1 5443 161 REPEATED METHAMPHETAMINE AND MODAFINIL INDUCE DIFFERENTIAL COGNITIVE EFFECTS AND SPECIFIC HISTONE ACETYLATION AND DNA METHYLATION PROFILES IN THE MOUSE MEDIAL PREFRONTAL CORTEX. METHAMPHETAMINE (METH) AND MODAFINIL ARE PSYCHOSTIMULANTS WITH DIFFERENT LONG-TERM COGNITIVE PROFILES: METH IS ADDICTIVE AND LEADS TO COGNITIVE DECLINE, WHEREAS MODAFINIL HAS LITTLE ABUSE LIABILITY AND IS A COGNITIVE ENHANCER. INCREASING EVIDENCE IMPLICATES EPIGENETIC MECHANISMS OF GENE REGULATION BEHIND THE LASTING CHANGES THAT DRUGS OF ABUSE AND OTHER PSYCHOTROPIC COMPOUNDS INDUCE IN THE BRAIN, LIKE THE CONTROL OF GENE EXPRESSION BY HISTONES 3 AND 4 TAILS ACETYLATION (H3AC AND H4AC) AND DNA CYTOSINE METHYLATION (5-MC). MICE WERE TREATED WITH A SEVEN-DAY REPEATED METH, MODAFINIL OR VEHICLE PROTOCOL AND EVALUATED IN THE NOVEL OBJECT RECOGNITION (NOR) TEST OR SACRIFICED 4DAYS AFTER LAST INJECTION FOR MOLECULAR ASSAYS. WE EVALUATED TOTAL H3AC, H4AC AND 5-MC LEVELS IN THE MEDIAL PREFRONTAL CORTEX (MPFC), H3AC AND H4AC PROMOTOR ENRICHMENT (CHIP) AND MRNA EXPRESSION (RT-PCR) OF NEUROTRANSMITTER SYSTEMS INVOLVED IN AROUSAL, WAKEFULNESS AND COGNITIVE CONTROL, LIKE DOPAMINERGIC (DRD1 AND DRD2), ALPHA-ADRENERGIC (ADRA1A AND ADRA1B), OREXINERGIC (HCRTR1 AND HCRTR2), HISTAMINERGIC (HRH1 AND HRH3) AND GLUTAMATERGIC (AMPA GRIA1 AND NMDA GRIN1) RECEPTORS. REPEATED METH AND MODAFINIL TREATMENT ELICITED DIFFERENT COGNITIVE OUTCOMES IN THE NOR TEST, WHERE MODAFINIL-TREATED MICE PERFORMED AS CONTROLS AND METH-TREATED MICE SHOWED IMPAIRED RECOGNITION MEMORY. METH-TREATED MICE ALSO SHOWED I) DECREASED LEVELS OF TOTAL H3AC AND H4AC, AND INCREASED LEVELS OF 5-MC, II) DECREASED H3AC ENRICHMENT AT PROMOTERS OF DRD2, HCRTR1/2, HRH1 AND GRIN1, AND INCREASED H4AC ENRICHMENT AT DRD1, HRH1 AND GRIN1, III) INCREASED MRNA OF DRD1A, GRIN1 AND GRIA1. MODAFINIL-TREATED MICE SHARED NONE OF THESE EFFECTS AND SHOWED INCREASED H3AC ENRICHMENT AND MRNA EXPRESSION AT ADRA1B. MODAFINIL AND METH SHOWED SIMILAR EFFECTS LINKED TO DECREASED H3AC IN HRH3, INCREASED H4AC IN HCRTR1, AND DECREASED MRNA EXPRESSION OF HCRTR2. THE SPECIFIC METH-INDUCED EPIGENETIC AND TRANSCRIPTIONAL CHANGES DESCRIBED HERE MAY BE RELATED TO THE LONG-TERM COGNITIVE DECLINE EFFECTS OF THE DRUG AND ITS DETRIMENTAL EFFECTS ON MPFC FUNCTION. THE LACK OF SIMILAR EPIGENETIC EFFECTS OF CHRONIC MODAFINIL ADMINISTRATION SUPPORTS THIS NOTION. 2018 2 6095 85 THE EFFECTS OF SINGLE-DOSE INJECTIONS OF MODAFINIL AND METHAMPHETAMINE ON EPIGENETIC AND FUNCTIONAL MARKERS IN THE MOUSE MEDIAL PREFRONTAL CORTEX: POTENTIAL ROLE OF DOPAMINE RECEPTORS. METH USE CAUSES NEUROADAPTATIONS THAT NEGATIVELY IMPACT THE PREFRONTAL CORTEX (PFC) LEADING TO ADDICTION AND ASSOCIATED COGNITIVE DECLINE IN ANIMALS AND HUMANS. IN CONTRAST, MODAFINIL ENHANCES COGNITION BY INCREASING PFC FUNCTION. ACCUMULATED EVIDENCE INDICATES THAT PSYCHOSTIMULANT DRUGS, INCLUDING MODAFINIL AND METH, REGULATE GENE EXPRESSION VIA EPIGENETIC MODIFICATIONS. IN THIS STUDY, WE MEASURED THE EFFECTS OF SINGLE-DOSE INJECTIONS OF MODAFINIL AND METH ON THE PROTEIN LEVELS OF ACETYLATED HISTONE H3 (H3AC) AND H4AC, DEACETYLASES HDAC1 AND HDAC2, AND OF THE NMDA SUBUNIT GLUN1 IN THE MEDIAL PFC (MPFC) OF MICE EUTHANIZED 1 H AFTER DRUG ADMINISTRATION. TO TEST IF DOPAMINE (DA) RECEPTORS (DRS) PARTICIPATE IN THE BIOCHEMICAL EFFECTS OF THE TWO DRUGS, WE INJECTED THE D1RS ANTAGONIST, SCH23390, OR THE D2RS ANTAGONIST, RACLOPRIDE, 30 MIN BEFORE ADMINISTRATION OF METH AND MODAFINIL. WE EVALUATED EACH DRUG EFFECT ON GLUTAMATE SYNAPTIC TRANSMISSION IN D1R-EXPRESSING LAYER V PYRAMIDAL NEURONS. WE ALSO MEASURED THE ENRICHMENT OF H3AC AND H4AC AT THE PROMOTERS OF SEVERAL GENES INCLUDING DA, NE, OREXIN, HISTAMINE, AND GLUTAMATE RECEPTORS, AND THEIR MRNA EXPRESSION, SINCE THEY ARE RESPONSIVE TO CHRONIC MODAFINIL AND METH TREATMENT. ACUTE MODAFINIL AND METH INJECTIONS CAUSED SIMILAR EFFECTS ON TOTAL HISTONE ACETYLATION, INCREASING H3AC AND DECREASING H4AC, AND THEY ALSO INCREASED HDAC1, HDAC2 AND GLUN1 PROTEIN LEVELS IN THE MOUSE MPFC. IN ADDITION, THE EFFECTS OF THE DRUGS WERE PREVENTED BY PRE-TREATMENT WITH D1RS AND D2RS ANTAGONISTS. SPECIFICALLY, THE CHANGES IN H4AC, HDAC2, AND GLUN1 WERE RESPONSIVE TO SCH23390, WHEREAS THOSE OF H3AC AND GLUN1 WERE RESPONSIVE TO RACLOPRIDE. WHOLE-CELL PATCH CLAMP IN TRANSGENIC BAC-DRD1A-TDTOMATO MICE SHOWED THAT METH, BUT NOT MODAFINIL, INDUCED PAIRED-PULSE FACILITATION OF EPSCS, SUGGESTING REDUCED PRESYNAPTIC PROBABILITY OF GLUTAMATE RELEASE ONTO LAYER V PYRAMIDAL NEURONS. ANALYSIS OF HISTONE 3/4 ENRICHMENT AT SPECIFIC PROMOTERS REVEALED: I) DISTINCT EFFECTS OF THE DRUGS ON HISTONE 3 ACETYLATION, WITH MODAFINIL INCREASING H3AC AT DRD1 AND ADRA1B PROMOTERS, BUT METH INCREASING H3AC AT ADRA1A; II) DISTINCT EFFECTS ON HISTONE 4 ACETYLATION ENRICHMENT, WITH MODAFINIL INCREASING H4AC AT THE DRD2 PROMOTER AND DECREASING IT AT HRH1, BUT METH INCREASING H4AC AT DRD1; III) COMPARABLE EFFECTS OF BOTH PSYCHOSTIMULANTS, INCREASING H3AC AT DRD2, HCRTR1, AND HRH1 PROMOTERS, DECREASING H3AC AT HRH3, INCREASING H4AC AT HCRTR1, AND DECREASING H4AC AT HCRTR2, HRH3, AND GRIN1 PROMOTERS. INTERESTINGLY, ONLY METH ALTERED MRNA LEVELS OF GENES WITH ALTERED HISTONE ACETYLATION STATUS, INDUCING INCREASED EXPRESSION OF DRD1A, ADRA1A, HCRTR1, AND HRH1, AND DECREASING GRIN1. OUR STUDY SUGGESTS THAT ALTHOUGH ACUTE METH AND MODAFINIL CAN BOTH INCREASE DA NEUROTRANSMISSION IN THE MPFC, THERE ARE SIMILAR AND CONTRASTING EPIGENETIC AND TRANSCRIPTIONAL CONSEQUENCES THAT MAY ACCOUNT FOR THEIR DIVERGENT CLINICAL EFFECTS. 2019 3 3312 41 HIPPOCAMPAL AND BEHAVIORAL DYSFUNCTIONS IN A MOUSE MODEL OF ENVIRONMENTAL STRESS: NORMALIZATION BY AGOMELATINE. STRESS-INDUCED ALTERATIONS IN NEURONAL PLASTICITY AND IN HIPPOCAMPAL FUNCTIONS HAVE BEEN SUGGESTED TO BE INVOLVED IN THE DEVELOPMENT OF MOOD DISORDERS. IN THIS CONTEXT, WE INVESTIGATED IN THE HIPPOCAMPUS THE ACTIVATION OF INTRACELLULAR SIGNALING CASCADES, THE EXPRESSION OF EPIGENETIC MARKERS AND PLASTICITY-RELATED GENES IN A MOUSE MODEL OF STRESS-INDUCED HYPERACTIVITY AND OF MIXED AFFECTIVE DISORDERS. WE ALSO DETERMINED WHETHER THE ANTIDEPRESSANT DRUG AGOMELATINE, A MT1/MT2 MELATONERGIC RECEPTOR AGONIST/5-HT2C RECEPTOR ANTAGONIST, COULD PREVENT SOME NEUROBIOLOGICAL AND BEHAVIORAL ALTERATIONS PRODUCED BY STRESS. C57BL/6J MICE, EXPOSED FOR 3 WEEKS TO DAILY UNPREDICTABLE SOCIO-ENVIRONMENTAL STRESSORS OF MILD INTENSITY, WERE TREATED DURING THE WHOLE PROCEDURE WITH AGOMELATINE (50 MG KG(-1) PER DAY, INTRAPERITONEAL). STRESSED MICE DISPLAYED ROBUST INCREASES IN EMOTIONAL AROUSAL, VIGILANCE AND MOTOR ACTIVITY, TOGETHER WITH A REWARD DEFICIT AND A REDUCTION IN ANXIETY-LIKE BEHAVIOR. NEUROBIOLOGICAL INVESTIGATIONS SHOWED AN INCREASED PHOSPHORYLATION OF INTRACELLULAR SIGNALING PROTEINS, INCLUDING ATF1, CREB AND P38, IN THE HIPPOCAMPUS OF STRESSED MICE. DECREASED HIPPOCAMPAL LEVEL OF THE REPRESSIVE EPIGENETIC MARKS HDAC2 AND H3K9ME2, AS WELL AS INCREASED LEVEL OF THE PERMISSIVE MARK H3K9/14AC SUGGESTED THAT CHRONIC MILD STRESS WAS ASSOCIATED WITH INCREASED GENE TRANSCRIPTION, AND CLEAR-CUT EVIDENCE WAS FURTHER INDICATED BY CHANGES IN NEUROPLASTICITY-RELATED GENES, INCLUDING ARC, BCL2, BDNF, GDNF, IGF1 AND NEUROD1. TOGETHER WITH OTHER FINDINGS, THE PRESENT DATA SUGGEST THAT CHRONIC ULTRA-MILD STRESS CAN MODEL THE HYPERACTIVITY OR PSYCHOMOTOR AGITATION, AS WELL AS THE MIXED AFFECTIVE BEHAVIORS OFTEN OBSERVED DURING THE MANIC STATE OF BIPOLAR DISORDER PATIENTS. INTERESTINGLY, AGOMELATINE COULD NORMALIZE BOTH THE BEHAVIORAL AND THE MOLECULAR ALTERATIONS INDUCED BY STRESS, PROVIDING FURTHER INSIGHTS INTO THE MECHANISM OF ACTION OF THIS NEW GENERATION ANTIDEPRESSANT DRUG. 2014 4 5967 37 TERMINATION OF ACUTE STRESS RESPONSE BY THE ENDOCANNABINOID SYSTEM IS REGULATED THROUGH LYSINE-SPECIFIC DEMETHYLASE 1-MEDIATED TRANSCRIPTIONAL REPRESSION OF 2-AG HYDROLASES ABHD6 AND MAGL. ACUTE ENVIRONMENTAL STRESS RARELY IMPLIES LONG-LASTING NEUROPHYSIOLOGICAL AND BEHAVIORAL ALTERATIONS. ON THE CONTRARY, CHRONIC STRESS EXERTS A POTENT TOXIC EFFECT AT THE GLUTAMATERGIC SYNAPSE WHOSE ALTERED PHYSIOLOGY HAS BEEN RECOGNIZED AS A CORE TRAIT OF NEUROPSYCHIATRIC DISORDERS. THE ENDOCANNABINOID SYSTEM (ECS) PLAYS AN IMPORTANT ROLE IN THE HOMEOSTATIC RESPONSE TO ACUTE STRESS. IN PARTICULAR, STRESS INDUCES SYNTHESIS OF ENDOCANNABINOID (ECB) 2-ARACHIDONYL GLYCEROL (2-AG). 2-AG STIMULATES PRESYNAPTIC CANNABINOID 1 (CB1) RECEPTOR CONTRIBUTING TO STRESS RESPONSE TERMINATION THROUGH INHIBITION OF GLUTAMATE RELEASE, RESTRAINING THEREAFTER ANXIETY AROUSAL. WE EMPLOY MOUSE MODELS OF STRESS RESPONSE COUPLED TO GENE EXPRESSION ANALYSES, UNRAVELLING THAT IN RESPONSE TO ACUTE PSYCHOSOCIAL STRESS IN THE MOUSE HIPPOCAMPUS, ECS-MEDIATED SYNAPTIC MODULATION IS ENHANCED VIA TRANSCRIPTIONAL REPRESSION OF TWO ENZYMES INVOLVED IN 2-AG DEGRADATION: ALPHA/BETA-HYDROLASE DOMAIN CONTAINING 6 (ABHD6) AND MONOACYLGLYCEROL LIPASE (MAGL). SUCH A PROCESS IS ORCHESTRATED BY THE EPIGENETIC COREPRESSOR LSD1 WHO DIRECTLY INTERACTS WITH PROMOTER REGULATORY REGIONS OF ABHD6 AND MAGL. REMARKABLY, NEGATIVE TRANSCRIPTIONAL CONTROL OF ABHD6 AND MAGL IS LOST IN THE HIPPOCAMPUS UPON CHRONIC PSYCHOSOCIAL STRESS, POSSIBLY CONTRIBUTING TO TRAUMA-INDUCED DRIFT OF SYNAPSE PHYSIOLOGY TOWARD UNCONTROLLED GLUTAMATE TRANSMISSION. WE PREVIOUSLY SHOWED THAT IN MICE LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INCREASES ITS HIPPOCAMPAL EXPRESSION IN RESPONSE TO PSYCHOSOCIAL STRESS PREVENTING EXCESSIVE CONSOLIDATION OF ANXIETY-RELATED PLASTICITY. IN THIS WORK, WE UNRAVEL A NODAL EPIGENETIC MODULATION OF ECB TURN OVER, SHEDDING NEW LIGHT ON THE MOLECULAR SUBSTRATE OF CONVERGING STRESS-TERMINATING EFFECTS DISPLAYED BY ECS AND LSD1. 2020 5 869 36 CHRONIC AGOMELATINE TREATMENT CORRECTS BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES INDUCED BY PRENATAL STRESS IN RATS. RATIONALE AND OBJECTIVES: THE RAT MODEL OF PRENATAL RESTRAINT STRESS (PRS) REPLICATES FACTORS THAT ARE IMPLICATED IN THE ETIOLOGY OF ANXIOUS/DEPRESSIVE DISORDERS. WE USED THIS MODEL TO TEST THE THERAPEUTIC EFFICACY OF AGOMELATINE, A NOVEL ANTIDEPRESSANT THAT BEHAVES AS A MIXED MT1/MT2 MELATONIN RECEPTOR AGONIST/5-HT(2C) SEROTONIN RECEPTOR ANTAGONIST. RESULTS: ADULT PRS RATS SHOWED BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES THAT WERE CONSISTENT WITH AN ANXIOUS/DEPRESSIVE PHENOTYPE. THESE INCLUDED AN INCREASED IMMOBILITY IN THE FORCED SWIM TEST, AN ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE, REDUCED HIPPOCAMPAL LEVELS OF PHOSPHORYLATED CAMP-RESPONSIVE ELEMENT BINDING PROTEIN (P-CREB), REDUCED HIPPOCAMPAL LEVELS OF MGLU2/3 AND MGLU5 METABOTROPIC GLUTAMATE RECEPTORS, AND REDUCED NEUROGENESIS IN THE VENTRAL HIPPOCAMPUS, THE SPECIFIC PORTION OF THE HIPPOCAMPUS THAT ENCODES MEMORIES RELATED TO STRESS AND EMOTIONS. ALL OF THESE CHANGES WERE REVERSED BY A 3- OR 6-WEEK TREATMENT WITH AGOMELATINE (40-50 MG/KG, I.P., ONCE A DAY). REMARKABLY, AGOMELATINE HAD NO EFFECT IN AGE-MATCHED CONTROL RATS, THEREBY BEHAVING AS A "DISEASE-DEPENDENT" DRUG. CONCLUSIONS: THESE DATA INDICATE THAT AGOMELATINE DID NOT ACT ON INDIVIDUAL SYMPTOMS BUT CORRECTED ALL ASPECTS OF THE PATHOLOGICAL EPIGENETIC PROGRAMMING TRIGGERED BY PRS. OUR FINDINGS STRONGLY SUPPORT THE ANTIDEPRESSANT ACTIVITY OF AGOMELATINE AND SUGGEST THAT THE DRUG IMPACTS MECHANISMS THAT LIE AT THE CORE OF ANXIOUS/DEPRESSIVE DISORDERS. 2011 6 5729 31 SLEEP, SLEEP HOMEOSTASIS AND AROUSAL DISTURBANCES IN ALCOHOLISM. THE EFFECTS OF ALCOHOL ON HUMAN SLEEP WERE FIRST DESCRIBED ALMOST 70 YEARS AGO. SINCE THEN, ACCUMULATING EVIDENCES SUGGEST THAT ALCOHOL INTAKE AT BED TIME IMMEDIATELY INDUCES SLEEP [REDUCES THE TIME TO FALL ASLEEP (SLEEP ONSET LATENCY), AND CONSOLIDATES AND ENHANCES THE QUALITY (DELTA POWER) AND THE QUANTITY OF SLEEP]. SUCH POTENT SLEEP PROMOTING ACTIVITY MAKES ALCOHOL AS ONE OF THE MOST COMMONLY USED "OVER THE COUNTER" SLEEP AID. HOWEVER, THE SOMNOGENIC EFFECTS, AFTER ALCOHOL INTAKE, SLOWLY WANE OFF AND OFTEN FOLLOWED BY SLEEP DISRUPTIONS DURING THE REST OF THE NIGHT. REPEATED USE OF ALCOHOL LEADS TO THE DEVELOPMENT OF RAPID TOLERANCE RESULTING INTO AN ALCOHOL ABUSE. MOREOVER, CHRONIC AND EXCESSIVE ALCOHOL INTAKE LEADS TO THE DEVELOPMENT OF ALCOHOL USE DISORDER (AUD). ALCOHOLICS, BOTH DURING DRINKING PERIODS AND DURING ABSTINENCES, SUFFER FROM A MULTITUDE OF SLEEP DISRUPTIONS MANIFESTED BY PROFOUND INSOMNIA, EXCESSIVE DAYTIME SLEEPINESS, AND ALTERED SLEEP ARCHITECTURE. FURTHERMORE, SUBJECTIVE AND OBJECTIVE INDICATORS OF SLEEP DISTURBANCES ARE PREDICTORS OF RELAPSE. FINALLY, WITHIN THE USA, IT IS ESTIMATED THAT SOCIETAL COSTS OF ALCOHOL-RELATED SLEEP DISORDERS EXCEED $18 BILLION. THUS, ALTHOUGH ALCOHOL ASSOCIATED SLEEP PROBLEMS HAVE SIGNIFICANT ECONOMIC AND CLINICAL CONSEQUENCES, VERY LITTLE IS KNOWN ABOUT HOW AND WHERE ALCOHOL ACTS TO AFFECT SLEEP. IN THIS REVIEW, A CONCEPTUAL FRAMEWORK AND CLINICAL RESEARCH FOCUSED ON UNDERSTANDING THE RELATIONSHIP BETWEEN ALCOHOL AND SLEEP IS FIRST DESCRIBED. IN THE NEXT SECTION, OUR NEW AND EXCITING PRECLINICAL STUDIES, TO UNDERSTAND THE CELLULAR AND MOLECULAR MECHANISM OF HOW ACUTE AND CHRONIC ALCOHOL AFFECTS SLEEP, ARE DESCRIBED. IN THE END, BASED ON OBSERVATIONS FROM OUR RECENT FINDINGS AND RELATED LITERATURE, OPPORTUNITIES FOR THE DEVELOPMENT OF INNOVATIVE STRATEGIES TO PREVENT AND TREAT AUD ARE PROPOSED. 2022 7 747 31 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE. 2021 8 949 40 CHRONIC METHAMPHETAMINE TREATMENT REDUCES THE EXPRESSION OF SYNAPTIC PLASTICITY GENES AND CHANGES THEIR DNA METHYLATION STATUS IN THE MOUSE BRAIN. METHAMPHETAMINE (METH) IS A HIGHLY ADDICTIVE PSYCHOSTIMULANT THAT MAY CAUSE LONG-LASTING SYNAPTIC DYSFUNCTION AND ABNORMAL GENE EXPRESSION. WE AIMED TO EXPLORE THE DIFFERENTIAL EXPRESSION OF SYNAPTIC PLASTICITY GENES IN CHRONIC METH-TREATED MOUSE BRAIN. WE USED THE RT(2) PROFILER PCR ARRAY AND THE REAL-TIME QUANTITATIVE PCR TO CHARACTERIZE DIFFERENTIALLY EXPRESSED SYNAPTIC PLASTICITY GENES IN THE FRONTAL CORTEX AND THE HIPPOCAMPUS OF CHRONIC METH-TREATED MICE COMPARED WITH NORMAL SALINE-TREATED MICE. WE FURTHER USED PYROSEQUENCING TO ASSESS DNA METHYLATION CHANGES IN THE CPG REGION OF THE FIVE IMMEDIATE EARLY GENES (IEGS) IN CHRONIC METH-TREATED MOUSE BRAIN. WE DETECTED SIX DOWNREGULATED GENES IN THE FRONTAL CORTEX AND THE HIPPOCAMPUS OF CHRONIC METH-TREATED MICE, INCLUDING FIVE IEGS (ARC, EGR2, FOS, KLF10, AND NR4A1) AND ONE NEURONAL RECEPTOR GENE (GRM1), COMPARED WITH NORMAL SALINE-TREATED GROUP, BUT ONLY FOUR GENES (ARC, EGR2, FOS, AND NR4A1) WERE CONFIRMED TO BE DIFFERENT. FURTHERMORE, WE FOUND SEVERAL CPG SITES OF THE ARC AND THE FOS THAT HAD SIGNIFICANT CHANGES IN DNA METHYLATION STATUS IN THE FRONTAL CORTEX OF CHRONIC METH-TREATED MICE, WHILE THE KLF10 AND THE NR4A1 THAT HAD SIGNIFICANT CHANGES IN THE HIPPOCAMPUS. OUR RESULTS SHOW THAT CHRONIC ADMINISTRATION OF METH MAY LEAD TO SIGNIFICANT DOWNREGULATION OF THE IEGS EXPRESSION IN BOTH THE FRONTAL CORTEX AND THE HIPPOCAMPUS, WHICH MAY PARTLY ACCOUNT FOR THE MOLECULAR MECHANISM OF THE ACTION OF METH. FURTHERMORE, THE CHANGES IN DNA METHYLATION STATUS OF THE IEGS IN THE BRAIN INDICATE THAT AN EPIGENETIC MECHANISM-DEPENDENT TRANSCRIPTIONAL REGULATION MAY CONTRIBUTE TO METH ADDICTION, WHICH WARRANTS ADDITIONAL STUDY. 2015 9 4212 40 METHAMPHETAMINE DOWNREGULATES STRIATAL GLUTAMATE RECEPTORS VIA DIVERSE EPIGENETIC MECHANISMS. BACKGROUND: CHRONIC METHAMPHETAMINE (METH) EXPOSURE CAUSES NEUROADAPTATIONS AT GLUTAMATERGIC SYNAPSES. METHODS: TO IDENTIFY THE METH-INDUCED EPIGENETIC UNDERPINNINGS OF THESE NEUROADAPTATIONS, WE INJECTED INCREASING METH DOSES TO RATS FOR 2 WEEKS AND MEASURED STRIATAL GLUTAMATE RECEPTOR EXPRESSION. WE THEN QUANTIFIED THE EFFECTS OF METH EXPOSURE ON HISTONE ACETYLATION. WE ALSO MEASURED METH-INDUCED CHANGES IN DNA METHYLATION AND DNA HYDROXYMETHYLATION. RESULTS: CHRONIC METH DECREASED TRANSCRIPT AND PROTEIN EXPRESSION OF GLUA1 AND GLUA2 ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC ACID RECEPTOR (AMPAR) AND GLUN1 N-METHYL-D-ASPARTATE RECEPTOR SUBUNITS. THESE CHANGES WERE ASSOCIATED WITH ALTERED ELECTROPHYSIOLOGICAL GLUTAMATERGIC RESPONSES IN STRIATAL NEURONS. CHROMATIN IMMUNOPRECIPITATION-POLYMERASE CHAIN REACTION REVEALED THAT METH DECREASED ENRICHMENT OF ACETYLATED HISTONE H4 ON GLUA1, GLUA2, AND GLUN1 PROMOTERS. METHAMPHETAMINE EXPOSURE ALSO INCREASED REPRESSOR ELEMENT-1 SILENCING TRANSCRIPTION FACTOR (REST) COREPRESSOR 1, METHYLATED CPG BINDING PROTEIN 2, AND HISTONE DEACETYLASE 2 ENRICHMENT, BUT NOT OF SIRTUIN 1 OR SIRTUIN 2, ONTO GLUA1 AND GLUA2 GENE SEQUENCES. MOREOVER, METH CAUSED INTERACTIONS OF REST COREPRESSOR 1 AND METHYLATED CPG BINDING PROTEIN 2 WITH HISTONE DEACETYLASE 2 AND OF REST WITH HISTONE DEACETYLASE 1. SURPRISINGLY, METHYLATED DNA IMMUNOPRECIPITATION AND HYDROXYMETHYLATED DNA IMMUNOPRECIPITATION-POLYMERASE CHAIN REACTION REVEALED METH-INDUCED DECREASED ENRICHMENT OF 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE AT GLUA1 AND GLUA2 PROMOTER SEQUENCES. IMPORTANTLY, THE HISTONE DEACETYLASE INHIBITOR, VALPROIC ACID, BLOCKED METH-INDUCED DECREASED EXPRESSION OF AMPAR AND N-METHYL-D-ASPARTATE RECEPTOR SUBUNITS. FINALLY, VALPROIC ACID ALSO ATTENUATED METH-INDUCED DECREASE H4K16AC RECRUITMENT ON AMPAR GENE SEQUENCES. CONCLUSIONS: THESE OBSERVATIONS SUGGEST THAT HISTONE H4 HYPOACETYLATION MAY BE THE MAIN DETERMINANT OF METH-INDUCED DECREASED STRIATAL GLUTAMATE RECEPTOR EXPRESSION. 2014 10 1818 35 EFFECTS OF CHRONIC METHAMPHETAMINE EXPOSURE ON REWARDING BEHAVIOR AND NEURODEGENERATION MARKERS IN ADULT MICE. RECREATIONAL AND MEDICAL USE OF STIMULANTS AMONG YOUNG ADULTS HAVE GAINED POPULARITY IN THE UNITED STATES OVER THE LAST DECADE AND THEIR USE MAY INCREASE VULNERABILITY TO BRAIN BIOCHEMICAL CHANGES AND ADDICTIVE BEHAVIORS. THE LONG-TERM EFFECTS OF CHRONIC STIMULANT EXPOSURE IN LATER ADULTHOOD HAVE NOT BEEN FULLY ELUCIDATED.OUR STUDY INVESTIGATED WHETHER CHRONIC EXPOSURE TO METHAMPHETAMINE (METH), AT A DOSE DESIGNED TO EMULATE HUMAN THERAPEUTIC DOSING FOR ADHD, WOULD PROMOTE BIOCHEMICAL ALTERATIONS AND AFFECT SENSITIVITY TO THE REWARDING EFFECTS OF SUBSEQUENT METH DOSING.GROUPS OF 3.5-MONTH-OLD MALE AND FEMALE C57BL/6J MICE WERE ADMINISTERED NON-CONTINGENT INTRAPERITONEAL INJECTIONS OF EITHER SALINE OR METH (1.4 MG/KG) TWICE A DAY FOR 1 MONTH (5 DAYS/WEEK). METH (0.5 MG/KG)-INDUCED CONDITIONED PLACE PREFERENCE (CPP) WAS TESTED IN MICE TO DETERMINE THE EFFECTS OF PREVIOUS METH EXPOSURE ON REWARD-RELATED BEHAVIOR. MICE WERE RANDOMLY ASSIGNED TO EXPERIMENT I (MALES AND FEMALES) OR EXPERIMENT II (FEMALES ONLY) IN WHICH CPP TESTING WAS RESPECTIVELY PERFORMED EITHER 0.5 OR 5 MONTHS AFTER THE END OF METH INJECTIONS, AT ~5 OR 10 MONTHS OLD RESPECTIVELY. THE MIDBRAIN AND STRIATUM, REGIONS INVOLVED IN REWARD CIRCUIT, WERE ASSESSED FOR MARKERS ASSOCIATED WITH NEUROTOXICITY, DOPAMINERGIC FUNCTION, NEUROINFLAMMATION AND EPIGENETIC CHANGES AFTER BEHAVIORAL TESTING.PREVIOUS EXPOSURE TO CHRONIC METH DID NOT HAVE SIGNIFICANT SHORT-TERM EFFECTS ON CPP RESPONSE BUT LED TO A DECREASED CPP RESPONSE IN 10-MONTH-OLD FEMALES. PREVIOUS EXPOSURE TO METH INDUCED SOME SHORT-TERM CHANGES TO BIOCHEMICAL MARKERS MEASURED IN A BRAIN REGION AND SEX-DEPENDENT MANNER, WHILE LONG-TERM CHANGES WERE ONLY OBSERVED WITH GFAP AND KDM5C.IN CONCLUSION, OUR DATA SUGGEST SEX- AND POST-EXPOSURE DURATION-DEPENDENT OUTCOMES AND WARRANT FURTHER EXPLORATION OF THE LONG-TERM NEUROBEHAVIORAL CONSEQUENCES OF PSYCHOSTIMULANT USE IN BOTH SEXES. 2023 11 1884 27 ENDOCANNABINOID-EPIGENETIC CROSS-TALK: A BRIDGE TOWARD STRESS COPING. THERE IS NO ARGUMENT WITH REGARD TO THE PHYSICAL AND PSYCHOLOGICAL STRESS-RELATED NATURE OF NEUROPSYCHIATRIC DISORDERS. YET, THE MECHANISMS THAT FACILITATE DISEASE ONSET STARTING FROM MOLECULAR STRESS RESPONSES ARE ELUSIVE. ENVIRONMENTAL STRESS CHALLENGES INDIVIDUALS' EQUILIBRIUM, ENHANCING HOMEOSTATIC REQUEST IN THE ATTEMPT TO STEER DOWN AROUSAL-INSTRUMENTAL MOLECULAR PATHWAYS THAT UNDERLIE HYPERVIGILANCE AND ANXIETY. A RELEVANT HOMEOSTATIC PATHWAY IS THE ENDOCANNABINOID SYSTEM (ECS). IN THIS REVIEW, WE SUMMARIZE RECENT DISCOVERIES UNAMBIGUOUSLY LISTING ECS AS A STRESS COPING MECHANISM. AS STRESS EVOKES HUGE EXCITATORY RESPONSES IN EMOTIONAL-RELEVANT LIMBIC AREAS, THE ECS LIMITS GLUTAMATE RELEASE VIA 2-ARACHYDONILGLYCEROL (2-AG) STRESS-INDUCED SYNTHESIS AND RETROGRADE CANNABINOID 1 (CB1)-RECEPTOR ACTIVATION AT THE SYNAPSE. HOWEVER, ECS SHOWS INTRINSIC VULNERABILITY AS 2-AG OVERSTIMULATION BY CHRONIC STRESS RAPIDLY LEADS TO CB1-RECEPTOR DESENSITIZATION. IN THIS REVIEW, WE EMPHASIZE THE PROTECTIVE ROLE OF 2-AG IN STRESS-RESPONSE TERMINATION AND STRESS RESILIENCY. INTERESTINGLY, WE DISCUSS ECS REGULATION WITH A FURTHER NUCLEAR HOMEOSTATIC SYSTEM WHOSE NATURE IS EXQUISITELY EPIGENETIC, ORCHESTRATED BY LYSINE SPECIFIC DEMETHYLASE 1. WE HERE EMPHASIZE A REMARKABLE EXAMPLE OF STRESS-COPING NETWORK WHERE TRANSCRIPTIONAL HOMEOSTASIS SUBSERVES SYNAPTIC AND BEHAVIORAL ADAPTATION, AIMING AT REDUCING PSYCHIATRIC EFFECTS OF TRAUMATIC EXPERIENCES. 2020 12 3377 23 HISTORICAL APPROACH AND EVOLUTION OF THE STRESS CONCEPT: A PERSONAL ACCOUNT. AS A MATTER OF RESEARCH OR AS A PROCESS, STRESS REMAINS ONE OF THE MOST CITED CONSTRUCT IN BIOMEDICAL LITERATURE; A MEDLINE SURVEY ACCOUNTS FOR MORE THAN 210,000 CITATIONS SINCE 1970. IT IS DIFFICULT TO DEFINE. IT IS FREQUENTLY USED IN A VAGUE MANNER, INCLUDING UNDIFFERENTLY THE AGENT, THE PROCESS, AND THE RESPONSE. THE CONCEPT IS MULTIDIMENSIONAL AND COMPOSITE, INCLUDING EMOTION AND AROUSAL. STRESS HAS AN IMPLICIT: IT IMPLIES ALTERATION OF A THEORETICAL BALANCE OR EQUILIBRIUM WITHIN PHYSIOLOGICAL SYSTEMS, AND IT SEEMS TO CHARACTERIZE A PROCESS LEADING TO DISEASE. LARGE INDIVIDUAL DIFFERENCES EXIST IN THE WAY TO REACT TO A STRESSOR. PSYCHOLOGICAL AND COGNITIVE DETERMINANTS ARE CENTRAL FOR THE COURSE OF THE PROCESS. THE HOMEOSTASIS CONCEPT IS NOT USEFUL ANYMORE AND HAS BEEN REPLACED BY THE MORE ACCURATE AND FLEXIBLE CONCEPT OF ALLOSTASIS. THE PHYSIOLOGICAL HORMONAL AND NEURAL BASES OF THIS PROCESS ARE NOW IDENTIFIED. NEW PERSPECTIVES IDENTIFY STRESSORS, CHRONIC OR NOT, TO BE A SOURCE OF VULNERABILITIES THROUGH EPIGENETIC MECHANISMS AND A SERIES OF BIOBEHAVIORAL DISORDERS CHARACTERISTIC OF OUR MODERN CIVILIZATIONS. THE EVOLUTION OF THE CONCEPT IS NOT LINEAR. IT HAS BEEN ENRICHED BY RECENT NEUROBIOLOGICAL-NEUROENDOCRINOLOGICAL DISCOVERIES AND ALSO BY BEHAVIORAL-COGNITIVE SCIENCES. 2007 13 6108 39 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS. 2019 14 2123 43 EPIGENETIC IMPACTS OF STRESS PRIMING OF THE NEUROINFLAMMATORY RESPONSE TO SARIN SURROGATE IN MICE: A MODEL OF GULF WAR ILLNESS. BACKGROUND: GULF WAR ILLNESS (GWI) IS AN ARCHETYPAL, MEDICALLY UNEXPLAINED, CHRONIC CONDITION CHARACTERISED BY PERSISTENT SICKNESS BEHAVIOUR AND NEUROIMMUNE AND NEUROINFLAMMATORY COMPONENTS. AN ESTIMATED 25-32% OF THE OVER 900,000 VETERANS OF THE 1991 GULF WAR FULFIL THE REQUIREMENTS OF A GWI DIAGNOSIS. IT HAS BEEN HYPOTHESISED THAT THE HIGH PHYSICAL AND PSYCHOLOGICAL STRESS OF COMBAT MAY HAVE INCREASED VULNERABILITY TO IRREVERSIBLE ACETYLCHOLINESTERASE (ACHE) INHIBITORS LEADING TO A PRIMING OF THE NEUROIMMUNE SYSTEM. A NUMBER OF STUDIES HAVE LINKED HIGH LEVELS OF PSYCHOPHYSIOLOGICAL STRESS AND TOXICANT EXPOSURES TO EPIGENETIC MODIFICATIONS THAT REGULATE GENE EXPRESSION. RECENT RESEARCH IN A MOUSE MODEL OF GWI HAS SHOWN THAT PRE-EXPOSURE WITH THE STRESS HORMONE CORTICOSTERONE (CORT) CAUSES AN INCREASE IN EXPRESSION OF SPECIFIC CHEMOKINES AND CYTOKINES IN RESPONSE TO DIISOPROPYL FLUOROPHOSPHATE (DFP), A SARIN SURROGATE AND IRREVERSIBLE ACHE INHIBITOR. METHODS: C57BL/6J MICE WERE EXPOSED TO CORT FOR 4 DAYS, AND EXPOSED TO DFP ON DAY 5, BEFORE SACRIFICE 6 H LATER. THE TRANSCRIPTOME WAS EXAMINED USING RNA-SEQ, AND THE EPIGENOME WAS EXAMINED USING REDUCED REPRESENTATION BISULFITE SEQUENCING AND H3K27AC CHIP-SEQ. RESULTS: WE SHOW TRANSCRIPTIONAL, HISTONE MODIFICATION (H3K27AC) AND DNA METHYLATION CHANGES IN GENES RELATED TO THE IMMUNE AND NEURONAL SYSTEM, POTENTIALLY RELEVANT TO NEUROINFLAMMATORY AND COGNITIVE SYMPTOMS OF GWI. FURTHER EVIDENCE SUGGESTS ALTERED PROPORTIONS OF MYELINATING OLIGODENDROCYTES IN THE FRONTAL CORTEX, PERHAPS CONNECTED TO WHITE MATTER DEFICITS SEEN IN GWI SUFFERERS. CONCLUSIONS: OUR FINDINGS MAY REFLECT THE EARLY CHANGES WHICH OCCURRED IN GWI VETERANS, AND WE OBSERVE ALTERATIONS IN SEVERAL PATHWAYS ALTERED IN GWI SUFFERERS. THESE CLOSE LINKS TO CHANGES SEEN IN VETERANS WITH GWI INDICATES THAT THIS MODEL REFLECTS THE ENVIRONMENTAL EXPOSURES RELATED TO GWI AND MAY PROVIDE A MODEL FOR BIOMARKER DEVELOPMENT AND TESTING FUTURE TREATMENTS. 2018 15 3177 35 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE. 2021 16 1761 36 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS. 2013 17 4848 34 OPIOID-INDUCED STRUCTURAL AND FUNCTIONAL PLASTICITY OF MEDIUM-SPINY NEURONS IN THE NUCLEUS ACCUMBENS. OPIOID USE DISORDER (OUD) IS A CHRONIC RELAPSING CLINICAL CONDITION WITH TREMENDOUS MORBIDITY AND MORTALITY THAT FREQUENTLY PERSISTS, DESPITE TREATMENT, DUE TO AN INDIVIDUAL'S UNDERLYING PSYCHOLOGICAL, NEUROBIOLOGICAL, AND GENETIC VULNERABILITIES. EVIDENCE SUGGESTS THAT THESE VULNERABILITIES MAY HAVE NEUROCHEMICAL, CELLULAR, AND MOLECULAR BASES. KEY NEUROPLASTIC EVENTS WITHIN THE MESOCORTICOLIMBIC SYSTEM THAT EMERGE THROUGH CHRONIC EXPOSURE TO OPIOIDS MAY HAVE A DETERMINATIVE INFLUENCE ON BEHAVIORAL SYMPTOMS ASSOCIATED WITH OUD. IN PARTICULAR, STRUCTURAL AND FUNCTIONAL ALTERATIONS IN THE DENDRITIC SPINES OF MEDIUM SPINY NEURONS (MSNS) WITHIN THE NUCLEUS ACCUMBENS (NAC) AND ITS DOPAMINERGIC PROJECTIONS FROM THE VENTRAL TEGMENTAL AREA (VTA) ARE BELIEVED TO FACILITATE THESE BEHAVIORAL SEQUELAE. ADDITIONALLY, GLUTAMATERGIC NEURONS FROM THE PREFRONTAL CORTEX, THE BASOLATERAL AMYGDALA, THE HIPPOCAMPUS, AND THE THALAMUS PROJECT TO THESE SAME MSNS, PROVIDING AN ENRICHED TARGET FOR SYNAPTIC PLASTICITY. HERE, WE REVIEW LITERATURE RELATED TO NEUROADAPTATIONS IN NAC MSNS FROM DOPAMINERGIC AND GLUTAMATERGIC PATHWAYS IN OUD. WE ALSO DESCRIBE NEW FINDINGS RELATED TO TRANSCRIPTIONAL, EPIGENETIC, AND MOLECULAR MECHANISMS IN MSN PLASTICITY IN THE DIFFERENT STAGES OF OUD. 2021 18 3977 38 LONG-TERM EFFECT OF POST-TRAUMATIC STRESS IN ADOLESCENCE ON DENDRITE DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN MALE RAT HIPPOCAMPUS AND PREFRONTAL CORTEX. EXPOSURE TO A HARSH ENVIRONMENT IN EARLY LIFE INCREASES IN THE RISK OF POST-TRAUMATIC STRESS DISORDER (PTSD) OF AN INDIVIDUAL. BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) PLAYS AN IMPORTANT ROLE IN NEURODEVELOPMENT IN DEVELOPMENTAL STAGES. BOTH CHRONIC AND TRAUMATIC STRESSES INDUCE A DECREASE IN THE LEVEL OF BDNF AND REDUCE NEURAL PLASTICITY, WHICH IS LINKED TO THE PATHOGENESIS OF PTSD. ALSO, STUDIES HAVE SHOWN THAT STRESS ALTERS THE EPIGENETIC MARKER H3K9ME2, WHICH CAN BIND TO THE PROMOTER REGION OF THE BDNF GENE AND REDUCE BDNF PROTEIN LEVEL. HOWEVER, THE LONG-TERM EFFECTS OF TRAUMATIC STRESS DURING ADOLESCENCE ON H3K9ME2, BDNF EXPRESSION AND DENDRITE DEVELOPMENT ARE NOT WELL-KNOWN. THE PRESENT STUDY ESTABLISHED A MODEL OF PTSD IN ADOLESCENT RATS USING AN INESCAPABLE FOOT SHOCK (IFS) PROCEDURE. ANXIETY-LIKE BEHAVIORS, SOCIAL INTERACTION BEHAVIOR AND MEMORY FUNCTION WERE ASSESSED BY THE OPEN FIELD TEST, ELEVATED PLUS MAZE TEST, THREE-CHAMBER SOCIABILITY TEST AND MORRIS WATER MAZE TEST. IN ADDITION, NEURONAL DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN HIPPOCAMPUS (HIP) AND PREFRONTAL CORTEX (PFC) WERE EVALUATED BY GOLGI STAINING, WESTERN BLOTTING, QRT-PCR ANALYSIS AND CHIP-QPCR ANALYSIS. ADDITIONALLY, THE UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (EHMT2) WAS USED FOR INTERVENTION. THE RESULTS SHOWED THAT THE IFS PROCEDURE INDUCED THE PTSD-LIKE BEHAVIORS IN RATS, RESULTED IN FEWER DENDRITE BRANCHES AND SHORTER DENDRITE LENGTH IN CA1 OF HIP AND PFC, INCREASED H3K9ME2 LEVEL AND DECREASED BDNF EXPRESSION IN HIP AND PFC. ALSO, ALTHOUGH ALL THE CHANGES CAN PERSIST TO ADULTHOOD, UNC0642 ADMINISTRATION RELIEVED MOST OF ALTERATIONS. OUR STUDY SUGGESTS THAT TRAUMATIC STRESS IN ADOLESCENCE LEADS TO IMMEDIATE AND LONG-TERM MENTAL DISORDERS, NEURONAL MORPHOLOGICAL CHANGES, LOWER BDNF LEVEL AND INCREASED H3K9ME2 LEVEL IN THE HIP AND PFC, INDICATING THAT H3K9ME2/BDNF DYSFUNCTION PLAYS A KEY ROLE IN PATHOGENESIS OF PTSD. 2020 19 265 42 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 3973 37 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008