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 4860 28 OREXIN SIGNALING MEDIATES THE ANTIDEPRESSANT-LIKE EFFECT OF CALORIE RESTRICTION. DURING PERIODS OF REDUCED FOOD AVAILABILITY, ANIMALS MUST RESPOND WITH BEHAVIORAL ADAPTATIONS THAT PROMOTE SURVIVAL. DESPITE THE FACT THAT MANY PSYCHIATRIC SYNDROMES INCLUDE DISORDERED EATING PATTERNS AS A COMPONENT OF THE ILLNESS, LITTLE IS KNOWN ABOUT THE NEUROBIOLOGY UNDERLYING BEHAVIORAL CHANGES INDUCED BY SHORT-TERM CALORIE RESTRICTION. PRESENTLY, WE DEMONSTRATE THAT 10 D OF CALORIE RESTRICTION, CORRESPONDING TO A 20-25% WEIGHT LOSS, CAUSES A MARKED ANTIDEPRESSANT-LIKE RESPONSE IN TWO RODENT MODELS OF DEPRESSION AND THAT THIS RESPONSE IS DEPENDENT ON THE HYPOTHALAMIC NEUROPEPTIDE OREXIN (HYPOCRETIN). WILD-TYPE MICE, BUT NOT MICE LACKING OREXIN, SHOW LONGER LATENCY TO IMMOBILITY AND LESS TOTAL IMMOBILITY IN THE FORCED SWIM TEST AFTER CALORIE RESTRICTION. IN THE SOCIAL DEFEAT MODEL OF CHRONIC STRESS, CALORIE RESTRICTION REVERSES THE BEHAVIORAL DEFICITS SEEN IN WILD-TYPE MICE BUT NOT IN OREXIN KNOCK-OUT MICE. ADDITIONALLY, CHRONIC SOCIAL DEFEAT STRESS INDUCES A PROLONGED REDUCTION IN THE EXPRESSION OF PREPRO-OREXIN MRNA VIA EPIGENETIC MODIFICATION OF THE OREXIN GENE PROMOTER, WHEREAS CALORIE RESTRICTION ENHANCES THE ACTIVATION OF OREXIN CELLS AFTER SOCIAL DEFEAT. TOGETHER, THESE DATA INDICATE THAT OREXIN PLAYS AN ESSENTIAL ROLE IN MEDIATING REDUCED DEPRESSION-LIKE SYMPTOMS INDUCED BY CALORIE RESTRICTION. 2008 4 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 5 4649 44 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 6 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 7 949 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 8 4647 41 NEUROPEPTIDE AND SMALL TRANSMITTER COEXISTENCE: FUNDAMENTAL STUDIES AND RELEVANCE TO MENTAL ILLNESS. NEUROPEPTIDES ARE AUXILIARY MESSENGER MOLECULES THAT ALWAYS CO-EXIST IN NERVE CELLS WITH ONE OR MORE SMALL MOLECULE (CLASSIC) NEUROTRANSMITTERS. NEUROPEPTIDES ACT BOTH AS TRANSMITTERS AND TROPHIC FACTORS, AND PLAY A ROLE PARTICULARLY WHEN THE NERVOUS SYSTEM IS CHALLENGED, AS BY INJURY, PAIN OR STRESS. HERE NEUROPEPTIDES AND COEXISTENCE IN MAMMALS ARE REVIEWED, BUT WITH SPECIAL FOCUS ON THE 29/30 AMINO ACID GALANIN AND ITS THREE RECEPTORS GALR1, -R2 AND -R3. IN PARTICULAR, GALANIN'S ROLE AS A CO-TRANSMITTER IN BOTH RODENT AND HUMAN NORADRENERGIC LOCUS COERULEUS (LC) NEURONS IS ADDRESSED. EXTENSIVE EXPERIMENTAL ANIMAL DATA STRONGLY SUGGEST A ROLE FOR THE GALANIN SYSTEM IN DEPRESSION-LIKE BEHAVIOR. THE TRANSLATIONAL POTENTIAL OF THESE RESULTS WAS TESTED BY STUDYING THE GALANIN SYSTEM IN POSTMORTEM HUMAN BRAINS, FIRST IN NORMAL BRAINS, AND THEN IN A COMPARISON OF FIVE REGIONS OF BRAINS OBTAINED FROM DEPRESSED PEOPLE WHO COMMITTED SUICIDE, AND FROM MATCHED CONTROLS. THE DISTRIBUTION OF GALANIN AND THE FOUR GALANIN SYSTEM TRANSCRIPTS IN THE NORMAL HUMAN BRAIN WAS DETERMINED, AND SELECTIVE AND PARALLEL CHANGES IN LEVELS OF TRANSCRIPTS AND DNA METHYLATION FOR GALANIN AND ITS THREE RECEPTORS WERE ASSESSED IN DEPRESSED PATIENTS WHO COMMITTED SUICIDE: UPREGULATION OF TRANSCRIPTS, E.G., FOR GALANIN AND GALR3 IN LC, PARALLELED BY A DECREASE IN DNA METHYLATION, SUGGESTING INVOLVEMENT OF EPIGENETIC MECHANISMS. IT IS HYPOTHESIZED THAT, WHEN EXPOSED TO SEVERE STRESS, THE NORADRENERGIC LC NEURONS FIRE IN BURSTS AND RELEASE GALANIN FROM THEIR SOMA/DENDRITES. GALANIN THEN ACTS ON SOMATO-DENDRITIC, INHIBITORY GALANIN AUTORECEPTORS, OPENING POTASSIUM CHANNELS AND INHIBITING FIRING. THE PURPOSE OF THESE AUTORECEPTORS IS TO ACT AS A 'BRAKE' TO PREVENT OVEREXCITATION, A BRAKE THAT IS ALSO PART OF RESILIENCE TO STRESS THAT PROTECTS AGAINST DEPRESSION. DEPRESSION THEN ARISES WHEN THE INHIBITION IS TOO STRONG AND LONG LASTING - A MALADAPTION, ALLOSTATIC LOAD, LEADING TO DEPLETION OF NA LEVELS IN THE FOREBRAIN. IT IS SUGGESTED THAT DISINHIBITION BY A GALANIN ANTAGONIST MAY HAVE ANTIDEPRESSANT ACTIVITY BY RESTORING FOREBRAIN NA LEVELS. A ROLE OF GALANIN IN DEPRESSION IS ALSO SUPPORTED BY A RECENT CANDIDATE GENE STUDY, SHOWING THAT VARIANTS IN GENES FOR GALANIN AND ITS THREE RECEPTORS CONFER INCREASED RISK OF DEPRESSION AND ANXIETY IN PEOPLE WHO EXPERIENCED CHILDHOOD ADVERSITY OR RECENT NEGATIVE LIFE EVENTS. IN SUMMARY, GALANIN, A NEUROPEPTIDE COEXISTING IN LC NEURONS, MAY PARTICIPATE IN THE MECHANISM UNDERLYING RESILIENCE AGAINST A SERIOUS AND COMMON DISORDER, MDD. EXISTING AND FURTHER RESULTS MAY LEAD TO AN INCREASED UNDERSTANDING OF HOW THIS ILLNESS DEVELOPS, WHICH IN TURN COULD PROVIDE A BASIS FOR ITS TREATMENT. 2018 9 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 10 219 33 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE. 2016 11 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 12 2827 42 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS. 2011 13 6525 39 TRANSCRIPTIONAL AND EPIGENETIC SUBSTRATES OF METHAMPHETAMINE ADDICTION AND WITHDRAWAL: EVIDENCE FROM A LONG-ACCESS SELF-ADMINISTRATION MODEL IN THE RAT. METHAMPHETAMINE USE DISORDER IS A CHRONIC NEUROPSYCHIATRIC DISORDER CHARACTERIZED BY RECURRENT BINGE EPISODES, INTERVALS OF ABSTINENCE, AND RELAPSES TO DRUG USE. HUMANS ADDICTED TO METHAMPHETAMINE EXPERIENCE VARIOUS DEGREES OF COGNITIVE DEFICITS AND OTHER NEUROLOGICAL ABNORMALITIES THAT COMPLICATE THEIR ACTIVITIES OF DAILY LIVING AND THEIR PARTICIPATION IN TREATMENT PROGRAMS. IMPORTANTLY, MODELS OF METHAMPHETAMINE ADDICTION IN RODENTS HAVE SHOWN THAT ANIMALS WILL READILY LEARN TO GIVE THEMSELVES METHAMPHETAMINE. RATS ALSO ACCELERATE THEIR INTAKE OVER TIME. MICROARRAY STUDIES HAVE ALSO SHOWN THAT METHAMPHETAMINE TAKING IS ASSOCIATED WITH MAJOR TRANSCRIPTIONAL CHANGES IN THE STRIATUM MEASURED WITHIN A SHORT OR LONGER TIME AFTER CESSATION OF DRUG TAKING. AFTER A 2-H WITHDRAWAL TIME, THERE WAS INCREASED EXPRESSION OF GENES THAT PARTICIPATE IN TRANSCRIPTION REGULATION. THESE INCLUDED CYCLIC AMP RESPONSE ELEMENT BINDING (CREB), ETS DOMAIN-CONTAINING PROTEIN (ELK1), AND MEMBERS OF THE FOS FAMILY OF TRANSCRIPTION FACTORS. OTHER GENES OF INTEREST INCLUDE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), TYROSINE KINASE RECEPTOR, TYPE 2 (TRKB), AND SYNAPTOPHYSIN. METHAMPHETAMINE-INDUCED TRANSCRIPTION WAS FOUND TO BE REGULATED VIA PHOSPHORYLATED CREB-DEPENDENT EVENTS. AFTER A 30-DAY WITHDRAWAL FROM METHAMPHETAMINE SELF-ADMINISTRATION, HOWEVER, THERE WAS MOSTLY DECREASED EXPRESSION OF TRANSCRIPTION FACTORS INCLUDING JUND. THERE WAS ALSO DOWNREGULATION OF GENES WHOSE PROTEIN PRODUCTS ARE CONSTITUENTS OF CHROMATIN-REMODELING COMPLEXES. ALTOGETHER, THESE GENOME-WIDE RESULTS SHOW THAT METHAMPHETAMINE ABUSE MIGHT BE ASSOCIATED WITH ALTERED REGULATION OF A DIVERSITY OF GENE NETWORKS THAT IMPACT CELLULAR AND SYNAPTIC FUNCTIONS. THESE TRANSCRIPTIONAL CHANGES MIGHT SERVE AS TRIGGERS FOR THE NEUROPSYCHIATRIC PRESENTATIONS OF HUMANS WHO ABUSE THIS DRUG. BETTER UNDERSTANDING OF THE WAY THAT GENE PRODUCTS INTERACT TO CAUSE METHAMPHETAMINE ADDICTION WILL HELP TO DEVELOP BETTER PHARMACOLOGICAL TREATMENT OF METHAMPHETAMINE ADDICTS. 2015 14 5651 30 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD. 2020 15 6388 39 THE ROLE OF SIRT1 IN THE BASOLATERAL AMYGDALA IN DEPRESSION-LIKE BEHAVIORS IN MICE. PREVIOUS INVESTIGATIONS HAVE IMPLICATED THE BASOLATERAL AMYGDALA (BLA) EPIGENETIC MECHANISMS IN THE PATHOPHYSIOLOGY OF DEPRESSION. SIRT1 IS A NAD+-DEPENDENT CLASS III HISTONE DEACETYLASE, WIDELY EXPRESSES IN BLA. HOWEVER, EPIGENETIC MECHANISMS IN THE BLA UNDER THE REGULATION OF SIRT1 IN THE DEPRESSION ARE LARGELY UNCHARACTERIZED. UNDER THE CHRONIC UNPREDICTABLE CHRONIC MILD STRESS (CUMS) MOUSE MODEL, WE USED ADENO-ASSOCIATED VIRAL VECTORS (AAV) THAT ENCODED SIRT1-SHRNA OR SIRT1 TO SPECIFICALLY KNOCKDOWN OR OVEREXPRESS SIRT1 IN BLA NEURONS, RESPECTIVELY. CUMS PROCEDURE INDUCED SIGNIFICANT DEPRESSION SYMPTOMS INCLUDING THE DECREASED SUCROSE PREFERENCE, THE LESS BODYWEIGHT GAINED, THE DECREASED IMMOBILE LATENCY AND THE INCREASED IMMOBILE TIME BOTH IN FORCED SWIM TEST (FST) AND TAIL SUSPENSION TEST (TST). KNOCKDOWN OF SIRT1 IN BLA GLUTAMATERGIC NEURONS REVERSED THESE DEPRESSION-LIKE BEHAVIORS AND RESTORED THE SYNAPTIC ABNORMALITIES. OVEREXPRESSION OF SIRT1 IN BLA GLUTAMATERGIC NEURONS INDUCED DEPRESSION-LIKE BEHAVIORS IN NON-STRESSED CONTROL MICE. THE RESULT OF PROTEIN EXPRESSIONS AND ULTRASTRUCTURAL CHANGES WERE CONSISTENT WITH THE BEHAVIORAL RESULTS. OUR STUDY SUGGESTED THAT DOWNREGULATION OF SIRT1 IN BLA HAS CERTAIN BENEFICIAL EFFECT ON CUMS-INDUCED DEPRESSION-LIKE BEHAVIORS SUCH AS ANOREXIA, ANHEDONIA, HOPELESSNESS AND DESPAIR. IN ADDITION, THE INCREASED EXPRESSION OF SIRT1 MAY BE THE IMMEDIATE CAUSE OF DEPRESSIVE-LIKE SYMPTOMS. THE ABNORMAL EXPRESSION OF SIRT1 MAY AFFECT THE TRANSCRIPTIONAL REGULATION MECHANISM AND SIGNALING PROTEIN ACETYLATION, AFFECTING NEUROPLASTICITY AND ULTIMATELY CONTRIBUTE TO MDD. IN THE STRESS-SUSCEPTIBLE MICE, THESE TWO MECHANISMS MAY CO-EXIST, BUT THE SPECIFIC MECHANISM NEEDS FURTHER RESEARCH. 2021 16 4828 44 OLANZAPINE INDUCED DNA METHYLATION CHANGES SUPPORT THE DOPAMINE HYPOTHESIS OF PSYCHOSIS. BACKGROUND: THE DOPAMINE (DA) HYPOTHESIS OF SCHIZOPHRENIA PROPOSES THE MENTAL ILLNESS IS CAUSED BY EXCESSIVE TRANSMISSION OF DOPAMINE IN SELECTED BRAIN REGIONS. MULTIPLE LINES OF EVIDENCE, INCLUDING BLOCKAGE OF DOPAMINE RECEPTORS BY ANTIPSYCHOTIC DRUGS THAT ARE USED TO TREAT SCHIZOPHRENIA, SUPPORT THE HYPOTHESIS. HOWEVER, THE DOPAMINE D2 RECEPTOR (DRD2) BLOCKADE CANNOT EXPLAIN SOME IMPORTANT ASPECTS OF THE THERAPEUTIC EFFECT OF ANTIPSYCHOTIC DRUGS. IN THIS STUDY, WE HYPOTHESIZED THAT ANTIPSYCHOTIC DRUGS COULD AFFECT THE TRANSCRIPTION OF GENES IN THE DA PATHWAY BY ALTERING THEIR EPIGENETIC PROFILE. METHODS: TO TEST THIS HYPOTHESIS, WE EXAMINED THE EFFECT OF OLANZAPINE, A COMMONLY USED ATYPICAL ANTIPSYCHOTIC DRUG, ON THE DNA METHYLATION STATUS OF GENES FROM DA NEUROTRANSMISSION IN THE BRAIN AND LIVER OF RATS. GENOMIC DNA ISOLATED FROM HIPPOCAMPUS, CEREBELLUM, AND LIVER OF OLANZAPINE TREATED (N = 2) AND CONTROL (N = 2) RATS WERE ANALYZED USING RAT SPECIFIC METHYLATION ARRAYS. RESULTS: OUR RESULTS SHOW THAT OLANZAPINE CAUSES METHYLATION CHANGES IN GENES ENCODING FOR DA RECEPTORS (DOPAMINE D1 RECEPTOR, DOPAMINE D2 RECEPTOR AND DOPAMINE D5 RECEPTOR), A DA TRANSPORTER (SOLUTE CARRIER FAMILY 18 MEMBER 2), A DA SYNTHESIS (DIFFERENTIAL DISPLAY CLONE 8), AND A DA METABOLISM (CATECHOL-O-METHYLTRANSFERASE). WE ASSESSED A TOTAL OF 40 GENES IN THE DA PATHWAY AND FOUND 19 TO BE DIFFERENTIALLY METHYLATED BETWEEN OLANZAPINE TREATED AND CONTROL RATS. MOST (17/19) GENES SHOWED AN INCREASE IN METHYLATION, IN THEIR PROMOTER REGIONS WITH IN SILICO ANALYSIS STRONGLY INDICATING A FUNCTIONAL POTENTIAL TO SUPPRESS TRANSCRIPTION IN THE BRAIN. CONCLUSION: OUR RESULTS SUGGEST THAT CHRONIC OLANZAPINE MAY REDUCE DA ACTIVITY BY ALTERING GENE METHYLATION. IT MAY ALSO EXPLAIN THE DELAYED THERAPEUTIC EFFECT OF ANTIPSYCHOTICS, WHICH OCCURS DESPITE RAPID DOPAMINE BLOCKADE. FURTHERMORE, GIVEN THE COMMON NATURE OF EPIGENETIC VARIATION, THIS LENDS INSIGHT INTO THE DIFFERENTIAL THERAPEUTIC RESPONSE OF PSYCHOTIC PATIENTS WHO DISPLAY ADEQUATE BLOCKAGE OF DOPAMINE RECEPTORS. 2013 17 2826 41 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 18 881 37 CHRONIC CLOZAPINE TREATMENT RESTRAINS VIA HDAC2 THE PERFORMANCE OF MGLU2 RECEPTOR AGONISM IN A RODENT MODEL OF ANTIPSYCHOTIC ACTIVITY. PRECLINICAL FINDINGS IN RODENT MODELS POINTED TOWARD ACTIVATION OF METABOTROPIC GLUTAMATE 2/3 (MGLU2/3) RECEPTORS AS A NEW PHARMACOLOGICAL APPROACH TO TREAT PSYCHOSIS. HOWEVER, MORE RECENT STUDIES FAILED TO SHOW CLINICAL EFFICACY OF MGLU2/3 RECEPTOR AGONISM IN SCHIZOPHRENIA PATIENTS. WE PREVIOUSLY PROPOSED THAT LONG-TERM ANTIPSYCHOTIC MEDICATION RESTRICTED THE THERAPEUTIC EFFECTS OF THESE GLUTAMATERGIC AGENTS. HOWEVER, LITTLE IS KNOWN ABOUT THE MOLECULAR MECHANISM UNDERLYING THE POTENTIAL REPERCUSSION OF PREVIOUS ANTIPSYCHOTIC EXPOSURE ON THE THERAPEUTIC PERFORMANCE OF MGLU2/3 RECEPTOR AGONISTS. HERE WE SHOW THAT THIS MALADAPTIVE EFFECT OF ANTIPSYCHOTIC TREATMENT IS MEDIATED MOSTLY VIA HISTONE DEACETYLASE 2 (HDAC2). CHRONIC TREATMENT WITH THE ANTIPSYCHOTIC CLOZAPINE LED TO A DECREASE IN MOUSE FRONTAL CORTEX MGLU2 MRNA, AN EFFECT THAT REQUIRED EXPRESSION OF BOTH HDAC2 AND THE SEROTONIN 5-HT(2A) RECEPTOR. THIS TRANSCRIPTIONAL ALTERATION OCCURRED IN ASSOCIATION WITH HDAC2-DEPENDENT REPRESSIVE HISTONE MODIFICATIONS AT THE MGLU2 PROMOTER. WE FOUND THAT CHRONIC CLOZAPINE TREATMENT DECREASED VIA HDAC2 THE CAPABILITIES OF THE MGLU2/3 RECEPTOR AGONIST LY379268 TO ACTIVATE G-PROTEINS IN THE FRONTAL CORTEX OF MICE. CHRONIC CLOZAPINE TREATMENT BLUNTED THE ANTIPSYCHOTIC-RELATED BEHAVIORAL EFFECTS OF LY379268, AN EFFECT THAT WAS NOT OBSERVED IN HDAC2 KNOCKOUT MICE. MORE IMPORTANTLY, CO-ADMINISTRATION OF THE CLASS I AND II HDAC INHIBITOR SAHA (VORINOSTAT) PRESERVED THE ANTIPSYCHOTIC PROFILE OF LY379268 AND FRONTAL CORTEX MGLU2/3 RECEPTOR DENSITY IN WILD-TYPE MICE. THESE FINDINGS RAISE CONCERNS ON THE DESIGN OF PREVIOUS CLINICAL STUDIES WITH MGLU2/3 AGONISTS, PROVIDING THE RATIONALE FOR THE DEVELOPMENT OF HDAC2 INHIBITORS AS A NEW EPIGENETIC-BASED APPROACH TO IMPROVE THE CURRENTLY LIMITED RESPONSE TO TREATMENT WITH GLUTAMATERGIC ANTIPSYCHOTICS. 2019 19 747 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 20 869 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