART, IMPLICATE THE INVOLVEMENT OF DA-MODULATED REWARD CIRCUITS IN PATHOLOGIC EATING BEHAVIORS. BASED ON A CONSENSUS OF NEUROSCIENCE RESEARCH TREATMENT OF BOTH GLUCOSE AND DRUG LIKE COCAINE, OPIATES SHOULD INCORPORATE DOPAMINE AGONIST THERAPY IN CONTRAST TO CURRENT THEORIES AND PRACTICES THAT UTILIZES DOPAMINE ANTAGONISTIC THERAPY. CONSIDERING THAT UP UNTIL NOW CLINICAL UTILIZATION OF POWERFUL DOPAMINE D2 AGONISTS HAVE FAILED DUE TO CHRONIC DOWN REGULATION OF D2 RECEPTORS NEWER TARGETS BASED ON NOVEL LESS POWERFUL D2 AGONISTS THAT UP-REGULATE D2 RECEPTORS SEEMS PRUDENT. WE ENCOURAGE NEW STRATEGIES TARGETED AT IMPROVING DA FUNCTION IN THE TREATMENT AND PREVENTION OF OBESITY A SUBTYPE OF REWARD DEFICIENCY. 2014 2 4631 42 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 3 4651 52 NEUROPROGRESSION IN SCHIZOPHRENIA: PATHWAYS UNDERPINNING CLINICAL STAGING AND THERAPEUTIC COROLLARIES. OBJECTIVE: WHILST DOPAMINERGIC DYSFUNCTION REMAINS A NECESSARY COMPONENT INVOLVED IN THE PATHOGENESIS OF SCHIZOPHRENIA, OUR CURRENT PHARMACOLOGICAL ARMOURY OF DOPAMINE ANTAGONISTS DOES LITTLE TO CONTROL THE NEGATIVE SYMPTOMS OF SCHIZOPHRENIA. THIS SUGGESTS OTHER PATHOLOGICAL PROCESSES MUST BE IMPLICATED. THIS PAPER AIMS TO ELABORATE ON SUCH THEORIES. METHODS: DATA FOR THIS REVIEW WERE SOURCED FROM THE ELECTRONIC DATABASE PUBMED, AND WAS NOT LIMITED BY LANGUAGE OR DATE OF PUBLICATION. RESULTS: IT HAS BEEN SUGGESTED THAT MULTIPLE 'HITS' MAY BE REQUIRED TO UNVEIL THE CLINICAL SYNDROME IN SUSCEPTIBLE INDIVIDUALS. SUCH HITS POTENTIALLY FIRST OCCUR IN UTERO, LEADING TO NEURONAL DISRUPTION, EPIGENETIC CHANGES AND THE ESTABLISHMENT OF AN ABNORMAL INFLAMMATORY RESPONSE. THE DEVELOPMENT OF SCHIZOPHRENIA MAY THEREFORE POTENTIALLY BE VIEWED AS A NEUROPROGRESSIVE RESPONSE TO THESE EARLY STRESSORS, DRIVEN ON BY CHANGES IN TRYPTOPHAN CATABOLITE (TRYCAT) METABOLISM, REACTIVE OXYGEN SPECIES HANDLING AND N-METHYL D-ASPARTATE (NMDA) CIRCUITRY. GIVEN THE POTENTIAL FOR SUCH PROGRESSION OVER TIME, IT IS PRUDENT TO EXPLORE THE NEW TREATMENT STRATEGIES WHICH MAY BE IMPLEMENTED BEFORE SUCH CHANGES BECOME ESTABLISHED. CONCLUSIONS: OUTSIDE OF THE DOPAMINERGIC MODEL, THE POTENTIAL PATHOGENESIS OF SCHIZOPHRENIA HAS YET TO BE FULLY ELUCIDATED, BUT COMMON THEMES INCLUDE NEUROPIL SHRINKAGE, THE DEVELOPMENT OF ABNORMAL NEURONAL CIRCUITRY, AND A CHRONIC INFLAMMATORY STATE WHICH FURTHER DISRUPTS NEURONAL FUNCTION. WHILST SOME EARLY NON-DOPAMINERGIC TREATMENTS SHOW PROMISE, NONE HAVE YET TO BE FULLY STUDIED IN APPROPRIATELY STRUCTURED RANDOMIZED CONTROLLED TRIALS AND THEY REMAIN LITTLE MORE THAN POTENTIAL ATTRACTIVE TARGETS. 2014 4 1796 43 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA. 2023 5 2092 26 EPIGENETIC EFFECT OF CHRONIC STRESS ON DOPAMINE SIGNALING AND DEPRESSION. BECAUSE OF THE COMPLEX CAUSAL FACTORS LEADING TO DEPRESSION, EPIGENETICS IS OF CONSIDERABLE INTEREST FOR THE UNDERSTANDING EFFECT OF STRESS IN DEPRESSION. DOPAMINE IS A KEY NEUROTRANSMITTER IMPORTANT IN MANY PHYSIOLOGICAL FUNCTIONS, INCLUDING MOTOR CONTROL, MOOD, AND THE REWARD PATHWAY. THESE FACTORS LEAD MANY DRUGS TO TARGET DOPAMINE RECEPTORS IN TREATING DEPRESSIVE DISORDERS. IN THIS REVIEW, WE TRY TO PORTRAY HOW CHRONIC STRESS AS AN EPIGENETIC FACTOR CHANGES THE GENE REGULATION PATTERN BY INTERRUPTING DOPAMINE SIGNALING MECHANISM. 2013 6 6775 43 [ALCOHOL DEPENDENCE MEDIATED BY MONOAMINE NEUROTRANSMITTERS IN THE CENTRAL NERVOUS SYSTEM]. ALCOHOL DEPENDENCE, A CHRONIC RELAPSING BRAIN DISEASE WITH THE CHARACTERISTICS OF DRINKING ALCOHOL OUT OF CONTROL, HAS BECOME A SERIOUS SOCIAL PROBLEM. MONOAMINE NEUROTRANSMITTERS, MAINLY INCLUDING DOPAMINE AND 5-HYDROXYTRYP NOTTAMINE, PLAY IMPORTANT ROLES IN THE OCCURRENCE, DEVELOPMENT AND NEURAL DYSFUNCTION OF ALCOHOL DEPENDENCE SYNDROME. IN THIS REVIEW, THE ROLES OF KEY FACTORS OF THE MONOAMINE SYSTEM (DOPAMINE RECEPTOR GENES, 5-HYDROXYTRYPTAMINE RECEPTOR GENES, TRANSPORTER GENES, TYROSINE HYDROXYLASE GENE, TRYPTOPHANHYDROXYLASE GENE AND MONOAMINE OXIDASE GENE) IN ALCOHOL DEPENDENCE WERE DISCUSSED, AND STRATEGIES FOR FURTHER STUDIES OF MOLECULAR MECHANISMS WERE PROPOSED BASED ON GENE KNOCKOUT MICE MODELS GENERATED IN OUR LABORATORY. THEN, COMBINING WITH STUDIES ON TYROSINE HYDROXYLASE ACTIVATOR CAMKII IN OUR LAB, THERAPEUTIC TARGETS WERE DISCUSSED. BESIDES, EPIGENETIC STRATEGIES FOR PREVENTION AND TREATMENT OF ALCOHOL DEPENDENCE SYNDROME WERE PROPOSED. FURTHERMORE, MANIPULATING METHYLATION LEVELS IN GENE REGULATORY REGIONS AND ALTERNATIVE SPLICING OF PRE-MRNAS MIGHT ALSO HAVE CLINICAL IMPLICATIONS. FINALLY, BASED ON NEW FINDINGS ON GENETIC POLYMORPHISM, IT IS OF GREAT POTENTIAL TO CARRY OUT INDIVIDUAL PREVENTION AND TREATMENT FOR PATIENTS SUFFERING FROM ALCOHOL DEPENDENCE. 2014 7 5649 28 SEX DIFFERENCES IN PSYCHOSTIMULANT ABUSE: IMPLICATIONS FOR ESTROGEN RECEPTORS AND HISTONE DEACETYLASES. SUBSTANCE ABUSE IS A CHRONIC PATHOLOGICAL DISORDER THAT NEGATIVELY AFFECTS MANY HEALTH AND NEUROLOGICAL PROCESSES. A GROWING BODY OF LITERATURE HAS REVEALED GENDER DIFFERENCES IN SUBSTANCE USE. COMPARED TO MEN, WOMEN DISPLAY DISTINCT DRUG-USE PHENOTYPES ACCOMPANIED BY RECOVERY AND REHABILITATION DISPARITIES. THESE OBSERVATIONS HAVE LED TO THE NOTION THAT SEX-DEPENDENT SUSCEPTIBILITIES EXIST ALONG THE PROGRESSION TO ADDICTION. WITHIN THIS SCOPE, NEUROADAPTATIONS FOLLOWING PSYCHOSTIMULANT EXPOSURE ARE THOUGHT TO BE DISTINCT FOR EACH SEX. THIS REVIEW SUMMARIZES CLINICAL FINDINGS AND ANIMAL RESEARCH REPORTING SEX DIFFERENCES IN THE SUBJECTIVE AND BEHAVIORAL RESPONSES TO COCAINE, METHAMPHETAMINE, AND NICOTINE. THIS DISCUSSION IS FOLLOWED BY AN EXAMINATION OF EPIGENETIC AND MOLECULAR ALTERATIONS IMPLICATED IN THE ADDICTION PROCESS. SPECIAL CONSIDERATION IS GIVEN TO HISTONE DEACETYLASES AND ESTROGEN RECEPTOR-MEDIATED GENE EXPRESSION. 2022 8 1722 31 DYSREGULATION OF BRAIN DOPAMINE SYSTEMS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD OR DEPRESSION) IS A DEBILITATING NEUROPSYCHIATRIC SYNDROME WITH GENETIC, EPIGENETIC, AND ENVIRONMENTAL CONTRIBUTIONS. DEPRESSION IS ONE OF THE LARGEST CONTRIBUTORS TO CHRONIC DISEASE BURDEN; IT AFFECTS MORE THAN ONE IN SIX INDIVIDUALS IN THE UNITED STATES. A WIDE ARRAY OF CELLULAR AND MOLECULAR MODIFICATIONS DISTRIBUTED ACROSS A VARIETY OF NEURONAL PROCESSES AND CIRCUITS UNDERLIE THE PATHOPHYSIOLOGY OF DEPRESSION-NO ESTABLISHED MECHANISM CAN EXPLAIN ALL ASPECTS OF THE DISEASE. MDD SUFFERS FROM A VAST TREATMENT GAP WORLDWIDE, AND LARGE NUMBERS OF INDIVIDUALS WHO REQUIRE TREATMENT DO NOT RECEIVE ADEQUATE CARE. THIS MINI-REVIEW FOCUSES ON DYSREGULATION OF BRAIN DOPAMINE (DA) SYSTEMS IN THE PATHOPHYSIOLOGY OF MDD AND DESCRIBING NEW CELLULAR TARGETS FOR POTENTIAL MEDICATION DEVELOPMENT FOCUSED ON DA-MODULATED MICRO-CIRCUITS. WE ALSO EXPLORE HOW NEURODEVELOPMENTAL FACTORS MAY MODIFY RISK FOR LATER EMERGENCE OF MDD, POSSIBLY THROUGH DOPAMINERGIC SUBSTRATES IN THE BRAIN. 2021 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 4654 40 NEUROSTEROIDS (ALLOPREGNANOLONE) AND ALCOHOL USE DISORDER: FROM MECHANISMS TO POTENTIAL PHARMACOTHERAPY. ALCOHOL USE DISORDER (AUD) IS A MULTIFACETED RELAPSING DISORDER THAT IS COMMONLY COMORBID WITH PSYCHIATRIC DISORDERS, INCLUDING ANXIETY. ALCOHOL EXPOSURE PRODUCES A PLETHORA OF EFFECTS ON NEUROBIOLOGY. CURRENTLY, THERAPEUTIC STRATEGIES ARE LIMITED, AND ONLY A FEW TREATMENTS - DISULFIRAM, ACAMPROSATE, AND NALTREXONE - ARE AVAILABLE. GIVEN THE COMPLEXITY OF THIS DISORDER, THERE IS A GREAT NEED FOR THE IDENTIFICATION OF NOVEL TARGETS TO DEVELOP NEW PHARMACOTHERAPY. THE GABAERGIC SYSTEM, THE PRIMARY INHIBITORY SYSTEM IN THE BRAIN, IS ONE OF THE WELL-KNOWN TARGETS FOR ALCOHOL AND IS RESPONSIBLE FOR THE ANXIOLYTIC EFFECTS OF ALCOHOL. INTERESTINGLY, GABAERGIC NEUROTRANSMISSION IS FINE-TUNED BY NEUROACTIVE STEROIDS THAT EXERT A REGULATORY ROLE ON SEVERAL ENDOCRINE SYSTEMS INVOLVED IN NEUROPSYCHIATRIC DISORDERS INCLUDING AUD. MOUNTING EVIDENCE INDICATES THAT ALCOHOL ALTERS THE BIOSYNTHESIS OF NEUROSTEROIDS, WHEREAS ACUTE ALCOHOL INCREASES AND CHRONIC ALCOHOL DECREASES ALLOPREGNANOLONE LEVELS. OUR RECENT WORK HIGHLIGHTED THAT CHRONIC ALCOHOL-INDUCED CHANGES IN NEUROSTEROID LEVELS ARE MEDIATED BY EPIGENETIC MODIFICATIONS, E.G., DNA METHYLATION, AFFECTING KEY ENZYMES INVOLVED IN NEUROSTEROID BIOSYNTHESIS. THESE CHANGES WERE ASSOCIATED WITH CHANGES IN GABA(A) RECEPTOR SUBUNIT EXPRESSION, SUGGESTING AN IMBALANCE BETWEEN EXCITATORY AND INHIBITORY SIGNALING IN AUD. THIS REVIEW WILL RECAPITULATE THE ROLE OF NEUROSTEROIDS IN THE REGULATION OF THE NEUROENDOCRINE SYSTEM, HIGHLIGHT THEIR ROLE IN THE OBSERVED ALLOSTATIC LOAD IN AUD, AND DEVELOP A FRAMEWORK FROM MECHANISMS TO POTENTIAL PHARMACOTHERAPY. 2022 11 1329 45 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 12 6324 35 THE ROLE OF ALPHA-SYNUCLEIN IN THE PATHOPHYSIOLOGY OF ALCOHOLISM. ALCOHOLISM HAS COMPLEX ETIOLOGY AND THERE IS EVIDENCE FOR BOTH GENETIC AND ENVIRONMENTAL FACTORS IN ITS PATHOPHYSIOLOGY. CHRONIC, LONG-TERM ALCOHOL ABUSE AND ALCOHOL DEPENDENCE ARE ASSOCIATED WITH NEURONAL LOSS WITH THE PREFRONTAL CORTEX BEING PARTICULARLY SUSCEPTIBLE TO NEUROTOXIC DAMAGE. THIS BRAIN REGION IS INVOLVED IN THE DEVELOPMENT AND PERSISTENCE OF ALCOHOL ADDICTION AND NEUROTOXIC DAMAGE IS LIKELY TO EXACERBATE THE REINFORCING EFFECTS OF ALCOHOL AND MAY HINDER TREATMENT. UNDERSTANDING THE MECHANISM OF ALCOHOL'S NEUROTOXIC EFFECTS ON THE BRAIN AND THE GENETIC RISK FACTORS ASSOCIATED WITH ALCOHOL ABUSE ARE THE FOCUS OF CURRENT RESEARCH. BECAUSE OF ITS WELL-ESTABLISHED ROLE IN NEURODEGENERATIVE AND NEUROPSYCHOLOGICAL DISORDERS, AND ITS EMERGING ROLE IN THE PATHOPHYSIOLOGY OF ADDICTION, HERE WE REVIEW THE GENETIC AND EPIGENETIC FACTORS INVOLVED IN REGULATING ALPHA-SYNUCLEIN EXPRESSION AND ITS POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF CHRONIC ALCOHOL ABUSE. ELUCIDATION OF THE MECHANISMS OF ALPHA-SYNUCLEIN REGULATION MAY PROVE BENEFICIAL IN UNDERSTANDING THE ROLE OF THIS KEY SYNAPTIC PROTEIN IN DISEASE AND ITS POTENTIAL FOR THERAPEUTIC MODULATION IN THE TREATMENT OF SUBSTANCE USE DISORDERS AS WELL AS OTHER NEURODEGENERATIVE DISEASES. 2013 13 4327 46 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 14 1984 36 EPIGENETIC ALTERATIONS IN PRESCRIPTION OPIOID MISUSE: NEW STRATEGIES FOR PRECISION PAIN MANAGEMENT. PRESCRIPTION OPIOIDS ARE USED FOR SOME CHRONIC PAIN CONDITIONS. HOWEVER, GENERALLY, LONG-TERM THERAPY HAS UNWANTED SIDE EFFECTS WHICH MAY TRIGGER ADDICTION, OVERDOSE, AND EVENTUALLY CAUSE DEATHS. OPIOID ADDICTION AND CHRONIC PAIN CONDITIONS HAVE BOTH BEEN ASSOCIATED WITH EVIDENCE OF GENETIC AND EPIGENETIC ALTERATIONS. DESPITE INTENSE RESEARCH INTEREST, MANY QUESTIONS ABOUT THE CONTRIBUTION OF EPIGENETIC CHANGES TO THIS TYPOLOGY OF ADDICTION VULNERABILITY AND DEVELOPMENT REMAIN UNANSWERED. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE EPIGENETIC MODIFICATIONS DETECTED IN SPECIFIC TISSUES OR BRAIN AREAS AND ASSOCIATED WITH OPIOID PRESCRIPTION AND MISUSE IN PATIENTS WHO HAVE INITIATED PRESCRIBED OPIOID MANAGEMENT FOR CHRONIC NON-CANCER PAIN. THE REVIEW CONSIDERS THE EFFECTS OF OPIOID EXPOSURE ON THE EPIGENOME IN CENTRAL AND PERIPHERAL TISSUES IN ANIMAL MODELS AND HUMAN SUBJECTS AND HIGHLIGHTS THE MECHANISMS IN WHICH OPIOID EPIGENETICS MAY BE INVOLVED. THIS WILL IMPROVE OUR CURRENT UNDERSTANDING, PROVIDE THE BASIS FOR TARGETED, PERSONALIZED PAIN MANAGEMENT, AND THUS BALANCE OPIOID RISKS AND BENEFITS IN MANAGING CHRONIC PAIN. 2021 15 679 31 BRAIN FOODS - THE ROLE OF DIET IN BRAIN PERFORMANCE AND HEALTH. THE PERFORMANCE OF THE HUMAN BRAIN IS BASED ON AN INTERPLAY BETWEEN THE INHERITED GENOTYPE AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING DIET. FOOD AND NUTRITION, ESSENTIAL IN MAINTENANCE OF BRAIN PERFORMANCE, ALSO AID IN PREVENTION AND TREATMENT OF MENTAL DISORDERS. BOTH THE OVERALL COMPOSITION OF THE HUMAN DIET AND SPECIFIC DIETARY COMPONENTS HAVE BEEN SHOWN TO HAVE AN IMPACT ON BRAIN FUNCTION IN VARIOUS EXPERIMENTAL MODELS AND EPIDEMIOLOGICAL STUDIES. THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF THE ROLE OF DIET IN 5 KEY AREAS OF BRAIN FUNCTION RELATED TO MENTAL HEALTH AND PERFORMANCE, INCLUDING: (1) BRAIN DEVELOPMENT, (2) SIGNALING NETWORKS AND NEUROTRANSMITTERS IN THE BRAIN, (3) COGNITION AND MEMORY, (4) THE BALANCE BETWEEN PROTEIN FORMATION AND DEGRADATION, AND (5) DETERIORATIVE EFFECTS DUE TO CHRONIC INFLAMMATORY PROCESSES. FINALLY, THE ROLE OF DIET IN EPIGENETIC REGULATION OF BRAIN PHYSIOLOGY IS DISCUSSED. 2021 16 4648 46 NEUROPEPTIDE Y IN ALCOHOL ADDICTION AND AFFECTIVE DISORDERS. NEUROPEPTIDE Y (NPY), A NEUROPEPTIDE HIGHLY CONSERVED THROUGHOUT EVOLUTION, IS PRESENT AT HIGH LEVELS IN THE CENTRAL NERVOUS SYSTEM (CNS), AS WELL AS IN PERIPHERAL TISSUES SUCH AS THE GUT AND CARDIOVASCULAR SYSTEM. THE PEPTIDE EXERTS ITS EFFECTS VIA MULTIPLE RECEPTOR SUBTYPES, ALL BELONGING TO THE G-PROTEIN-COUPLED RECEPTOR SUPERFAMILY. OF THESE SUBTYPES, THE Y1 AND THE Y2 ARE THE MOST THOROUGHLY CHARACTERIZED, FOLLOWED BY THE Y5 SUBTYPE. NPY AND ITS RECEPTORS HAVE BEEN SHOWN TO BE OF IMPORTANCE IN CENTRAL REGULATION OF EVENTS UNDERLYING, FOR EXAMPLE, AFFECTIVE DISORDERS, DRUG/ALCOHOL USE DISORDERS, AND ENERGY HOMEOSTASIS. FURTHERMORE, WITHIN THE CNS, NPY ALSO AFFECTS SLEEP REGULATION AND CIRCADIAN RHYTHM, MEMORY FUNCTION, TISSUE GROWTH, AND PLASTICITY. THE POTENTIAL ROLES OF NPY IN THE ETIOLOGY AND PATHOPHYSIOLOGY OF MOOD AND ANXIETY DISORDERS, AS WELL AS ALCOHOL USE DISORDERS, HAVE BEEN EXTENSIVELY STUDIED. THIS FOCUS WAS PROMPTED BY EARLY INDICATIONS FOR AN INVOLVEMENT OF NPY IN ACUTE RESPONSES TO STRESS, AND, LATER, ALSO DATA POINTING TO A ROLE IN ALTERATIONS WITHIN THE CNS DURING CHRONIC, OR REPEATED, EXPOSURE TO ADVERSE EVENTS. THESE FUNCTIONS OF NPY, IN ADDITION TO THE PEPTIDE'S REGULATION OF DISEASE STATES, SUGGEST THAT MODULATION OF THE ACTIVITY OF THE NPY SYSTEM VIA RECEPTOR AGONISTS/ANTAGONISTS MAY BE A PUTATIVE TREATMENT MECHANISM IN AFFECTIVE DISORDERS AS WELL AS ALCOHOL USE DISORDERS. IN THIS REVIEW, WE PRESENT AN OVERVIEW OF FINDINGS WITH REGARD TO THE NPY SYSTEM IN RELATION TO ANXIETY AND STRESS, ACUTE AS WELL AS CHRONIC; FURTHERMORE WE DISCUSS POST-TRAUMATIC STRESS DISORDER AND, IN PART DEPRESSION. IN ADDITION, WE SUMMARIZE FINDINGS ON ALCOHOL USE DISORDERS AND RELATED BEHAVIORS. FINALLY, WE BRIEFLY TOUCH UPON GENETIC AS WELL AS EPIGENETIC MECHANISMS THAT MAY BE OF IMPORTANCE FOR NPY FUNCTION AND REGULATION. IN CONCLUSION, WE SUGGEST THAT MODULATION OF NPY-ERGIC ACTIVITY WITHIN THE CNS, VIA LIGANDS AIMED AT DIFFERENT RECEPTOR SUBTYPES, MAY BE ATTRACTIVE TARGETS FOR TREATMENT DEVELOPMENT FOR AFFECTIVE DISORDERS, AS WELL AS FOR ALCOHOL USE DISORDERS. 2017 17 4642 40 NEURONAL PLASTICITY: A LINK BETWEEN STRESS AND MOOD DISORDERS. ALTHOUGH STRESS REPRESENTS THE MAJOR ENVIRONMENTAL ELEMENT OF SUSCEPTIBILITY FOR MOOD DISORDERS, THE RELATIONSHIP BETWEEN STRESS AND DISEASE REMAINS TO BE FULLY ESTABLISHED. IN THE PRESENT ARTICLE WE REVIEW THE EVIDENCE IN SUPPORT FOR A ROLE OF NEURONAL PLASTICITY, AND IN PARTICULAR OF NEUROTROPHIC FACTORS. EVEN THOUGH DECREASED LEVELS OF NOREPINEPHRINE AND SEROTONIN MAY UNDERLIE DEPRESSIVE SYMPTOMS, COMPELLING EVIDENCE NOW SUGGESTS THAT MOOD DISORDERS ARE CHARACTERIZED BY REDUCED NEURONAL PLASTICITY, WHICH CAN BE BROUGHT ABOUT BY EXPOSURE TO STRESS AT DIFFERENT STAGES OF LIFE. INDEED THE EXPRESSION OF NEUROTROPHIC MOLECULES, SUCH AS THE NEUROTROPHIN BDNF, IS REDUCED IN DEPRESSED SUBJECTS AS WELL AS IN EXPERIMENTAL ANIMALS EXPOSED TO ADVERSE EXPERIENCE AT EARLY STAGES OF LIFE OR AT ADULTHOOD. THESE CHANGES SHOW AN ANATOMICAL SPECIFICITY AND MIGHT BE SUSTAINED BY EPIGENETIC MECHANISMS. PHARMACOLOGICAL INTERVENTION MAY NORMALIZE SUCH DEFECTS AND IMPROVE NEURONAL FUNCTION THROUGH THE MODULATION OF THE SAME FACTORS THAT ARE DEFECTIVE IN DEPRESSION. SEVERAL STUDIES HAVE DEMONSTRATED THAT CHRONIC, BUT NOT ACUTE, ANTIDEPRESSANT TREATMENT INCREASES THE EXPRESSION OF BDNF AND MAY ENHANCE ITS LOCALIZATION AT SYNAPTIC LEVEL. ANTIDEPRESSANT TREATMENT CAN NORMALIZE DEFICITS IN NEUROTROPHIN EXPRESSION PRODUCED BY CHRONIC STRESS PARADIGMS, BUT MAY ALSO ALTER THE MODULATION OF BDNF UNDER ACUTE STRESSFUL CONDITIONS. IN SUMMARY, THERE IS GOOD AGREEMENT IN CONSIDERING NEURONAL PLASTICITY, AND THE EXPRESSION OF KEY PROTEINS SUCH AS THE NEUROTROPHIN BDNF, AS A CENTRAL PLAYER FOR THE EFFECTS OF STRESS ON BRAIN FUNCTION AND ITS IMPLICATION FOR PSYCHOPATHOLOGY. ACCORDINGLY, EFFECTIVE TREATMENTS SHOULD NOT LIMIT THEIR EFFECTS TO THE CONTROL OF NEUROTRANSMITTER AND HORMONAL DYSFUNCTIONS, BUT SHOULD BE ABLE TO NORMALIZE DEFECTIVE MECHANISMS THAT SUSTAIN THE IMPAIRMENT OF NEURONAL PLASTICITY. 2009 18 38 32 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003 19 265 55 ADVERSE EFFECTS OF RECREATIONAL AND MEDICAL CANNABIS. PURPOSE OF REVIEW: THIS COMPREHENSIVE REVIEW DISCUSSES THE ADVERSE EFFECTS KNOWN TODAY ABOUT MARIJUANA, FOR EITHER MEDICAL OR RECREATIONAL USE. IT REVIEWS THE ROLE OF CANNABIS IN THE TREATMENT OF CHRONIC PAIN, COGNITIVE AND NEUROLOGICAL ADVERSE EFFECTS, SPECIAL CASES AND ADDICTION. RECENT FINDINGS: CANNABINOIDS WORK THROUGH THE ENDOCANNABINOIDS SYSTEM AND INHIBIT THE RELEASE OF GABA AND GLUTAMATE IN THE BRAIN, IMPACT NEUROMODULATION, AS WELL AS DOPAMINE, ACETYLCHOLINE AND NOREPINEPHRINE RELEASE. THEY AFFECT REWARD, LEARNING AND PAIN. THE USE OF CANNABIS IS INCREASING NATIONALLY AND WORLD-WIDE FOR BOTH RECREATIONAL AND MEDICINAL PURPOSES, HOWEVER, THERE IS RELATIVELY ONLY LOW QUALITY EVIDENCE TO THE EFFICACY AND ADVERSE EFFECTS OF THIS. CANNABIS AND ITS DERIVATIVES MAY BE USED FOR TREATMENT OF CHRONIC PAIN. THEY ARE VIA CB1 RECEPTORS THAT ARE THOUGHT TO MODULATE NOCICEPTIVE SIGNALS IN THE BRAIN. CB2 RECEPTORS IN THE DRG LIKELY AFFECT PAIN INTEGRATION IN THE AFFERENT PATHWAYS, AND PERIPHERALLY CB2 ALSO AFFECTS NORADRENERGIC PATHWAYS INFLUENCING PAIN. A LARGE PROPORTION OF USERS MAY SEE MORE THAN 50% OF CHRONIC PAIN ALLEVIATION COMPARED WITH PLACEBO. CANNABIS AFFECTS COGNITION, MOST NOTABLY EXECUTIVE FUNCTION, MEMORY AND ATTENTION, AND MAY DETERIORATE THE BOUNDARY BETWEEN EMOTIONAL AND EXECUTIVE PROCESSING. CANNABIS IMPAIRS MEMORY IN THE SHORT RUN, WHICH BECOME MORE SIGNIFICANT WITH CHRONIC USE, AND MAY ALSO BE ACCOMPANIED BY POORER EFFORT, SLOWER PROCESSING AND IMPACTED ATTENTION. IT IS GENERALLY BELIEVED THAT LONG-TERM USE AND EARLIER AGE ARE RISK FACTOR FOR NEUROCOGNITIVE DEFICITS; NEUROIMAGING STUDIES HAVE SHOWN REDUCED HIPPOCAMPAL VOLUME AND DENSITY. EXECUTIVE FUNCTIONS AND MEMORY ARE WORSE IN ADOLESCENT USERS VERSUS ADULTS. CANNABIS ADDICTION IS DIFFERENT AND LIKELY LESS COMMON THAN OTHER ADDICTIVE SUBSTANCES, BUT UP TO 10% OF USERS MEET CRITERIA FOR LIFETIME CANNABIS DEPENDENCE. ADDICTION PATTERNS MAY BE LINKED TO GENETIC AND EPIGENETIC DIFFERENCES. IT IS STILL UNCLEAR WHETHER ABSTINENCE REVERSES PATTERNS OF ADDICTION, AND MORE RESEARCH IS REQUIRED INTO THIS TOPIC. SUMMARY: CANNABIS USE HAS BECOME MORE ABUNDANT FOR BOTH MEDICAL AND RECREATIONAL USE. IT CARRIES LIKELY BENEFITS IN THE FORM OF ANALGESIA, ANTI-EMESIS AND IMPROVED APPETITE IN CHRONIC PATIENTS. THE EVIDENCE REVIEWING ADVERSE EFFECTS OF THIS USE ARE STILL LIMITED, HOWEVER, EXITING DATA POINTS TO A CLEAR LINK WITH NEUROCOGNITIVE DETERIORATION, BACKED BY LOSS OF BRAIN VOLUME AND DENSITY. ADDICTION IS LIKELY COMPLEX AND VARIABLE, AND NO GOOD DATA EXISTS TO SUPPORT TREATMENT AT THIS POINT. IT IS BECOMING CLEAR THAT USE IN EARLIER AGES CARRIES A HIGHER RISK FOR LONG-TERM DEFICITS. AS WITH ANY OTHER DRUG, THESE RISKS SHOULD BE CONSIDERED ALONGSIDE BENEFITS PRIOR TO A DECISION ON CANNABIS USE. 2021 20 636 46 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