1 4649 276 NEUROPEPTIDES AND NEUROPEPTIDE RECEPTORS: DRUG TARGETS, AND PEPTIDE AND NON-PEPTIDE LIGANDS: A TRIBUTE TO PROF. DIETER SEEBACH. THE NUMBER OF NEUROPEPTIDES AND THEIR CORRESPONDING RECEPTORS HAS INCREASED STEADILY OVER THE LAST FOURTY YEARS: INITIALLY, PEPTIDES WERE ISOLATED FROM GUT OR BRAIN (E.G., SUBSTANCE P, SOMATOSTATIN), THEN BY TARGETED MINING IN SPECIFIC REGIONS (E.G., CORTISTATIN, OREXIN IN THE BRAIN), OR BY DEORPHANIZATION OF G-PROTEIN-COUPLED RECEPTORS (GPCRS; OREXIN, GHRELIN RECEPTORS) AND THROUGH THE COMPLETION THE HUMAN GENOME PROJECT. NEUROPEPTIDES (AND THEIR RECEPTORS) HAVE REGIONALLY RESTRICTED DISTRIBUTIONS IN THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM. THE NEUROPEPTIDE SIGNALING IS SOMEWHAT MORE DISTINCT SPATIALLY THAN SIGNALING WITH CLASSICAL, LOW-MOLECULAR-WEIGHT NEUROTRANSMITTERS THAT ARE MORE WIDELY EXPRESSED, AND, THEREFORE, ONE ASSUMES THAT DRUGS ACTING AT NEUROPEPTIDE RECEPTORS MAY HAVE MORE SELECTIVE PHARMACOLOGICAL ACTIONS WITH POSSIBLY FEWER SIDE EFFECTS THAN DRUGS ACTING ON GLUTAMATERGIC, GABAERGIC, MONOAMINERGIC, OR CHOLINERGIC SYSTEMS. NEUROPEPTIDE RECEPTORS, WHICH MAY HAVE A FEW OR MULTIPLE SUBTYPES AND SPLICE VARIANTS, BELONG ALMOST EXCLUSIVELY TO THE GPCR FAMILY ALSO KNOWN AS SEVEN-TRANSMEMBRANE RECEPTORS (7TM), A FAVORITE CLASS OF DRUG TARGETS IN THE PHARMACEUTICAL INDUSTRY. MOST NEUROPEPTIDES ARE CO-STORED AND CO-RELEASED WITH CLASSIC NEUROTRANSMITTERS, ALBEIT OFTEN ONLY AT HIGHER FREQUENCIES OF STIMULATION OR AT BURSTING ACTIVITY, THUS RESTRICTING THE NEUROPEPTIDE SIGNALING TO SPECIFIC CIRCUMSTANCES, ANOTHER REASON TO ASSUME THAT NEUROPEPTIDE DRUG MIMICS MAY HAVE LESS SIDE EFFECTS. NEUROPEPTIDES POSSESS A WIDE SPECTRUM OF FUNCTIONS FROM NEUROHORMONE, NEUROTRANSMITTER TO GROWTH FACTOR, BUT ALSO AS KEY INFLAMMATORY MEDIATORS. NEUROPEPTIDES BECOME 'ACTIVE' WHEN THE NERVOUS SYSTEM IS CHALLENGED, E.G., BY STRESS, INJURY, DRUG ABUSE, OR NEUROPSYCHIATRIC DISORDERS WITH GENETIC, EPIGENETIC, AND/OR ENVIRONMENTAL COMPONENTS. THE UNSUSPECTED NUMBER OF TRUE NEUROPEPTIDES AND THEIR COGNATE RECEPTORS PROVIDES OPPORTUNITIES TO IDENTIFY NOVEL TARGETS FOR THE TREATMENT OF BOTH CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS. BOTH, RECEPTOR SUBTYPE-SELECTIVE ANTAGONISTS AND AGONISTS ARE BEING DEVELOPED, AS ILLUSTRATED BY THE SUCCESS OF SOMATOSTATIN AGONISTS, ANGIOTENSIN, AND ENDOTHELIN ANTAGONISTS, AND THE EXPECTED CLINICAL APPLICATIONS OF NK-1/2/3 (SUBSTANCE P) RECEPTOR ANTAGONISTS, CRF, VASOPRESSIN, NPY, NEUROTENSIN, OREXIN ANTAGONISTS, OR NEUROPEPTIDE RECEPTOR MODULATORS; SUCH LIGANDS HAVE EFFICACY IN PRECLINICAL OR CLINICAL MODELS OF PAIN AND NEUROPSYCHIATRIC DISEASES, SUCH AS MIGRAINE, CHRONIC/NEUROPATHIC PAIN, ANXIETY, SLEEP DISORDERS, DEPRESSION, AND SCHIZOPHRENIA. IN ADDITION, BOTH POSITIVE AND NEGATIVE ALLOSTERIC MODULATORS HAVE BEEN DESCRIBED WITH INTERESTING IN VIVO ACTIVITIES (E.G., AT GALANIN RECEPTORS). THE FIELD HAS BECOME MORE COMPLEX NOW THAT AN INCREASING NUMBER OF HETEROMERIC NEUROPEPTIDE RECEPTORS ARE DESCRIBED, E.G., GHRELIN RECEPTORS WITH 5-HT(2C) OR DOPAMINE D(1), D(2) RECEPTORS. AT LONG LAST, STRUCTURE-BASED DRUG DISCOVERY CAN NOW BE ENVISAGED WITH CONFIDENCE, SINCE CRYSTAL OR SOLUTION STRUCTURE OF GPCRS AND GPCR-LIGAND COMPLEXES, INCLUDING PEPTIDE RECEPTORS, ARE PUBLISHED ALMOST ON A MONTHLY BASIS. FINALLY, ALTHOUGH MOST COMPOUNDS ACTING AT PEPTIDE RECEPTORS ARE STILL PEPTIDOMIMETICS, THE LAST DECADE HAS SEEN THE EMERGENCE OF LOW-MOLECULAR-WEIGHT NONPEPTIDE LIGANDS (E.G., FOR OREXIN, GHRELIN, OR NEUROKININ RECEPTORS), AND SURPRISING PROGRESS HAS BEEN MADE WITH BETA- AND GAMMA-PEPTIDES AS VERY STABLE AND POTENT MIMETICS OF, E.G., SOMATOSTATIN (SRIF), WHERE THE NATIVE SRIF HAS A HALF-LIFE LIMITED TO 2-3 MIN. THIS LAST POINT WILL BE ILLUSTRATED MORE SPECIFICALLY, AS WE HAVE HAD A LONG-STANDING COLLABORATION WITH PROF. D. SEEBACH TO WHOM THIS REVIEW IS DEDICATED AT THE OCCASION OF HIS 75TH BIRTHDAY. 2012 2 4648 59 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 3 6130 39 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015 4 6895 31 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION. 2009 5 1199 40 CORTICOTROPIN RELEASING FACTOR-BINDING PROTEIN (CRF-BP) AS A POTENTIAL NEW THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE AND STRESS DISORDERS. ALZHEIMER'S DISEASE IS THE MOST COMMON CAUSE OF DEMENTIA AND ONE OF THE MOST COMPLEX HUMAN NEURODEGENERATIVE DISEASES. NUMEROUS STUDIES HAVE DEMONSTRATED A CRITICAL ROLE OF THE ENVIRONMENT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THE DISEASE, WHERE DAILY LIFE STRESS PLAYS AN IMPORTANT ROLE. A LOT OF EPIGENETIC STUDIES HAVE LED TO THE CONCLUSION THAT CHRONIC STRESS AND STRESS-RELATED DISORDERS PLAY AN IMPORTANT PART IN THE ONSET OF NEURODEGENERATIVE DISORDERS, AND AN ENORMOUS AMOUNT OF RESEARCH YIELDED VALUABLE DISCOVERIES BUT HAS SO FAR NOT LED TO THE DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR ALZHEIMER'S DISEASE. CORTICOTROPIN-RELEASING FACTOR (CRF) IS ONE OF THE MAJOR HORMONES AND AT THE SAME TIME A NEUROPEPTIDE ACTING IN STRESS RESPONSE. DEREGULATION OF PROTEIN LEVELS OF CRF IS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, BUT LITTLE IS KNOWN ABOUT THE PRECISE ROLES OF CRF AND ITS BINDING PROTEIN, CRF-BP, IN NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE KEY EVIDENCE FOR AND AGAINST THE INVOLVEMENT OF STRESS-ASSOCIATED MODULATION OF THE CRF SYSTEM IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE AND DISCUSS HOW RECENT FINDINGS COULD LEAD TO NEW POTENTIAL TREATMENT POSSIBILITIES IN ALZHEIMER'S DISEASE BY USING CRF-BP AS A THERAPEUTIC TARGET. 2019 6 4631 33 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 7 1676 34 DRUG ADDICTION: FROM BENCH TO BEDSIDE. DRUG ADDICTION IS RESPONSIBLE FOR MILLIONS OF DEATHS PER YEAR AROUND THE WORLD. STILL, ITS MANAGEMENT AS A CHRONIC DISEASE IS SHADOWED BY MISCONCEPTIONS FROM THE GENERAL PUBLIC. INDEED, DRUG CONSUMERS ARE OFTEN LABELLED AS "WEAK", "IMMORAL" OR "DEPRAVED". CONSEQUENTLY, DRUG ADDICTION IS OFTEN PERCEIVED AS AN INDIVIDUAL PROBLEM AND NOT SOCIETAL. IN TECHNICAL TERMS, DRUG ADDICTION IS DEFINED AS A CHRONIC, RELAPSING DISEASE RESULTING FROM SUSTAINED EFFECTS OF DRUGS ON THE BRAIN. THROUGH A BETTER CHARACTERISATION OF THE CEREBRAL CIRCUITS INVOLVED, AND THE LONG-TERM MODIFICATIONS OF THE BRAIN INDUCED BY ADDICTIVE DRUGS ADMINISTRATIONS, FIRST, WE MIGHT BE ABLE TO CHANGE THE WAY THE GENERAL PUBLIC SEE THE PATIENT WHO IS SUFFERING FROM DRUG ADDICTION, AND SECOND, WE MIGHT BE ABLE TO FIND NEW TREATMENTS TO NORMALISE THE ALTERED BRAIN HOMEOSTASIS. IN THIS REVIEW, WE SYNTHETISE THE CONTRIBUTION OF FUNDAMENTAL RESEARCH TO THE UNDERSTANDING DRUG ADDICTION AND ITS CONTRIBUTION TO POTENTIAL NOVEL THERAPEUTICS. MOSTLY BASED ON DRUG-INDUCED MODIFICATIONS OF SYNAPTIC PLASTICITY AND EPIGENETIC MECHANISMS (AND THEIR BEHAVIOURAL CORRELATES) AND AFTER DEMONSTRATION OF THEIR REVERSIBILITY, WE TRIED TO HIGHLIGHT PROMISING THERAPEUTICS. WE ALSO UNDERLINE THE SPECIFIC TEMPORAL DYNAMICS AND PSYCHOSOCIAL ASPECTS OF THIS COMPLEX PSYCHIATRIC DISEASE ADDING PARAMETERS TO BE CONSIDERED IN CLINICAL TRIALS AND PAVING THE WAY TO TEST NEW THERAPEUTIC VENUES. 2021 8 6226 20 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 9 1688 48 DUAL BET/HDAC INHIBITION TO RELIEVE NEUROPATHIC PAIN: RECENT ADVANCES, PERSPECTIVES, AND FUTURE OPPORTUNITIES. DESPITE THE INTENSE RESEARCH ON DEVELOPING NEW THERAPIES FOR NEUROPATHIC PAIN STATES, AVAILABLE TREATMENTS HAVE LIMITED EFFICACY AND UNFAVORABLE SAFETY PROFILES. EPIGENETIC ALTERATIONS HAVE A GREAT INFLUENCE ON THE DEVELOPMENT OF CANCER AND NEUROLOGICAL DISEASES, AS WELL AS NEUROPATHIC PAIN. HISTONE ACETYLATION HAS PREVAILED AS ONE OF THE WELL INVESTIGATED EPIGENETIC MODIFICATIONS IN THESE DISEASES. ALTERED SPINAL ACTIVITY OF HISTONE DEACETYLASE (HDAC) AND BROMO AND EXTRA TERMINAL DOMAIN (BET) HAVE BEEN DESCRIBED IN NEUROPATHIC PAIN MODELS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS SHOWED PAIN-RELIEVING ACTIVITY. OVER THE LAST DECADES HDACS AND BETS HAVE BEEN THE FOCUS OF DRUG DISCOVERY STUDIES, LEADING TO THE DEVELOPMENT OF NUMEROUS SMALL-MOLECULE INHIBITORS. CLINICAL TRIALS TO EVALUATE THEIR ANTICANCER ACTIVITY SHOWED GOOD EFFICACY BUT RAISED TOXICITY CONCERNS THAT LIMITED TRANSLATION TO THE CLINIC. TO MAXIMIZE ACTIVITY AND MINIMIZE TOXICITY, THESE COMPOUNDS CAN BE APPLIED IN COMBINATION OF SUB-MAXIMAL DOSES TO PRODUCE ADDITIVE OR SYNERGISTIC INTERACTIONS (COMBINATION THERAPY). RECENTLY, OF PARTICULAR INTEREST, DUAL BET/HDAC INHIBITORS (MULTI-TARGET DRUGS) HAVE BEEN DEVELOPED TO ASSURE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE. THIS REVIEW WILL SUMMARIZE THE MOST RECENT ADVANCES WITH THESE STRATEGIES, DESCRIBING ADVANTAGES AND LIMITATIONS OF SINGLE DRUG TREATMENT VS COMBINATION REGIMENS. THIS REVIEW WILL ALSO PROVIDE A FOCUS ON DUAL BET/HDAC DRUG DISCOVERY INVESTIGATIONS AS FUTURE THERAPEUTIC OPPORTUNITY FOR HUMAN THERAPY OF NEUROPATHIC PAIN. 2021 10 4198 37 METABOLIC PROFILING DISTINGUISHES THREE SUBTYPES OF ALZHEIMER'S DISEASE. THE CAUSE OF ALZHEIMER'S DISEASE IS INCOMPLETELY DEFINED, AND NO TRULY EFFECTIVE THERAPY EXISTS. HOWEVER, MULTIPLE STUDIES HAVE IMPLICATED METABOLIC ABNORMALITIES SUCH AS INSULIN RESISTANCE, HORMONAL DEFICIENCIES, AND HYPERHOMOCYSTEINEMIA. OPTIMIZING METABOLIC PARAMETERS IN A COMPREHENSIVE WAY HAS YIELDED COGNITIVE IMPROVEMENT, BOTH IN SYMPTOMATIC AND ASYMPTOMATIC INDIVIDUALS. THEREFORE, EXPANDING THE STANDARD LABORATORY EVALUATION IN PATIENTS WITH DEMENTIA MAY BE REVEALING. HERE I REPORT THAT METABOLIC PROFILING REVEALS THREE ALZHEIMER'S DISEASE SUBTYPES. THE FIRST IS INFLAMMATORY, IN WHICH MARKERS SUCH AS HS-CRP AND GLOBULIN:ALBUMIN RATIO ARE INCREASED. THE SECOND TYPE IS NON-INFLAMMATORY, IN WHICH THESE MARKERS ARE NOT INCREASED, BUT OTHER METABOLIC ABNORMALITIES ARE PRESENT. THE THIRD TYPE IS A VERY DISTINCTIVE CLINICAL ENTITY THAT AFFECTS RELATIVELY YOUNG INDIVIDUALS, EXTENDS BEYOND THE TYPICAL ALZHEIMER'S DISEASE INITIAL DISTRIBUTION TO AFFECT THE CORTEX WIDELY, IS CHARACTERIZED BY EARLY NON-AMNESTIC FEATURES SUCH AS DYSCALCULIA AND APHASIA, IS OFTEN MISDIAGNOSED OR LABELED ATYPICAL ALZHEIMER'S DISEASE, TYPICALLY AFFECTS APOE4-NEGATIVE INDIVIDUALS, AND IS ASSOCIATED WITH STRIKING ZINC DEFICIENCY. GIVEN THE INVOLVEMENT OF ZINC IN MULTIPLE ALZHEIMER'S-RELATED METABOLIC PROCESSES, SUCH AS INSULIN RESISTANCE, CHRONIC INFLAMMATION, ADAM10 PROTEOLYTIC ACTIVITY, AND HORMONAL SIGNALING, THIS SYNDROME OF ALZHEIMER'S-PLUS WITH LOW ZINC (APLZ) WARRANTS FURTHER METABOLIC, GENETIC, AND EPIGENETIC CHARACTERIZATION. 2015 11 2993 39 GENETIC PAIN LOSS DISORDERS. GENETIC PAIN LOSS INCLUDES CONGENITAL INSENSITIVITY TO PAIN (CIP), HEREDITARY SENSORY NEUROPATHIES AND, IF AUTONOMIC NERVES ARE INVOLVED, HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY (HSAN). THIS HETEROGENEOUS GROUP OF DISORDERS HIGHLIGHTS THE ESSENTIAL ROLE OF NOCICEPTION IN PROTECTING AGAINST TISSUE DAMAGE. PATIENTS WITH GENETIC PAIN LOSS HAVE RECURRENT INJURIES, BURNS AND POORLY HEALING WOUNDS AS DISEASE HALLMARKS. CIP AND HSAN ARE CAUSED BY PATHOGENIC GENETIC VARIANTS IN >20 GENES THAT LEAD TO DEVELOPMENTAL DEFECTS, NEURODEGENERATION OR ALTERED NEURONAL EXCITABILITY OF PERIPHERAL DAMAGE-SENSING NEURONS. THESE GENETIC VARIANTS LEAD TO HYPERACTIVITY OF SODIUM CHANNELS, DISTURBED HAEM METABOLISM, ALTERED CLATHRIN-MEDIATED TRANSPORT AND IMPAIRED GENE REGULATORY MECHANISMS AFFECTING EPIGENETIC MARKS, LONG NON-CODING RNAS AND REPETITIVE ELEMENTS. THERAPIES FOR PAIN LOSS DISORDERS ARE MAINLY SYMPTOMATIC BUT THE FIRST TARGETED THERAPIES ARE BEING TESTED. CONVERSELY, CHRONIC PAIN REMAINS ONE OF THE GREATEST UNRESOLVED MEDICAL CHALLENGES, AND THE GENES AND MECHANISMS ASSOCIATED WITH PAIN LOSS OFFER NEW TARGETS FOR ANALGESICS. GIVEN THE PROGRESS THAT HAS BEEN MADE, THE COMING YEARS ARE PROMISING BOTH IN TERMS OF TARGETED TREATMENTS FOR PAIN LOSS DISORDERS AND THE DEVELOPMENT OF INNOVATIVE PAIN MEDICINES BASED ON KNOWLEDGE OF THESE GENETIC DISEASES. 2022 12 6534 70 TRANSCRIPTIONAL REGULATION OF NMDA RECEPTOR EXPRESSION. THE N-METHYL-D-ASPARTATE (NMDA) SUBTYPES OF GLUTAMATE RECEPTORS ARE INTIMATELY INVOLVED IN A NUMBER OF IMPORTANT NEURONAL ACTIVITIES IN MAMMALIAN NERVOUS SYSTEMS INCLUDING NEURONAL MIGRATION, SYNAPTOGENESIS, NEURONAL PLASTICITY, NEURONAL SURVIVAL, AND EXCITOTOXICITY. THROUGH THESE ACTIVITIES, NMDA RECEPTORS (NRS) PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF DRUG ADDICTION, PAIN PERCEPTION, AND THE PATHOGENESIS OF NEUROLOGICAL DISORDERS SUCH AS SCHIZOPHRENIA AND HUNTINGTON'S DISEASE [1-10]. IT IS GENERALLY BELIEVED THAT ABERRANT OR PATHOLOGICAL NR EFFECTS OCCUR MAINLY VIA ABNORMAL RECEPTOR ACTIVITY, RESULTING FROM ALTERED AVAILABILITY OF AGONISTS OR MODIFIED QUALITY OR QUANTITY OF MEMBRANE-ASSOCIATED RECEPTORS. IN MAMMALS, FUNCTIONAL NRS ARE HETEROTETRAMERS OF SUBUNITS ENCODED BY THREE GENE FAMILIES, I.E., NMDAR1 (NR1 OR GRIN1), NMDAR2 (NR2 OR GRIN2), AND NMDAR3 (NR3 OR GRIN3) [3,4,11]. THE NR1 FAMILY HAS ONE GENE; THE NR2 FAMILY HAS FOUR (DESIGNATED A THROUGH D); AND THE NR3 FAMILY HAS TWO (A AND B). STRUCTURALLY, NR1 IS AN ESSENTIAL COMPONENT FOUND IN ALL TETRAMERS, WHILE DIFFERENT NR2 MEMBERS ARE INCORPORATED BASED ON AGE AND NERVOUS SYSTEM REGION. NR3 PROTEINS FUNCTION AS NEGATIVE COMPONENTS WHEN INCLUDED IN THE STRUCTURES [3,4,11,12]. EIGHT VARIANTS OF NR1 PROTEIN ARE PRODUCED BY ALTERNATIVE SPLICING AND DISTRIBUTED DIFFERENTIALLY IN NERVOUS SYSTEMS [13-15]. THIS COMPLEX COMPOSITION OF DIFFERENT SUBUNITS AND SPLICING VARIANTS FORMS THE PRIMARY BASIS OF THE FUNCTIONAL DIVERSITY OF NRS. FROM JANUARY 1992 TO JUNE 2007, MORE THAN 1000 RESEARCH ARTICLES RELEVANT TO NR EXPRESSION WERE PUBLISHED. IN SUM, THEY CONCLUDED THAT THE EXPRESSION OF NR GENES IS CELL- OR TISSUE-SPECIFIC, RELATIVELY STABLE, AND REGULATED DIFFERENTIALLY BY VARIOUS PHYSIOLOGICAL, PHARMACOLOGICAL, AND PATHOLOGICAL FACTORS. MOST OF THESE CONCLUSIONS WERE BASED ON ASSESSMENTS OF CHANGES OF THE STEADY STATE LEVELS OF MRNA AND PROTEIN THAT MAY BE DRIVEN BY NUMEROUS SOPHISTICATED MECHANISMS. TRANSCRIPTION IS THE INITIAL STEP AND GENERALLY THE MOST SENSITIVE TO CELLULAR NEEDS AND ENVIRONMENTAL CUES. THUS, IT SERVES AS A MAJOR MECHANISM CONTROLLING GENE EXPRESSION [16]. PRECISE SPATIAL AND TEMPORAL EXPRESSION OF A SELECTIVE SET OF GENES DETERMINES PHENOTYPIC DIFFERENCES AMONG DISTINCT TISSUES AND CELLS IN HIGHER EUKARYOTES [16-18]. IN THE CASE OF THE NR GENE FAMILIES, TRANSCRIPTION OF EACH SUBUNIT GENE IN A GIVEN NEURON OR CELL MUST BE COORDINATELY CONTROLLED BUT DIFFERENTIALLY RESPONSIVE TO CELL TYPE, DEVELOPMENTAL STAGE, AND ENVIRONMENTAL SIGNALS TO MAINTAIN HEALTHY CELLULAR FUNCTION. HOW THIS COORDINATED CONTROL TAKES PLACE IS AN IMPORTANT AND CHALLENGING QUESTION. THIS CHAPTER REVIEWS STUDIES THAT EXPLORE THE TRANSCRIPTIONAL CONTROL OF NR GENES. IT DISCUSSES STUDIES OF PROMOTER AND REGULATORY SEQUENCES, REGULATORY UNITS, DEVELOPMENTAL REGULATION, CELL TYPE SPECIFICITY, GROWTH FACTOR REGULATION, NEUROLOGICAL DISORDERS, AND EPIGENETIC MECHANISMS. 2009 13 78 39 A NEW MECHANISTIC APPROACH FOR THE TREATMENT OF CHRONIC NEUROPATHIC PAIN WITH NITROUS OXIDE INTEGRATED FROM A SYSTEMS BIOLOGY NARRATIVE REVIEW. THE LIMITATIONS OF THE CURRENTLY AVAILABLE TREATMENTS FOR CHRONIC NEUROPATHIC PAIN HIGHLIGHT THE NEED FOR SAFER AND MORE EFFECTIVE ALTERNATIVES. THE AUTHORS CARRIED OUT A FOCUSED REVIEW USING A SYSTEMS BIOLOGY APPROACH TO INTEGRATE THE COMPLEX MECHANISMS OF NOCICEPTION AND NEUROPATHIC PAIN, AND TO DECIPHER THE EFFECTS OF NITROUS OXIDE (N(2)O) ON THOSE PATHWAYS, BEYOND THE KNOWN EFFECT OF N(2)O ON N-METHYL-D-ASPARTATE RECEPTORS. THIS REVIEW IDENTIFIED A NUMBER OF POTENTIAL MECHANISMS BY WHICH N(2)O COULD IMPACT THE PROCESSES INVOLVED IN PERIPHERAL AND CENTRAL SENSITIZATION. IN THE ASCENDING PATHWAY, THE EFFECTS OF N(2)O INCLUDE ACTIVATING TWIK-RELATED K(+) CHANNEL 1 POTASSIUM CHANNELS ON FIRST-ORDER NEURONS, BLOCKING VOLTAGE-DEPENDENT CALCIUM CHANNELS TO ATTENUATE NEURONAL EXCITABILITY, ATTENUATING POSTSYNAPTIC GLUTAMATERGIC RECEPTOR ACTIVATION, AND POSSIBLY BLOCKING VOLTAGE-DEPENDENT SODIUM CHANNELS. IN THE DESCENDING PATHWAY, N(2)O INDUCES THE RELEASE OF ENDOGENOUS OPIOID LIGANDS AND STIMULATES NOREPINEPHRINE RELEASE. IN ADDITION, N(2)O MAY MEDIATE EPIGENETIC CHANGES BY INHIBITING METHIONINE SYNTHASE, A KEY ENZYME INVOLVED IN DNA AND RNA METHYLATION. THIS COULD EXPLAIN WHY THIS SHORT-ACTING ANALGESIC HAS SHOWN LONG-LASTING ANTI-PAIN SENSITIZATION EFFECTS IN ANIMAL MODELS OF CHRONIC PAIN. THESE NEW HYPOTHESES SUPPORT THE RATIONALE FOR INVESTIGATING N(2)O, EITHER ALONE OR IN COMBINATION WITH OTHER ANALGESICS, FOR THE MANAGEMENT OF CHRONIC NEUROPATHIC PAIN. 2021 14 6846 44 [MIGRAINE: IGNITION OF THE BRAIN]. ALTHOUGH OUR KNOWLEDGE OF WHICH SYSTEMS ARE ACTIVATED DURING MIGRAINE IS REASONABLY COMPLETE, WHY THE SYSTEM IS ACTIVATED REMAINS UNKNOWN. INCORPORATING THE FINDINGS OBTAINED IN STUDIES ON PAIN IN GENERAL HAS ALLOWED A MORE INTEGRATED MODEL TO BE GENERATED. ACCORDING TO THIS NEW MODEL, THERE IS AN ANATOMICAL SUBSTRATE CONSISTING IN A COMPLEX FRAMEWORK OF PAIN THAT IS MADE UP NOT ONLY OF THE TRIGEMINOVASCULAR SYSTEM (END PATHWAY) BUT OF A NUMBER OF NETWORKS THAT ARE IN TURN CONNECTED TO ONE ANOTHER, LIKE THE NEUROLIMBIC, THE ASCENDING AND DESCENDING MODULATORY SYSTEM. THIS COMPLEX NETWORK IS RESPONSIBLE FOR MODULATING AND CONVEYING NOCICEPTIVE SIGNALS. IN PATIENTS WITH MIGRAINE, HYPEREXCITABILITY OF THIS FRAMEWORK IS CONDITIONED BY GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS AFFECTING CHROMATIN, WHICH MODULATES THE ACTIVITY OF GENES WITHOUT MODIFYING THE DNA SEQUENCE, AND WHICH ARE CAPABLE OF MODULATING THE EXPRESSION OF GENES INVOLVED IN A NUMBER OF DIFFERENT ASPECTS, SUCH AS PLASTICITY, SYSTEM EXCITABILITY, MEMORY OF PAIN OR MOODS. IN TURN, THE PRESENCE OF EXTERNAL FACTORS (SUCH AS ENVIRONMENTAL CHANGES OR ALCOHOL) AND INTERNAL FACTORS (SUCH AS HORMONES OR SLEEP DISORDERS) CONTRIBUTE TO ACTIVATE THIS LOADED ANATOMICAL SUBSTRATE, RESULTING IN THE ATTACK OF MIGRAINE. 2013 15 789 54 CELLULAR AND MOLECULAR MECHANISMS DRIVING NEUROPATHIC PAIN: RECENT ADVANCEMENTS AND CHALLENGES. CURRENT PHARMACOTHERAPEUTICS FOR NEUROPATHIC PAIN OFFER ONLY SYMPTOMATIC RELIEF WITHOUT TREATING THE UNDERLYING PATHOPHYSIOLOGY. ADDITIONALLY, THEY ARE ASSOCIATED WITH VARIOUS DOSE-LIMITING SIDE EFFECTS. PAIN RESEARCH IN THE PAST FEW DECADES HAS REVOLVED AROUND THE ROLE OF OXIDATIVE-NITROSATIVE STRESS, PROTEIN KINASES, GLIAL CELL ACTIVATION, AND INFLAMMATORY SIGNALING CASCADES BUT HAS FAILED TO PRODUCE SPECIFIC AND EFFECTIVE THERAPIES. AREAS COVERED: THIS REVIEW FOCUSES ON RECENT ADVANCES IN CELLULAR AND MOLECULAR MECHANISMS OF NEUROPATHIC PAIN THAT MAY BE TRANSLATED INTO FUTURE THERAPIES. WE DISCUSS EMERGING TARGETS SUCH AS WNT SIGNALING MECHANISMS, THE TETRAHYDROBIOPTERIN PATHWAY, MRG RECEPTORS, ENDOGENOUS LIPID MEDIATORS, MICRO-RNAS AND THEIR ROLES IN PAIN REGULATION. RECENT EVIDENCE IS ALSO PRESENTED REGARDING GENETIC AND EPIGENETIC MECHANISMS OF PAIN MODULATION. EXPERT OPINION: DURING CHRONIC NEUROPATHIC PAIN, MALADAPTATION OCCURS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, INCLUDING A SHIFT IN MICROGLIAL PHENOTYPE FROM A SURVEILLANCE STATE TO AN ACTIVATED STATE. MICROGLIAL ACTIVATION LEADS TO AN ALTERED EXPRESSION OF CELL SURFACE PROTEINS, GROWTH FACTORS, AND INTRACELLULAR SIGNALING MOLECULES THAT CONTRIBUTE TO DEVELOPMENT OF A NEUROINFLAMMATORY CASCADE AND CHRONIC PAIN SENSITIZATION. SPECIFIC TARGETING OF THESE CELLULAR AND MOLECULAR MECHANISMS MAY PROVIDE THE KEY TO DEVELOPMENT OF EFFECTIVE NEUROPATHIC PAIN THERAPIES THAT HAVE MINIMAL SIDE EFFECTS. 2018 16 6300 44 THE PUTATIVE ROLE OF ENVIRONMENTAL ALUMINIUM IN THE DEVELOPMENT OF CHRONIC NEUROPATHOLOGY IN ADULTS AND CHILDREN. HOW STRONG IS THE EVIDENCE AND WHAT COULD BE THE MECHANISMS INVOLVED? THE CONCEPTUALISATION OF AUTISTIC SPECTRUM DISORDER AND ALZHEIMER'S DISEASE HAS UNDERGONE SOMETHING OF A PARADIGM SHIFT IN RECENT YEARS AND RATHER THAN BEING VIEWED AS SINGLE ILLNESSES WITH A UNITARY PATHOGENESIS AND PATHOPHYSIOLOGY THEY ARE INCREASINGLY CONSIDERED TO BE HETEROGENEOUS SYNDROMES WITH A COMPLEX MULTIFACTORIAL AETIOPATHOGENESIS, INVOLVING A HIGHLY COMPLEX AND DIVERSE COMBINATION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ONE SUCH ENVIRONMENTAL FACTOR IMPLICATED AS A POTENTIAL CAUSE IN BOTH SYNDROMES IS ALUMINIUM, AS AN ELEMENT OR AS PART OF A SALT, RECEIVED, FOR EXAMPLE, IN ORAL FORM OR AS AN ADJUVANT. SUCH ADMINISTRATION HAS THE POTENTIAL TO INDUCE PATHOLOGY VIA SEVERAL ROUTES SUCH AS PROVOKING DYSFUNCTION AND/OR ACTIVATION OF GLIAL CELLS WHICH PLAY AN INDISPENSABLE ROLE IN THE REGULATION OF CENTRAL NERVOUS SYSTEM HOMEOSTASIS AND NEURODEVELOPMENT. OTHER ROUTES INCLUDE THE GENERATION OF OXIDATIVE STRESS, DEPLETION OF REDUCED GLUTATHIONE, DIRECT AND INDIRECT REDUCTIONS IN MITOCHONDRIAL PERFORMANCE AND INTEGRITY, AND INCREASING THE PRODUCTION OF PROINFLAMMATORY CYTOKINES IN BOTH THE BRAIN AND PERIPHERALLY. THE MECHANISMS WHEREBY ENVIRONMENTAL ALUMINIUM COULD CONTRIBUTE TO THE DEVELOPMENT OF THE HIGHLY SPECIFIC PATTERN OF NEUROPATHOLOGY SEEN IN ALZHEIMER'S DISEASE ARE DESCRIBED. ALSO DETAILED ARE SEVERAL MECHANISMS WHEREBY SIGNIFICANT QUANTITIES OF ALUMINIUM INTRODUCED VIA IMMUNISATION COULD PRODUCE CHRONIC NEUROPATHOLOGY IN GENETICALLY SUSCEPTIBLE CHILDREN. ACCORDINGLY, IT IS RECOMMENDED THAT THE USE OF ALUMINIUM SALTS IN IMMUNISATIONS SHOULD BE DISCONTINUED AND THAT ADULTS SHOULD TAKE STEPS TO MINIMISE THEIR EXPOSURE TO ENVIRONMENTAL ALUMINIUM. 2017 17 2176 32 EPIGENETIC MECHANISMS OF CHRONIC PAIN. NEUROPATHIC AND INFLAMMATORY PAIN PROMOTE A LARGE NUMBER OF PERSISTING ADAPTATIONS AT THE CELLULAR AND MOLECULAR LEVEL, ALLOWING EVEN TRANSIENT TISSUE OR NERVE DAMAGE TO ELICIT CHANGES IN CELLS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC PAIN AND ASSOCIATED SYMPTOMS. THERE IS EVIDENCE THAT INJURY-INDUCED CHANGES IN CHROMATIN STRUCTURE DRIVE STABLE CHANGES IN GENE EXPRESSION AND NEURAL FUNCTION, WHICH MAY CAUSE SEVERAL SYMPTOMS, INCLUDING ALLODYNIA, HYPERALGESIA, ANXIETY, AND DEPRESSION. RECENT FINDINGS ON EPIGENETIC CHANGES IN THE SPINAL CORD AND BRAIN DURING CHRONIC PAIN MAY GUIDE FUNDAMENTAL ADVANCES IN NEW TREATMENTS. HERE, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETIC REGULATION IN THE NERVOUS SYSTEM AND THEN DISCUSS THE STILL-LIMITED LITERATURE THAT DIRECTLY IMPLICATES EPIGENETIC MODIFICATIONS IN CHRONIC PAIN SYNDROMES. 2015 18 2000 30 EPIGENETIC AND NON-CODING REGULATION OF ALCOHOL ABUSE AND ADDICTION. ALCOHOL USE DISORDER IS A CHRONIC DEBILITATED CONDITION ADVERSELY AFFECTING THE LIVES OF MILLIONS OF INDIVIDUALS THROUGHOUT THE MODERN WORLD. INDIVIDUALS SUFFERING FROM AN ALCOHOL USE DISORDER DIAGNOSIS FREQUENTLY HAVE SERIOUS COOCCURRING CONDITIONS, WHICH OFTEN FURTHER EXACERBATES PROBLEMATIC DRINKING BEHAVIOR. COMPREHENDING THE BIOCHEMICAL PROCESSES UNDERLYING THE PROGRESSION AND PERPETUATION OF DISEASE IS ESSENTIAL FOR MITIGATING MALADAPTIVE BEHAVIOR IN ORDER TO RESTORE BOTH PHYSIOLOGICAL AND PSYCHOLOGICAL HEALTH. THE RANGE OF CELLULAR AND BIOLOGICAL SYSTEMS CONTRIBUTING TO, AND AFFECTED BY, ALCOHOL USE DISORDER AND OTHER COMORBID DISORDERS NECESSITATES A FUNDAMENTAL GRASP OF INTRICATE FUNCTIONAL RELATIONSHIPS THAT GOVERN MOLECULAR BIOLOGY. EPIGENETIC FACTORS ARE RECOGNIZED AS ESSENTIAL MEDIATORS OF CELLULAR BEHAVIOR, ORCHESTRATING A SYMPHONY OF GENE EXPRESSION CHANGES WITHIN MULTICELLULAR ENVIRONMENTS THAT ARE ULTIMATELY RESPONSIBLE FOR DIRECTING HUMAN BEHAVIOR. UNDERSTANDING THE EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISMS INVOLVED IN THE PATHOGENESIS OF DISEASE IS IMPORTANT FOR IMPROVING AVAILABLE PHARMACOTHERAPIES AND REDUCING THE INCIDENCE OF ALCOHOL ABUSE AND COOCCURRING CONDITIONS. 2021 19 677 37 BRAIN CIRCUITS AT RISK IN PSYCHIATRIC DISEASES AND PHARMACOLOGICAL PATHWAYS. THE MULTIPLE BRAIN CIRCUITS INVOLVED IN PSYCHIATRIC DISEASES MAY APPEAR DAUNTING, BUT WE PREFER TO CONCENTRATE ON A SELECT FEW, WITH A PARTICULAR SENSITIVITY TO STRESS AND NEURODEVELOPMENTAL ISSUES, WITH A CLEAR PHARMACOTHERAPY. THIS REVIEW IS STRUCTURED AROUND 1. THE KEY CIRCUITS, THEIR ROLE IN HEALTH AND DISEASE, AND THE NEUROTRANSMITTERS MAINTAINING THEM, 2. THE INFLUENCE OF UPBRINGING, STRESS, CHRONOBIOLOGY, INFLAMMATION AND INFECTION, 3. THE GENETIC AND EPIGENETIC INFLUENCE ON THESE CIRCUITS, PARTICULARLY REGARDING COPY NUMBER VARIANTS AND NEURONAL PLASTICITY, 4. THE USE AND ABUSE OF PHARMACOLOGICAL AGENTS WITH THE PARTICULAR RISKS OF STRESS AND CHRONOBIOLOGY AT CRITICAL PERIODS. A MAJOR EMPHASIS IS PLACED ON THE LINKS BETWEEN HIPPOCAMPUS, PREFRONTAL CORTEX AND AMYGDALA/PERIAQUEDUCTAL GREY WHICH CONTROL SPECIFIC ASPECTS OF COGNITION, MOOD, PAIN AND EVEN VIOLENCE. SOME OF THE RESEARCH FINDINGS WERE FROM THE INNOVATIVE MEDICINE INITIATIVE (IMI) NEWMEDS, A 22MEURO ACADEMIC/INDUSTRIAL CONSORTIUM ON THE BRAIN CIRCUITS CRITICAL FOR PSYCHIATRIC DISEASE. 2021 20 6137 35 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION. 2022