1 4212 117 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 2 5502 30 RGFP109, A HISTONE DEACETYLASE INHIBITOR ATTENUATES L-DOPA-INDUCED DYSKINESIA IN THE MPTP-LESIONED MARMOSET: A PROOF-OF-CONCEPT STUDY. BACKGROUND: L-3,4-DIHYDROXYPHENYLALANINE (L-DOPA)-INDUCED DYSKINESIA (LID) ARE A COMPLICATION OF CHRONIC DOPAMINE REPLACEMENT THERAPY IN PARKINSON'S DISEASE (PD). RECENT STUDIES HAVE SUGGESTED THAT THE MECHANISMS UNDERLYING DEVELOPMENT AND EXPRESSION OF LID IN PD MAY INVOLVE EPIGENETIC CHANGES THAT INCLUDE DEACETYLATION OF STRIATAL HISTONE PROTEINS. WE HYPOTHESISED THAT INHIBITION OF HISTONE DEACETYLASE, THE ENZYME RESPONSIBLE OF HISTONE DEACETYLATION, WOULD ALLEVIATE LID. METHODS: FOUR FEMALE COMMON MARMOSET (CALLITHRIX JACCHUS) WERE RENDERED PARKINSONIAN BY ADMINISTRATION OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP). FOLLOWING STABILISATION OF THE PARKINSONIAN PHENOTYPE, MARMOSETS WERE PRIMED TO EXHIBIT DYSKINESIA WITH CHRONIC ADMINISTRATION OF L-DOPA. WE THEN INVESTIGATED THE EFFECTS OF THE BRAIN-PENETRANT HISTONE DEACETYLASE INHIBITOR, RGFP109 (30 MG/KG P.O. ONCE DAILY FOR 6 DAYS), ON LID AND L-DOPA ANTI-PARKINSONIAN EFFICACY. RESULTS: RGFP109 HAD NO ACUTE EFFECTS ON DYSKINESIA AFTER SINGLE OR 6 DAYS ONCE-DAILY TREATMENT (BOTH P > 0.05). HOWEVER, ONE WEEK FOLLOWING CESSATION OF RGFP109, DYSKINESIA AND DURATION OF ON-TIME WITH DISABLING DYSKINESIA WERE REDUCED BY 37% AND 50%, RESPECTIVELY (BOTH P < 0.05), COMPARED TO THAT SEEN PREVIOUSLY WITH L-DOPA ALONE. THERE WAS NO CHANGE IN ANTI-PARKINSONIAN ACTIONS OF, OR ON-TIME DURATION AFFORDED BY, L-DOPA (P > 0.05). CONCLUSIONS: HISTONE DEACETYLATION INHIBITION MAY REPRESENT A NOVEL APPROACH TO REVERSE ESTABLISHED LID IN PD AND IMPROVE QUALITY OF THE ANTI-PARKINSONIAN BENEFIT PROVIDED BY L-DOPA. 2013 3 5838 31 STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE THE SENSITIVITY TO SOCIAL DEFEAT STRESS IN MICE THROUGH EPIGENETIC REGULATION. THE GLOBAL NUMBER OF PATIENTS WITH DEPRESSION INCREASES IN CORRELATION TO EXPOSURE TO SOCIAL STRESS. CHRONIC STRESS DOES NOT TRIGGER DEPRESSION IN ALL INDIVIDUALS, AS SOME REMAIN RESILIENT. THE UNDERLYING MOLECULAR MECHANISMS THAT CONTRIBUTE TO STRESS SENSITIVITY HAVE BEEN POORLY UNDERSTOOD, ALTHOUGH REVEALING THE REGULATION OF STRESS SENSITIVITY COULD HELP DEVELOP TREATMENTS FOR DEPRESSION. WE PREVIOUSLY FOUND THAT STRIATAL SHATI/NAT8L, AN N-ACETYLTRANSFERASE, WAS INCREASED IN A DEPRESSION MOUSE MODEL. WE INVESTIGATED THE ROLES OF SHATI/NAT8L IN STRESS SENSITIVITY IN MICE AND FOUND THAT SHATI/NAT8L AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS IN THE DORSAL STRIATUM WERE INCREASED IN STRESS-SUSCEPTIBLE MICE BUT NOT IN RESILIENT MICE EXPOSED TO REPEATED SOCIAL DEFEAT STRESS (RSDS). KNOCKDOWN OF SHATI/NAT8L IN THE DORSAL STRIATUM INDUCED RESILIENCE TO RSDS. IN ADDITION, BLOCKADE OF BDNF SIGNALING IN THE DORSAL STRIATUM BY ANA-12, A BDNF-SPECIFIC RECEPTOR TROPOMYOSIN-RECEPTOR-KINASE B (TRKB) INHIBITOR, ALSO INDUCED RESILIENCE TO STRESS. SHATI/NAT8L IS CORRELATED WITH BDNF EXPRESSION AFTER RSDS, AND BDNF IS DOWNSTREAM OF SHATI/NAT8L PATHWAYS IN THE DORSAL STRIATUM; SHATI/NAT8L IS EPIGENETICALLY REGULATED BY BDNF VIA HISTONE ACETYLATION. OUR RESULTS DEMONSTRATE THAT STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE STRESS SENSITIVITY THROUGH EPIGENETIC REGULATION. THE STRIATAL SHATI/NAT8L-BDNF PATHWAY COULD BE A NOVEL TARGET FOR TREATMENTS OF DEPRESSION AND COULD ESTABLISH A NOVEL THERAPEUTIC STRATEGY FOR DEPRESSION PATIENTS. 2021 4 5018 32 PERSISTENT INFLAMMATION-INDUCED UP-REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTES SYNAPTIC DELIVERY OF ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTOR GLUA1 SUBUNITS IN DESCENDING PAIN MODULATORY CIRCUITS. THE ENHANCED AMPA RECEPTOR PHOSPHORYLATION AT GLUA1 SERINE 831 SITES IN THE CENTRAL PAIN-MODULATING SYSTEM PLAYS A PIVOTAL ROLE IN DESCENDING PAIN FACILITATION AFTER INFLAMMATION, BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. WE SHOW HERE THAT, IN THE RAT BRAIN STEM, IN THE NUCLEUS RAPHE MAGNUS, WHICH IS A CRITICAL RELAY IN THE DESCENDING PAIN-MODULATING SYSTEM OF THE BRAIN, PERSISTENT INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND ADJUVANT (CFA) CAN ENHANCE AMPA RECEPTOR-MEDIATED EXCITATORY POSTSYNAPTIC CURRENTS AND THE GLUA2-LACKING AMPA RECEPTOR-MEDIATED RECTIFICATION INDEX. WESTERN BLOT ANALYSIS SHOWED AN INCREASE IN GLUA1 PHOSPHORYLATION AT SER-831 BUT NOT AT SER-845. THIS WAS ACCOMPANIED BY AN INCREASE IN DISTRIBUTION OF THE SYNAPTIC GLUA1 SUBUNIT. IN PARALLEL, THE LEVEL OF HISTONE H3 ACETYLATION AT BDNF GENE PROMOTER REGIONS WAS REDUCED SIGNIFICANTLY 3 DAYS AFTER CFA INJECTION, AS INDICATED BY CHIP ASSAYS. THIS WAS CORRELATED WITH AN INCREASE IN BDNF MRNA LEVELS AND BDNF PROTEIN LEVELS. SEQUESTERING ENDOGENOUS EXTRACELLULAR BDNF WITH TRKB-IGG IN THE NUCLEUS RAPHE MAGNUS DECREASED AMPA RECEPTOR-MEDIATED SYNAPTIC TRANSMISSION AND GLUA1 PHOSPHORYLATION AT SER-831 3 DAYS AFTER CFA INJECTION. UNDER THE SAME CONDITIONS, BLOCKADE OF TRKB RECEPTOR FUNCTIONS, PHOSPHOLIPASE C, OR PKC IMPAIRED GLUA1 PHOSPHORYLATION AT SER-831 AND DECREASED EXCITATORY POSTSYNAPTIC CURRENTS MEDIATED BY GLUA2-LACKING AMPA RECEPTORS. TAKEN TOGETHER, THESE RESULTS SUGGEST THAT EPIGENETIC UP-REGULATION OF BDNF BY PERIPHERAL INFLAMMATION INDUCES GLUR1 PHOSPHORYLATION AT SER-831 SITES THROUGH ACTIVATION OF THE PHOSPHOLIPASE C-PKC SIGNALING CASCADE, LEADING TO THE TRAFFICKING OF GLUA1 TO PAIN-MODULATING NEURONAL SYNAPSES. 2014 5 5535 25 ROLE OF BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS IN RELAPSE TO COCAINE-SEEKING BEHAVIOR IN MICE. COCAINE ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER CHARACTERIZED BY COMPULSIVE DRUG SEEKING. PRELIMINARY STUDY SUGGESTED THAT BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC READER PROTEIN, PARTICIPATES IN COCAINE-INDUCED REWARD AND NEUROPLASTICITY. HOWEVER, THE EXACT ROLE OF BRD4 IN COCAINE ADDICTION, PARTICULARLY COCAINE RELAPSE, REMAINS ELUSIVE. IN THIS STUDY, WE FOUND THAT BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS (NAC) WAS CLOSELY RELATED TO THE MAINTENANCE OF COCAINE REINFORCEMENT AND RELAPSE IN DIFFERENT COCAINE EXPOSURE PARADIGMS. COCAINE SIGNIFICANTLY INCREASED THE BINDING OF PHOSPHORYLATED BRD4 (PBRD4) AT THE PROMOTER OF GRIA2 AND BDNF GENES IN THE NAC. (+)JQ1, A SELECTIVE BRD4 INHIBITOR, MARKEDLY REDUCED THE REINFORCEMENT AND REINSTATEMENT OF COCAINE-SEEKING BEHAVIORS, WHICH WAS ACCOMPANIED BY THE DECREASED EXPRESSIONS OF GRIA2 AND BDNF. FURTHERMORE, CHROMATIN IMMUNOPRECIPITATION ASSAY SHOWED THAT (+)JQ1 CLEARLY ATTENUATED COCAINE-ENHANCED BINDING OF PBRD4 AT THE PROMOTOR OF GRIA2 AND BDNF GENES. BLOCKADE OF CASEIN KINASE II SIGNIFICANTLY ATTENUATED BRD4 PHOSPHORYLATION AND COCAINE RELAPSE-LIKE BEHAVIORS, SUGGESTING THE IMPORTANT ROLE OF PBRD4 IN MODULATING COCAINE EFFECT. TOGETHER, OUR FINDINGS SUGGEST THAT BRD4 PHOSPHORYLATION IN THE NAC MODULATES MULTIPLE ADDICTION-RELATED BEHAVIORS OF COCAINE AND PARTICULARLY RELAPSE TO COCAINE-SEEKING BEHAVIORS. INHIBITION OF BRD4 ACTIVITY MAY BE A NOVEL TARGET AGAINST COCAINE ADDICTION AND RELAPSE. 2020 6 856 23 CHROMATIN ACCESSIBILITY MAPPING OF THE STRIATUM IDENTIFIES TYROSINE KINASE FYN AS A THERAPEUTIC TARGET FOR HEROIN USE DISORDER. THE CURRENT OPIOID EPIDEMIC NECESSITATES A BETTER UNDERSTANDING OF HUMAN ADDICTION NEUROBIOLOGY TO DEVELOP EFFICACIOUS TREATMENT APPROACHES. HERE, WE PERFORM GENOME-WIDE ASSESSMENT OF CHROMATIN ACCESSIBILITY OF THE HUMAN STRIATUM IN HEROIN USERS AND MATCHED CONTROLS. OUR STUDY REVEALS DISTINCT NEURONAL AND NON-NEURONAL EPIGENETIC SIGNATURES, AND IDENTIFIES A LOCUS IN THE PROXIMITY OF THE GENE ENCODING TYROSINE KINASE FYN AS THE MOST AFFECTED REGION IN NEURONS. FYN EXPRESSION, KINASE ACTIVITY AND THE PHOSPHORYLATION OF ITS TARGET TAU ARE INCREASED BY HEROIN USE IN THE POST-MORTEM HUMAN STRIATUM, AS WELL AS IN RATS TRAINED TO SELF-ADMINISTER HEROIN AND PRIMARY STRIATAL NEURONS TREATED WITH CHRONIC MORPHINE IN VITRO. PHARMACOLOGICAL OR GENETIC MANIPULATION OF FYN ACTIVITY SIGNIFICANTLY ATTENUATES HEROIN SELF-ADMINISTRATION AND RESPONDING FOR DRUG-PAIRED CUES IN RODENTS. OUR FINDINGS SUGGEST THAT STRIATAL FYN IS AN IMPORTANT DRIVER OF HEROIN-RELATED NEURODEGENERATIVE-LIKE PATHOLOGY AND DRUG-TAKING BEHAVIOR, MAKING FYN A PROMISING THERAPEUTIC TARGET FOR HEROIN USE DISORDER. 2020 7 5021 33 PERSISTENT PAIN MAINTAINS MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL THROUGH REDUCED MECP2 REPRESSION OF GLUA1 IN RAT CENTRAL AMYGDALA. AS LONG-TERM OPIOIDS ARE INCREASINGLY USED FOR CONTROL OF CHRONIC PAIN, HOW PAIN AFFECTS THE REWARDING EFFECT OF OPIOIDS AND HENCE RISK OF PRESCRIPTION OPIOID MISUSE AND ABUSE REMAINS A HEALTHCARE CONCERN AND A CHALLENGING ISSUE IN CURRENT PAIN MANAGEMENT. IN THIS STUDY, USING A RAT MODEL OF MORPHINE SELF-ADMINISTRATION, WE INVESTIGATED THE MOLECULAR MECHANISMS UNDERLYING THE IMPACT OF PAIN ON OPERANT BEHAVIOR OF MORPHINE INTAKE AND MORPHINE SEEKING BEFORE AND AFTER MORPHINE WITHDRAWAL. WE FOUND THAT RATS WITH PERSISTENT PAIN CONSUMED A SIMILAR AMOUNT OF DAILY MORPHINE TO THAT IN CONTROL RATS WITHOUT PAIN, BUT MAINTAINED THEIR LEVEL-PRESSING BEHAVIOR OF MORPHINE SEEKING AFTER ABSTINENCE OF MORPHINE AT 0.2 MG/KG, WHEREAS THIS BEHAVIOR WAS GRADUALLY DIMINISHED IN CONTROL RATS. IN THE CENTRAL NUCLEUS OF AMYGDALA (CEA), A LIMBIC STRUCTURE CRITICALLY INVOLVED IN THE AFFECTIVE DIMENSION OF PAIN, PROTEINS OF GLUA1 SUBUNITS OF GLUTAMATE AMPA RECEPTORS WERE UPREGULATED DURING MORPHINE WITHDRAWAL, AND VIRAL KNOCKDOWN OF CEA GLUA1 ELIMINATED THE MORPHINE-SEEKING BEHAVIOR IN WITHDRAWN RATS OF THE PAIN GROUP. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT THE METHYL CPG-BINDING PROTEIN 2 (MECP2) WAS ENRICHED IN THE PROMOTER REGION OF GRIA1 ENCODING GLUA1 AND THIS ENRICHMENT WAS SIGNIFICANTLY ATTENUATED IN WITHDRAWN RATS OF THE PAIN GROUP. FURTHERMORE, VIRAL OVEREXPRESSION OF CEA MECP2 REPRESSED THE GLUA1 LEVEL AND ELIMINATED THE MAINTENANCE OF MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL. THESE RESULTS SUGGEST DIRECT MECP2 REPRESSION OF GLUA1 FUNCTION AS A LIKELY MECHANISM FOR MORPHINE-SEEKING BEHAVIOR MAINTAINED BY LONG-LASTING AFFECTIVE PAIN AFTER MORPHINE WITHDRAWAL. 2015 8 135 37 ABERRANT CPG METHYLATION MEDIATES ABNORMAL TRANSCRIPTION OF MAO-A INDUCED BY ACUTE AND CHRONIC L-3,4-DIHYDROXYPHENYLALANINE ADMINISTRATION IN SH-SY5Y NEURONAL CELLS. L-3,4-DIHYDROXYPHENYLALANINE (L-DOPA) REMAINS THE MOST EFFECTIVE DRUG FOR THERAPY OF PARKINSON'S DISEASE (PD); HOWEVER, LONG-TERM USE OF IT CAUSES SERIOUS SIDE EFFECTS. L-DOPA-INDUCED DYSKINESIA (LID) HAS CONSISTENTLY BEEN RELATED TO L-DOPA-DERIVED EXCESSIVE DOPAMINE RELEASE, BUT THE MECHANISMS HAVE NOT BEEN ADDRESSED VERY CLEAR. MONOAMINE OXIDASE A (MAO-A) IS ONE OF THE KEY ENZYMES IN DOPAMINE METABOLISM AND THEREFORE MAY BE INVOLVED IN L-DOPA-INDUCED SIDE EFFECTS. AND, EPIGENETIC MODIFICATION CONTROLS MAO-A GENE TRANSCRIPTION. TO INVESTIGATE THE EFFECTS OF L-DOPA ON MAO-A TRANSCRIPTION AND ITS UNDERLYING EPIGENETIC MECHANISM, NEURONAL SH-SY5Y CELLS WERE TREATED WITH L-DOPA FOR 24 H (ACUTE) AND FOR 7-21 DAYS (CHRONIC). RESULTS SHOWED THAT CHRONIC L-DOPA ADMINISTRATION RESULTED IN A DOSE-DEPENDENT AND TIME-DEPENDENT DOWNREGULATION OF MAO-A, WHEREAS ACUTE L-DOPA ADMINISTRATION INDUCED UPREGULATION OF MAO-A TRANSCRIPTION AND EXPRESSION. MEANWHILE, CHRONIC L-DOPA EXPOSURE INDUCED CPG HYPERMETHYLATION IN MAO-A PROMOTER, WHILE ACUTE L-DOPA ADMINISTRATION CAUSED CPG HYPOMETHYLATION. AND, CPG DEMETHYLATION RESULTED IN REACTIVATION OF MAO-A TRANSCRIPTION. THESE RESULTS INDICATED THAT ABERRANT CPG METHYLATION MIGHT PLAY A KEY ROLE IN MAO-A TRANSCRIPTIONAL MISREGULATION IN L-DOPA ADMINISTRATION. IN ADDITION, RESULTS SHOWED THAT ACUTE L-DOPA ADMINISTRATION INDUCED DOWNREGULATION OF DNA METHYLTRANSFERASE 3A (DNMT3A). TRANSCRIPTION OF TEN-ELEVEN TRANSLOCATION 1 (TET1) WERE SIGNIFICANTLY DOWNREGULATED IN CHRONIC L-DOPA ADMINISTRATION. THESE DATA INDICATED THAT IN CHRONIC L-DOPA ADMINISTRATION, TET1 DOWNREGULATION MIGHT MEDIATE CPG HYPERMETHYLATION, WHICH IS RESPONSIBLE FOR THE DOWNREGULATION OF MAO-A TRANSCRIPTION. IN CONTRAST, IN ACUTE L-DOPA ADMINISTRATION, DNMT3A DOWNREGULATION MIGHT MEDIATE HYPOMETHYLATION, CONTRIBUTING TO THE MAO-A UPREGULATION. IN CONCLUSION, OUR FINDINGS SUGGESTED THAT TET1 AND DNMTS MIGHT MEDIATE ABERRANT CPG METHYLATION, ASSOCIATED WITH THE MISREGULATION OF MAO-A IN L-DOPA ADMINISTRATION, WHICH MIGHT CONTRIBUTE TO DOPAMINE RELEASE ABNORMALLY LEADING TO THE SIDE EFFECTS OF L-DOPA. 2017 9 69 28 A MEDIAL PREFRONTAL CORTEX-NUCLEUS ACUMENS CORTICOTROPIN-RELEASING FACTOR CIRCUITRY FOR NEUROPATHIC PAIN-INCREASED SUSCEPTIBILITY TO OPIOID REWARD. RECENT STUDIES HAVE SHOWN THAT PERSISTENT PAIN FACILITATES THE RESPONSE TO MORPHINE REWARD. HOWEVER, THE CIRCUIT MECHANISM UNDERLYING THIS PROCESS REMAINS AMBIGUOUS. IN THIS STUDY, USING CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE IN MICE, WE FOUND THAT PERSISTENT NEUROPATHIC PAIN REDUCED THE MINIMUM NUMBER OF MORPHINE CONDITIONING SESSIONS REQUIRED TO INDUCE CONDITIONED PLACE PREFERENCE (CPP) BEHAVIOR. THIS DOSE OF MORPHINE HAD NO EFFECT ON THE PAIN THRESHOLD. IN THE MEDIAL PREFRONTAL CORTEX (MPFC), WHICH IS INVOLVED IN BOTH PAIN AND EMOTION PROCESSING, CORTICOTROPIN-RELEASING FACTOR (CRF) EXPRESSING NEURONAL ACTIVITY WAS INCREASED IN CCI MICE. CHEMOGENETIC INHIBITION OF MPFC CRF NEURONS REVERSED CCI-INDUCED MORPHINE CPP FACILITATION. FURTHERMORE, THE NUCLEUS ACUMENS (NAC) RECEIVED MPFC CRF FUNCTIONAL PROJECTIONS THAT EXERTED EXCITATORY EFFECTS ON NAC NEURONS. OPTOGENETIC INHIBITION OF MPCF NEURONAL TERMINALS OR LOCAL INFUSION OF THE CRF RECEPTOR 1 (CRFR1) ANTAGONIST IN THE NAC RESTORED THE EFFECTS OF NEUROPATHIC PAIN ON MORPHINE-INDUCED CPP BEHAVIOR, BUT NOT IN NORMAL MICE. ON A MOLECULAR LEVEL, IN CCI MICE, CRFR1 PROTEIN EXPRESSION WAS INCREASED IN THE NAC BY A HISTONE DIMETHYLTRANSFERASE G9A-MEDIATED EPIGENETIC MECHANISM. LOCAL G9A KNOCKDOWN INCREASED THE EXPRESSION OF CRFR1 AND MIMICKED CCI-INDUCED HYPERSENSITIVITY TO ACQUIRING MORPHINE CPP. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE A PREVIOUSLY UNKNOWN AND SPECIFIC MPFC CRF ENGAGEMENT OF NAC NEURONAL CIRCUITS, THE SENSITIZATION OF WHICH FACILITATES BEHAVIORAL RESPONSES TO MORPHINE REWARD IN NEUROPATHIC PAIN STATES VIA CRFR1S. 2018 10 2773 25 EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASES 1 AND 2 ACTIVATION BY ADDICTIVE DRUGS: A SIGNAL TOWARD PATHOLOGICAL ADAPTATION. ADDICTION IS A CHRONIC AND RELAPSING PSYCHIATRIC DISORDER THAT IS THOUGHT TO OCCUR IN VULNERABLE INDIVIDUALS. SYNAPTIC PLASTICITY EVOKED BY DRUGS OF ABUSE IN THE SO-CALLED NEURONAL CIRCUITS OF REWARD HAS BEEN PROPOSED TO UNDERLIE BEHAVIORAL ADAPTATIONS THAT CHARACTERIZE ADDICTION. BY INCREASING DOPAMINE IN THE STRIATUM, ADDICTIVE DRUGS ALTER THE BALANCE OF DOPAMINE AND GLUTAMATE SIGNALS CONVERGING ONTO STRIATAL MEDIUM-SIZED SPINY NEURONS (MSNS) AND ACTIVATE INTRACELLULAR EVENTS INVOLVED IN LONG-TERM BEHAVIORAL ALTERATIONS. OUR LABORATORY CONTRIBUTED TO THE IDENTIFICATION OF SALIENT MOLECULAR CHANGES INDUCED BY ADMINISTRATION OF ADDICTIVE DRUGS TO RODENTS. WE PIONEERED THE OBSERVATION THAT A COMMON FEATURE OF ADDICTIVE DRUGS IS TO ACTIVATE, BY A DOUBLE TYROSINE/THREONINE PHOSPHORYLATION, THE EXTRACELLULAR SIGNAL-REGULATED KINASES 1 AND 2 (ERK1/2) IN THE STRIATUM, WHICH CONTROL A PLETHORA OF SUBSTRATES, SOME OF THEM BEING CRITICALLY INVOLVED IN COCAINE-MEDIATED MOLECULAR AND BEHAVIORAL ADAPTATIONS. HEREIN, WE REVIEW HOW THE INTERPLAY BETWEEN DOPAMINE AND GLUTAMATE SIGNALING CONTROLS COCAINE-INDUCED ERK1/2 ACTIVATION IN MSNS. WE EMPHASIZE THE KEY ROLE OF N-METHYL-D-ASPARTATE RECEPTOR POTENTIATION BY D1 RECEPTOR TO TRIGGER ERK1/2 ACTIVATION AND ITS SUBSEQUENT NUCLEAR TRANSLOCATION WHERE IT MODULATES BOTH EPIGENETIC AND GENETIC PROCESSES ENGAGED BY COCAINE. WE DISCUSS HOW COCAINE-INDUCED LONG-TERM SYNAPTIC AND STRUCTURAL PLASTICITY OF MSNS, AS WELL AS BEHAVIORAL ADAPTATIONS, ARE INFLUENCED BY ERK1/2-CONTROLLED TARGETS. WE CONCLUDE THAT A BETTER KNOWLEDGE OF MOLECULAR MECHANISMS UNDERLYING ERK1/2 ACTIVATION BY DRUGS OF ABUSE AND/OR ITS ROLE IN LONG-TERM NEURONAL PLASTICITY IN THE STRIATUM MAY PROVIDE A NEW ROUTE FOR THERAPEUTIC TREATMENT IN ADDICTION. 2014 11 4878 36 OVEREXPRESSION OF THE HISTONE DIMETHYLTRANSFERASE G9A IN NUCLEUS ACCUMBENS SHELL INCREASES COCAINE SELF-ADMINISTRATION, STRESS-INDUCED REINSTATEMENT, AND ANXIETY. REPEATED EXPOSURE TO COCAINE INDUCES LASTING EPIGENETIC CHANGES IN NEURONS THAT PROMOTE THE DEVELOPMENT AND PERSISTENCE OF ADDICTION. ONE EPIGENETIC ALTERATION INVOLVES REDUCTIONS IN LEVELS OF THE HISTONE DIMETHYLTRANSFERASE G9A IN NUCLEUS ACCUMBENS (NAC) AFTER CHRONIC COCAINE ADMINISTRATION. THIS REDUCTION IN G9A MAY ENHANCE COCAINE REWARD BECAUSE OVEREXPRESSING G9A IN THE NAC DECREASES COCAINE-CONDITIONED PLACE PREFERENCE. THEREFORE, WE HYPOTHESIZED THAT HSV-MEDIATED G9A OVEREXPRESSION IN THE NAC SHELL (NACSH) WOULD ATTENUATE COCAINE SELF-ADMINISTRATION (SA) AND COCAINE-SEEKING BEHAVIOR. INSTEAD, WE FOUND THAT G9A OVEREXPRESSION, AND THE RESULTING INCREASE IN HISTONE 3 LYSINE 9 DIMETHYLATION (H3K9ME2), INCREASES SENSITIVITY TO COCAINE REINFORCEMENT AND ENHANCES MOTIVATION FOR COCAINE IN SELF-ADMINISTERING MALE RATS. MOREOVER, WHEN G9A OVEREXPRESSION IS LIMITED TO THE INITIAL 15 D OF COCAINE SA TRAINING, IT PRODUCES AN ENDURING POSTEXPRESSION ENHANCEMENT IN COCAINE SA AND PROLONGED (OVER 5 WEEKS) INCREASES IN REINSTATEMENT OF COCAINE SEEKING INDUCED BY FOOT-SHOCK STRESS, BUT IN THE ABSENCE OF CONTINUED GLOBAL ELEVATIONS IN H3K9ME2. THE INCREASE IN STRESS-INDUCED REINSTATEMENT IS PARALLELED BY HEIGHTENED ANXIETY MEASURES, SUGGESTING THAT COUNTERING THE COCAINE-INDUCED DECREASES IN ENDOGENOUS G9A WITH ECTOPIC G9A OVEREXPRESSION LEADS TO LASTING ANXIOGENIC EFFECTS. FINALLY, WE FOUND AN ENDURING REDUCTION IN PHOSPHORYLATED CAMP-RESPONSE ELEMENT BINDING PROTEIN LEVELS IN THE NACSH THAT COULD ACCOUNT FOR THE INCREASED ANXIETY. THESE DATA DEMONSTRATE A NOVEL ROLE FOR G9A IN PROMOTING COMORBID COCAINE ADDICTION AND ANXIETY AND SUGGEST THAT INCREASED EPIGENETIC REPRESSION OF TRANSCRIPTION THROUGH H3K9 DURING COCAINE USE CAN HAVE LONG-LASTING AND UNEXPECTED NEGATIVE CONSEQUENCES ON BEHAVIOR.SIGNIFICANCE STATEMENT COCAINE ADDICTION IS A NEUROPSYCHIATRIC DISORDER THAT IS DETRIMENTAL TO SOCIETY AND CURRENTLY HAS NO EFFECTIVE TREATMENTS. THE DIFFICULTY IN TREATING DRUG ADDICTION IS COMPOUNDED BY THE HIGH COMORBIDITY WITH OTHER PSYCHIATRIC ILLNESSES, INCLUDING ANXIETY DISORDERS. HERE, WE DEMONSTRATE THAT G9A, AN EPIGENETIC REPRESSOR OF GENE EXPRESSION, ACTING IN THE NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, IS CAPABLE OF INCREASING BOTH ADDICTION- AND ANXIETY-LIKE BEHAVIORS IN RATS. THESE FINDINGS ARE INTRIGUING BECAUSE REPEATED COCAINE EXPOSURE DECREASES G9A IN THIS REGION AND THEREBY ENHANCES EXPRESSION OF CERTAIN ADDICTION-PROMOTING GENES. HOWEVER, OUR RESULTS SUGGEST THAT COUNTERING THIS COCAINE-INDUCED DECREASE IN G9A ACTIVITY ACTUALLY EXACERBATES ADDICTION AND SENSITIVITY TO RELAPSE UNDER STRESSFUL SITUATIONS. 2018 12 4236 30 METHYLATION OF THE TYROSINE HYDROXYLASE GENE IS DYSREGULATED BY COCAINE DEPENDENCE IN THE HUMAN STRIATUM. COCAINE DEPENDENCE IS A CHRONIC, RELAPSING DISORDER CAUSED BY LASTING CHANGES IN THE BRAIN. ANIMAL STUDIES HAVE IDENTIFIED COCAINE-RELATED ALTERATIONS IN STRIATAL DNA METHYLATION; HOWEVER, IT IS UNCLEAR HOW METHYLATION IS RELATED TO COCAINE DEPENDENCE IN HUMANS. WE GENERATED METHYLOMIC PROFILES OF THE NUCLEUS ACCUMBENS USING HUMAN POSTMORTEM BRAINS FROM A COHORT OF INDIVIDUALS WITH COCAINE DEPENDENCE AND HEALTHY CONTROLS (N = 25 PER GROUP). WE FOUND HYPERMETHYLATION IN A CLUSTER OF CPGS WITHIN THE GENE BODY OF TYROSINE HYDROXYLASE (TH), CONTAINING A PUTATIVE BINDING SITE FOR THE EARLY GROWTH RESPONSE 1 (EGR1) TRANSCRIPTION FACTOR, WHICH IS HYPERMETHYLATED IN THE CAUDATE NUCLEUS OF COCAINE-DEPENDENT INDIVIDUALS. WE REPLICATED THIS FINDING AND FOUND IT TO BE SPECIFIC TO STRIATAL NEURONAL NUCLEI. FURTHERMORE, THIS LOCUS DEMONSTRATES ENHANCER ACTIVITY WHICH IS ATTENUATED BY METHYLATION AND ENHANCED BY EGR1 OVEREXPRESSION. THESE RESULTS SUGGEST THAT COCAINE DEPENDENCE ALTERS THE EPIGENETIC REGULATION OF DOPAMINERGIC SIGNALING GENES. 2021 13 3203 33 HDAC3 ACTIVITY WITHIN THE NUCLEUS ACCUMBENS REGULATES COCAINE-INDUCED PLASTICITY AND BEHAVIOR IN A CELL-TYPE-SPECIFIC MANNER. EPIGENETIC MECHANISMS REGULATE PROCESSES OF NEUROPLASTICITY CRITICAL TO COCAINE-INDUCED BEHAVIORS. THIS INCLUDES THE CLASS I HISTONE DEACETYLASE (HDAC) HDAC3, KNOWN TO ACT AS A NEGATIVE REGULATOR OF COCAINE-ASSOCIATED MEMORY FORMATION WITHIN THE NUCLEUS ACCUMBENS (NAC). DESPITE THIS, IT REMAINS UNKNOWN HOW COCAINE ALTERS HDAC3-DEPENDENT MECHANISMS. HERE, WE PROFILED HDAC3 EXPRESSION AND ACTIVITY IN TOTAL NAC MOUSE TISSUE FOLLOWING COCAINE EXPOSURE. ALTHOUGH CHRONIC COCAINE DID NOT AFFECT EXPRESSION OF HDAC3 WITHIN THE NAC, CHRONIC COCAINE DID AFFECT PROMOTER-SPECIFIC CHANGES IN HDAC3 AND H4K8AC OCCUPANCY. THESE CHANGES IN PROMOTER OCCUPANCY CORRELATED WITH COCAINE-INDUCED CHANGES IN EXPRESSION OF PLASTICITY-RELATED GENES. TO CAUSALLY DETERMINE WHETHER COCAINE-INDUCED PLASTICITY IS MEDIATED BY HDAC3'S DEACETYLASE ACTIVITY, WE OVEREXPRESSED A DEACETYLASE-DEAD HDAC3 POINT MUTANT (HDAC3-Y298H-V5) WITHIN THE NAC OF ADULT MALE MICE. WE FOUND THAT DISRUPTING HDAC3'S ENZYMATIC ACTIVITY ALTERED SELECTIVE CHANGES IN GENE EXPRESSION AND SYNAPTIC PLASTICITY FOLLOWING COCAINE EXPOSURE, DESPITE HAVING NO EFFECTS ON COCAINE-INDUCED BEHAVIORS. IN FURTHER ASSESSING HDAC3'S ROLE WITHIN THE NAC, WE OBSERVED THAT CHRONIC COCAINE INCREASES HDAC3 EXPRESSION IN DRD1 BUT NOT DRD2-CELLS OF THE NAC. MOREOVER, WE DISCOVERED THAT HDAC3 ACTS SELECTIVELY WITHIN D1R CELL-TYPES TO REGULATE COCAINE-ASSOCIATED MEMORY FORMATION AND COCAINE-SEEKING. OVERALL, THESE RESULTS SUGGEST THAT COCAINE INDUCES CELL-TYPE-SPECIFIC CHANGES IN EPIGENETIC MECHANISMS TO PROMOTE PLASTICITY IMPORTANT FOR DRIVING COCAINE-RELATED BEHAVIORS.SIGNIFICANCE STATEMENT DRUGS OF ABUSE ALTER MOLECULAR MECHANISMS THROUGHOUT THE REWARD CIRCUITRY THAT CAN LEAD TO PERSISTENT DRUG-ASSOCIATED BEHAVIORS. EPIGENETIC REGULATORS ARE CRITICAL DRIVERS OF DRUG-INDUCED CHANGES IN GENE EXPRESSION. HERE, WE DEMONSTRATE THAT THE ACTIVITY OF AN EPIGENETIC ENZYME PROMOTES NEUROPLASTICITY WITHIN THE NUCLEUS ACCUMBENS (NAC) CRITICAL TO COCAINE ACTION. IN ADDITION, WE DEMONSTRATE THAT THESE CHANGES IN EPIGENETIC ACTIVITY DRIVE COCAINE-SEEKING BEHAVIORS IN A CELL-TYPE-SPECIFIC MANNER. THESE FINDINGS ARE KEY IN UNDERSTANDING AND TARGETING COCAINE'S IMPACT OF NEURAL CIRCUITRY AND BEHAVIOR. 2021 14 2012 33 EPIGENETIC BASIS OF OPIATE SUPPRESSION OF BDNF GENE EXPRESSION IN THE VENTRAL TEGMENTAL AREA. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS A CRUCIAL ROLE IN MODULATING NEURAL AND BEHAVIORAL PLASTICITY TO DRUGS OF ABUSE. WE FOUND A PERSISTENT DOWNREGULATION OF EXON-SPECIFIC BDNF EXPRESSION IN THE VENTRAL TEGMENTAL AREA (VTA) IN RESPONSE TO CHRONIC OPIATE EXPOSURE, WHICH WAS MEDIATED BY SPECIFIC EPIGENETIC MODIFICATIONS AT THE CORRESPONDING BDNF GENE PROMOTERS. EXPOSURE TO CHRONIC MORPHINE INCREASED STALLING OF RNA POLYMERASE II AT THESE BDNF PROMOTERS IN VTA AND ALTERED PERMISSIVE AND REPRESSIVE HISTONE MODIFICATIONS AND OCCUPANCY OF THEIR REGULATORY PROTEINS AT THE SPECIFIC PROMOTERS. FURTHERMORE, WE FOUND THAT MORPHINE SUPPRESSED BINDING OF PHOSPHO-CREB (CAMP RESPONSE ELEMENT BINDING PROTEIN) TO BDNF PROMOTERS IN VTA, WHICH RESULTED FROM ENRICHMENT OF TRIMETHYLATED H3K27 AT THE PROMOTERS, AND THAT DECREASED NURR1 (NUCLEAR RECEPTOR RELATED-1) EXPRESSION ALSO CONTRIBUTED TO BDNF REPRESSION AND ASSOCIATED BEHAVIORAL PLASTICITY TO MORPHINE. OUR FINDINGS SUGGEST PREVIOUSLY UNKNOWN EPIGENETIC MECHANISMS OF MORPHINE-INDUCED MOLECULAR AND BEHAVIORAL NEUROADAPTATIONS. 2015 15 5503 24 RGS9-2--CONTROLLED ADAPTATIONS IN THE STRIATUM DETERMINE THE ONSET OF ACTION AND EFFICACY OF ANTIDEPRESSANTS IN NEUROPATHIC PAIN STATES. THE STRIATAL PROTEIN REGULATOR OF G-PROTEIN SIGNALING 9-2 (RGS9-2) PLAYS A KEY MODULATORY ROLE IN OPIOID, MONOAMINE, AND OTHER G-PROTEIN-COUPLED RECEPTOR RESPONSES. HERE, WE USE THE MURINE SPARED-NERVE INJURY MODEL OF NEUROPATHIC PAIN TO INVESTIGATE THE MECHANISM BY WHICH RGS9-2 IN THE NUCLEUS ACCUMBENS (NAC), A BRAIN REGION INVOLVED IN MOOD, REWARD, AND MOTIVATION, MODULATES THE ACTIONS OF TRICYCLIC ANTIDEPRESSANTS (TCAS). PREVENTION OF RGS9-2 ACTION IN THE NAC INCREASES THE EFFICACY OF THE TCA DESIPRAMINE AND DRAMATICALLY ACCELERATES ITS ONSET OF ACTION. BY CONTROLLING THE ACTIVATION OF EFFECTOR MOLECULES BY G PROTEIN ALPHA AND BETAGAMMA SUBUNITS, RGS9-2 AFFECTS SEVERAL PROTEIN INTERACTIONS, PHOSPHOPROTEIN LEVELS, AND THE FUNCTION OF THE EPIGENETIC MODIFIER HISTONE DEACETYLASE 5, WHICH ARE IMPORTANT FOR TCA RESPONSIVENESS. FURTHERMORE, INFORMATION FROM RNA-SEQUENCING ANALYSIS REVEALS THAT RGS9-2 IN THE NAC AFFECTS THE EXPRESSION OF MANY GENES KNOWN TO BE INVOLVED IN NOCICEPTION, ANALGESIA, AND ANTIDEPRESSANT DRUG ACTIONS. OUR FINDINGS PROVIDE NOVEL INFORMATION ON NAC-SPECIFIC CELLULAR MECHANISMS THAT MEDIATE THE ACTIONS OF TCAS IN NEUROPATHIC PAIN STATES. 2015 16 4163 30 MECP2 REPRESSION OF G9A IN REGULATION OF PAIN AND MORPHINE REWARD. OPIOIDS ARE COMMONLY USED FOR PAIN RELIEF, BUT THEIR STRONG REWARDING EFFECTS DRIVE OPIOID MISUSE AND ABUSE. HOW PAIN AFFECTS THE LIABILITY OF OPIOID ABUSE IS UNKNOWN AT PRESENT. IN THIS STUDY, WE IDENTIFIED AN EPIGENETIC REGULATING CASCADE ACTIVATED BY BOTH PAIN AND THE OPIOID MORPHINE. BOTH PERSISTENT PAIN AND REPEATED MORPHINE UPREGULATED THE TRANSCRIPTIONAL REGULATOR MECP2 IN MOUSE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT MECP2 BOUND TO AND REPRESSED THE TRANSCRIPTIONAL REPRESSOR HISTONE DIMETHYLTRANSFERASE G9A, REDUCING G9A-CATALYZED REPRESSIVE MARK H3K9ME2 IN CEA. REPRESSION OF G9A ACTIVITY INCREASED EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF). BEHAVIORALLY, PERSISTENT INFLAMMATORY PAIN INCREASED THE SENSITIVITY TO ACQUIRING MORPHINE-INDUCED, REWARD-RELATED BEHAVIOR OF CONDITIONED PLACE PREFERENCE IN MICE. LOCAL VIRAL VECTOR-MEDIATED MECP2 OVEREXPRESSION, CRE-INDUCED G9A KNOCKDOWN, AND CEA APPLICATION OF BDNF MIMICKED, WHEREAS MECP2 KNOCKDOWN INHIBITED, THE PAIN EFFECT. THESE RESULTS SUGGEST THAT MECP2 DIRECTLY REPRESSES G9A AS A SHARED MECHANISM IN CENTRAL AMYGDALA FOR REGULATION OF EMOTIONAL RESPONSES TO PAIN AND OPIOID REWARD, AND FOR THEIR BEHAVIORAL INTERACTION. 2014 17 2740 29 EXPOSURE TO EARLY LIFE STRESS RESULTS IN EPIGENETIC CHANGES IN NEUROTROPHIC FACTOR GENE EXPRESSION IN A PARKINSONIAN RAT MODEL. EARLY LIFE ADVERSITY INCREASES THE RISK OF MENTAL DISORDERS LATER IN LIFE. CHRONIC EARLY LIFE STRESS MAY ALTER NEUROTROPHIC FACTOR GENE EXPRESSION INCLUDING THOSE FOR BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) AND GLIAL CELL DERIVED NEUROTROPHIC FACTOR (GDNF) THAT ARE IMPORTANT IN NEURONAL GROWTH, SURVIVAL, AND MAINTENANCE. MATERNAL SEPARATION WAS USED IN THIS STUDY TO MODEL EARLY LIFE STRESS. FOLLOWING UNILATERAL INJECTION OF A MILD DOSE OF 6-HYDROXYDOPAMINE (6-OHDA), WE MEASURED CORTICOSTERONE (CORT) IN THE BLOOD AND STRIATUM OF STRESSED AND NONSTRESSED RATS; WE ALSO MEASURED DNA METHYLATION AND BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM USING REAL TIME PCR. IN THE PRESENCE OF STRESS, WE FOUND THAT THERE WAS INCREASED CORTICOSTERONE CONCENTRATION IN BOTH BLOOD AND STRIATAL TISSUE. FURTHER TO THIS, WE FOUND HIGHER DNA METHYLATION AND DECREASED NEUROTROPHIC FACTOR GENE EXPRESSION. 6-OHDA LESION INCREASED NEUROTROPHIC FACTOR GENE EXPRESSION IN BOTH STRESSED AND NONSTRESSED RATS BUT THIS INCREASE WAS HIGHER IN THE NONSTRESSED RATS. OUR RESULTS SUGGEST THAT EXPOSURE TO EARLY POSTNATAL STRESS INCREASES CORTICOSTERONE CONCENTRATION WHICH LEADS TO INCREASED DNA METHYLATION. THIS EFFECT RESULTS IN DECREASED BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM LEADING TO DECREASED PROTECTION AGAINST SUBSEQUENT INSULTS LATER IN LIFE. 2016 18 2826 34 FLUOXETINE EPIGENETICALLY ALTERS THE CAMKIIALPHA PROMOTER IN NUCLEUS ACCUMBENS TO REGULATE DELTAFOSB BINDING AND ANTIDEPRESSANT EFFECTS. CHRONIC SOCIAL DEFEAT STRESS IN MICE PRODUCES A SUSCEPTIBLE PHENOTYPE CHARACTERIZED BY SEVERAL BEHAVIORAL ABNORMALITIES CONSISTENT WITH HUMAN DEPRESSION THAT ARE REVERSED BY CHRONIC BUT NOT ACUTE EXPOSURE TO ANTIDEPRESSANT MEDICATIONS. RECENT WORK IN ADDICTION MODELS DEMONSTRATES THAT THE TRANSCRIPTION FACTOR DELTAFOSB AND PROTEIN KINASE CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKII) ARE CO-REGULATED IN NUCLEUS ACCUMBENS (NAC), A BRAIN REWARD REGION IMPLICATED IN BOTH ADDICTION AND DEPRESSION MODELS INCLUDING SOCIAL DEFEAT. PREVIOUS WORK HAS ALSO DEMONSTRATED THAT DELTAFOSB IS INDUCED IN NAC AFTER CHRONIC SOCIAL DEFEAT STRESS OR AFTER CHRONIC ANTIDEPRESSANT TREATMENT, WHEREIN IT MEDIATES A PRO-RESILIENCE OR ANTIDEPRESSANT-LIKE PHENOTYPE. HERE, USING CHROMATIN IMMUNOPRECIPITATION ASSAYS, WE FOUND THAT DELTAFOSB BINDS THE CAMKIIALPHA GENE PROMOTER IN NAC AND THAT THIS BINDING INCREASES AFTER MICE ARE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS. PARADOXICALLY, CHRONIC EXPOSURE TO THE ANTIDEPRESSANT FLUOXETINE REDUCES BINDING OF DELTAFOSB TO THE CAMKIIALPHA PROMOTER AND REDUCES CAMKII EXPRESSION IN NAC, DESPITE THE FACT THAT DELTAFOSB IS INDUCED UNDER THESE CONDITIONS. THESE DATA SUGGEST A NOVEL EPIGENETIC MECHANISM OF ANTIDEPRESSANT ACTION, WHEREBY FLUOXETINE INDUCES SOME CHROMATIN CHANGE AT THE CAMKIIALPHA PROMOTER, WHICH BLOCKS THE DELTAFOSB BINDING. INDEED, CHRONIC FLUOXETINE REDUCES ACETYLATION AND INCREASES LYSINE-9 DIMETHYLATION OF HISTONE H3 AT THE CAMKIIALPHA PROMOTER IN NAC, EFFECTS ALSO SEEN IN DEPRESSED HUMANS EXPOSED TO ANTIDEPRESSANTS. OVEREXPRESSION OF CAMKII IN NAC BLOCKS FLUOXETINE'S ANTIDEPRESSANT EFFECTS IN THE CHRONIC SOCIAL DEFEAT PARADIGM, WHEREAS INHIBITION OF CAMKII ACTIVITY IN NAC MIMICS FLUOXETINE EXPOSURE. THESE FINDINGS SUGGEST THAT EPIGENETIC SUPPRESSION OF CAMKIIALPHA EXPRESSION IN NAC IS BEHAVIORALLY RELEVANT AND OFFER A NOVEL PATHWAY FOR POSSIBLE THERAPEUTIC INTERVENTION IN DEPRESSION AND RELATED SYNDROMES. 2014 19 3315 28 HIPPOCAMPAL MU OPIOID RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN RAT. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCED BY LONG-TERM BRAIN CHANGES. UNDERSTANDING THE NEUROCHEMICAL CHANGES UNDERLYING THE REINFORCING EFFECTS OF THIS DRUG OF ABUSE IS CRITICAL FOR REDUCING THE SOCIETAL BURDEN OF DRUG ADDICTION. THE MU OPIOID RECEPTOR PLAYS A MAJOR ROLE IN DRUG REWARD. THIS RECEPTOR IS MODULATED BY CHRONIC COCAINE TREATMENT IN SPECIFIC BRAIN STRUCTURES, BUT FEW STUDIES INVESTIGATED NEUROCHEMICAL ADAPTATIONS INDUCED BY VOLUNTARY COCAINE INTAKE. IN THIS STUDY, WE INVESTIGATED WHETHER INTRAVENOUS COCAINE-SELF ADMINISTRATION (0.33 MG/KG/INJECTION, FIXED-RATIO 1 [FR1], 10 DAYS) IN RATS INDUCES TRANSCRIPTIONAL AND FUNCTIONAL CHANGES OF THE MU OPIOID RECEPTOR IN REWARD-RELATED BRAIN REGIONS. EPIGENETIC PROCESSES WITH HISTONE MODIFICATIONS WERE EXAMINED FOR TWO ACTIVATING MARKS, H3K4ME3, AND H3K27AC. WE FOUND AN INCREASE OF MU OPIOID RECEPTOR GENE EXPRESSION ALONG WITH A POTENTIATION OF ITS FUNCTIONALITY IN HIPPOCAMPUS OF COCAINE SELF-ADMINISTERING ANIMALS COMPARED TO SALINE CONTROLS. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR REVEALED NO MODIFICATIONS OF THE HISTONE MARK H3K4ME3 AND H3K27AC LEVELS AT MU OPIOID RECEPTOR PROMOTER. OUR STUDY HIGHLIGHTS THE HIPPOCAMPUS AS AN IMPORTANT TARGET TO FURTHER INVESTIGATE NEUROADAPTIVE PROCESSES LEADING TO COCAINE ADDICTION. 2021 20 6602 20 TWO KINDS OF TRANSCRIPTION FACTORS MEDIATE CHRONIC MORPHINE-INDUCED DECREASE IN MIR-105 IN MEDIAL PREFRONTAL CORTEX OF RATS. CHRONIC MORPHINE ADMINISTRATION ALTERS GENE EXPRESSION IN DIFFERENT BRAIN REGIONS, AN EFFECT WHICH MAY CONTRIBUTE TO PLASTIC CHANGES ASSOCIATED WITH ADDICTIVE BEHAVIOR. THIS CHANGE IN GENE EXPRESSION IS MOST POSSIBLY MEDIATED BY ADDICTIVE DRUG-INDUCED EPIGENETIC REMODELING OF GENE EXPRESSION PROGRAMS. OUR PREVIOUS STUDIES SHOWED THAT CHRONIC MORPHINE-INDUCED DECREASE OF MIR-105 IN THE MEDIAL PREFRONTAL CORTEX (MPFC) CONTRIBUTED TO CONTEXT-INDUCED RETRIEVAL OF MORPHINE WITHDRAWAL MEMORY. HOWEVER, HOW CHRONIC MORPHINE TREATMENT DECREASES MIR-105 IN THE MPFC STILL REMAINS UNKNOWN. THE PRESENT STUDY SHOWS THAT CHRONIC MORPHINE INDUCES ADDICTION-RELATED CHANGE IN MIR-105 IN THE MPFC VIA TWO KINDS OF TRANSCRIPTION FACTORS: THE FIRST TRANSCRIPTION FACTOR IS CREB ACTIVATED BY MU RECEPTORS-ERK-P90RSK SIGNALING PATHWAY AND THE SECOND TRANSCRIPTION FACTOR IS GLUCOCORTICOID RECEPTOR (GR), WHICH AS A NEGATIVE TRANSCRIPTION FACTOR, MEDIATES CHRONIC MORPHINE-INDUCED DECREASE IN MIR-105 IN THE MPFC OF RATS. 2022