1 882 119 CHRONIC COCAINE-INDUCED H3 ACETYLATION AND TRANSCRIPTIONAL ACTIVATION OF CAMKIIALPHA IN THE NUCLEUS ACCUMBENS IS CRITICAL FOR MOTIVATION FOR DRUG REINFORCEMENT. THE REGULATION OF GENE EXPRESSION IN THE BRAIN REWARD REGIONS IS KNOWN TO CONTRIBUTE TO THE PATHOGENESIS AND PERSISTENCE OF DRUG ADDICTION. INCREASING EVIDENCE SUGGESTS THAT THE REGULATION OF GENE TRANSCRIPTION IS MEDIATED BY EPIGENETIC MECHANISMS THAT ALTER THE CHROMATIN STRUCTURE AT SPECIFIC GENE PROMOTERS. TO BETTER UNDERSTAND THE INVOLVEMENT OF EPIGENETIC REGULATION IN DRUG REINFORCEMENT PROPERTIES, RATS WERE SUBJECTED TO COCAINE SELF-ADMINISTRATION PARADIGM. DAILY HISTONE DEACETYLASE (HDAC) INHIBITOR INFUSIONS IN THE SHELL OF THE NUCLEUS ACCUMBENS (NAC) CAUSED AN UPWARD SHIFT IN THE DOSE-RESPONSE CURVE UNDER FIXED-RATIO SCHEDULE AND INCREASED THE BREAK POINT UNDER PROGRESSIVE-RATIO SCHEDULE, INDICATING ENHANCED MOTIVATION FOR SELF-ADMINISTERED DRUG. THE EFFECT OF THE HDAC INHIBITOR IS ATTRIBUTED TO THE INCREASED ELEVATION OF HISTONE ACETYLATION INDUCED BY CHRONIC, BUT NOT ACUTE, COCAINE EXPERIENCE. IN CONTRAST, NEUTRALIZING THE CHRONIC COCAINE-INDUCED INCREASE IN HISTONE MODIFICATION BY THE BILATERAL OVEREXPRESSION OF HDAC4 IN THE NAC SHELL REDUCED DRUG MOTIVATION. THE ASSOCIATION BETWEEN THE MOTIVATION FOR COCAINE AND THE TRANSCRIPTIONAL ACTIVATION OF ADDICTION-RELATED GENES BY H3 ACETYLATION IN THE NAC SHELL WAS ANALYZED. AMONG THE GENES ACTIVATED BY CHRONIC COCAINE EXPERIENCES, THE EXPRESSION OF CAMKIIALPHA, BUT NOT CAMKIIBETA, CORRELATED POSITIVELY WITH MOTIVATION FOR THE DRUG. LENTIVIRUS-MEDIATED SHRNA KNOCKDOWN EXPERIMENTS SHOWED THAT CAMKIIALPHA, BUT NOT CAMKIIBETA, IN THE NAC SHELL IS ESSENTIAL FOR THE MAINTENANCE OF MOTIVATION TO SELF-ADMINISTERED COCAINE. THESE FINDINGS SUGGEST THAT CHRONIC DRUG-USE-INDUCED TRANSCRIPTIONAL ACTIVATION OF GENES, SUCH AS CAMKIIALPHA, MODULATED BY H3 ACETYLATION IN THE NAC IS A CRITICAL REGULATORY MECHANISM UNDERLYING MOTIVATION FOR DRUG REINFORCEMENT. 2010 2 3315 43 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 3 6207 41 THE INHIBITION OF HISTONE DEACETYLASES REDUCES THE REINSTATEMENT OF COCAINE-SEEKING BEHAVIOR IN RATS. DRUG ADDICTION IS A CHRONIC BRAIN DISEASE CHARACTERIZED BY A PERSISTENT RISK OF RELAPSE, EVEN AFTER A LONG PERIOD OF ABSTINENCE. A CURRENT HYPOTHESIS STATES THAT RELAPSE RESULTS FROM LASTING NEUROADAPTATIONS THAT ARE INDUCED IN RESPONSE TO REPEATED DRUG ADMINISTRATION. THE ADAPTATIONS REQUIRE GENE EXPRESSION, SOME OF WHICH BEING UNDER THE CONTROL OF STABLE EPIGENETIC REGULATIONS. WE HAVE PREVIOUSLY DEMONSTRATED THAT PRETREATMENT WITH HISTONE DEACETYLASE (HDAC) INHIBITORS REDUCES THE COCAINE REINFORCING PROPERTIES AS WELL AS THE MOTIVATION OF RATS FOR COCAINE. WE SHOW HERE THAT THE SAME HDAC INHIBITORS, TRICHOSTATIN A AND PHENYLBUTYRATE, SIGNIFICANTLY REDUCED THE COCAINE-SEEKING BEHAVIOR INDUCED BY THE COMBINATION OF A COCAINE INJECTION TOGETHER WITH THE EXPOSURE TO A LIGHT CUE PREVIOUSLY ASSOCIATED WITH COCAINE TAKING. REINSTATEMENT OF DRUG-SEEKING BEHAVIOR WAS CARRIED OUT AFTER A 3-WEEK WITHDRAWAL PERIOD, WHICH CAME AFTER TEN DAILY SESSIONS OF COCAINE INTRAVENOUS SELF-ADMINISTRATION. OUR RESULTS SUGGEST THAT PHARMACOLOGICAL TREATMENT AIMED AT MODULATING EPIGENETIC REGULATION, AND PARTICULARLY TREATMENT THAT WOULD INHIBIT HDAC ACTIVITY, COULD REDUCE THE RISK OF RELAPSE, A MAJOR DRAWBACK IN THE TREATMENT OF DRUG ADDICTION. 2011 4 3314 45 HIPPOCAMPAL CANNABINOID 1 RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN MALE RATS. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCING LONG-TERM NEUROPLASTIC CHANGES THAT, IN TURN, CONTRIBUTE TO MALADAPTIVE BEHAVIORS. THIS BEHAVIORAL DYSREGULATION IS ASSOCIATED WITH TRANSCRIPTIONAL REPROGRAMMING IN BRAIN REWARD CIRCUITRY, ALTHOUGH THE MECHANISMS UNDERLYING THIS MODULATION REMAIN POORLY UNDERSTOOD. THE ENDOGENOUS CANNABINOID SYSTEM MAY PLAY A ROLE IN THIS PROCESS IN THAT CANNABINOID MECHANISMS MODULATE DRUG REWARD AND CONTRIBUTE TO COCAINE-INDUCED NEURAL ADAPTATIONS. IN THIS STUDY, WE INVESTIGATED WHETHER COCAINE SELF-ADMINISTRATION INDUCES LONG-TERM ADAPTATIONS, INCLUDING TRANSCRIPTIONAL MODIFICATIONS AND ASSOCIATED EPIGENETIC PROCESSES. WE FIRST EXAMINED ENDOCANNABINOID GENE EXPRESSION IN REWARD-RELATED BRAIN REGIONS OF THE RAT FOLLOWING SELF-ADMINISTERED (0.33 MG/KG INTRAVENOUS, FR1, 10 DAYS) COCAINE INJECTIONS. INTERESTINGLY, WE FOUND INCREASED CNR1 EXPRESSION IN SEVERAL STRUCTURES, INCLUDING PREFRONTAL CORTEX, NUCLEUS ACCUMBENS, DORSAL STRIATUM, HIPPOCAMPUS, HABENULA, AMYGDALA, LATERAL HYPOTHALAMUS, VENTRAL TEGMENTAL AREA, AND ROSTROMEDIAL TEGMENTAL NUCLEUS, WITH MOST PRONOUNCED EFFECTS IN THE HIPPOCAMPUS. ENDOCANNABINOID LEVELS, MEASURED BY MASS SPECTROMETRY, WERE ALSO ALTERED IN THIS STRUCTURE. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR IN THE HIPPOCAMPUS REVEALED THAT TWO ACTIVATING HISTONE MARKS, H3K4ME3 AND H3K27AC, WERE ENRICHED AT SPECIFIC ENDOCANNABINOID GENES FOLLOWING COCAINE INTAKE. TARGETING CB1 RECEPTORS USING CHROMOSOME CONFORMATION CAPTURE, WE HIGHLIGHTED SPATIAL CHROMATIN RE-ORGANIZATION IN THE HIPPOCAMPUS, AS WELL AS IN THE NUCLEUS ACCUMBENS, SUGGESTING THAT DESTABILIZATION OF THE CHROMATIN MAY CONTRIBUTE TO NEURONAL RESPONSES TO COCAINE. OVERALL, OUR RESULTS HIGHLIGHT A KEY ROLE FOR THE HIPPOCAMPUS IN COCAINE-INDUCED PLASTICITY AND BROADEN THE UNDERSTANDING OF NEURONAL ALTERATIONS ASSOCIATED WITH ENDOCANNABINOID SIGNALING. THE LATTER SUGGESTS THAT EPIGENETIC MODIFICATIONS CONTRIBUTE TO MALADAPTIVE BEHAVIORS ASSOCIATED WITH CHRONIC DRUG USE. 2022 5 5535 37 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 4878 47 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 7 4218 48 METHYL SUPPLEMENTATION ATTENUATES COCAINE-SEEKING BEHAVIORS AND COCAINE-INDUCED C-FOS ACTIVATION IN A DNA METHYLATION-DEPENDENT MANNER. EPIGENETIC MECHANISMS, SUCH AS HISTONE MODIFICATIONS, REGULATE RESPONSIVENESS TO DRUGS OF ABUSE, SUCH AS COCAINE, BUT RELATIVELY LITTLE IS KNOWN ABOUT THE REGULATION OF ADDICTIVE-LIKE BEHAVIORS BY DNA METHYLATION. TO INVESTIGATE THE INFLUENCE OF DNA METHYLATION ON THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ON DRUG-SEEKING BEHAVIOR, RATS RECEIVING METHYL SUPPLEMENTATION VIA CHRONIC L-METHIONINE (MET) UNDERWENT EITHER A SENSITIZATION REGIMEN OF INTERMITTENT COCAINE INJECTIONS OR INTRAVENOUS SELF-ADMINISTRATION OF COCAINE, FOLLOWED BY CUE-INDUCED AND DRUG-PRIMED REINSTATEMENT. MET BLOCKED SENSITIZATION TO THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ATTENUATED DRUG-PRIMED REINSTATEMENT, WITH NO EFFECT ON CUE-INDUCED REINSTATEMENT OR SUCROSE SELF-ADMINISTRATION AND REINSTATEMENT. FURTHERMORE, UPREGULATION OF DNA METHYLTRANSFERASE 3A AND 3B AND GLOBAL DNA HYPOMETHYLATION WERE OBSERVED IN THE NUCLEUS ACCUMBENS CORE (NAC), BUT NOT IN THE MEDIAL PREFRONTAL CORTEX (MPFC), OF COCAINE-PRETREATED RATS. GLUTAMATERGIC PROJECTIONS FROM THE MPFC TO THE NAC ARE CRITICALLY INVOLVED IN THE REGULATION OF COCAINE-PRIMED REINSTATEMENT, AND ACTIVATION OF BOTH BRAIN REGIONS IS SEEN IN HUMAN ADDICTS WHEN REEXPOSED TO THE DRUG. WHEN COMPARED WITH VEHICLE-PRETREATED RATS, THE IMMEDIATE EARLY GENE C-FOS (A MARKER OF NEURONAL ACTIVATION) WAS UPREGULATED IN THE NAC AND MPFC OF COCAINE-PRETREATED RATS AFTER COCAINE-PRIMED REINSTATEMENT, AND CHRONIC MET TREATMENT BLOCKED ITS INDUCTION IN BOTH REGIONS. COCAINE-INDUCED C-FOS EXPRESSION IN THE NAC WAS ASSOCIATED WITH REDUCED METHYLATION AT CPG DINUCLEOTIDES IN THE C-FOS GENE PROMOTER, EFFECTS REVERSED BY MET TREATMENT. OVERALL, THESE DATA SUGGEST THAT DRUG-SEEKING BEHAVIORS ARE, IN PART, ATTRIBUTABLE TO A DNA METHYLATION-DEPENDENT PROCESS, LIKELY OCCURRING AT SPECIFIC GENE LOCI (E.G., C-FOS) IN THE REWARD PATHWAY. 2015 8 1677 24 DRUG ADDICTION: HYPERKATIFEIA/NEGATIVE REINFORCEMENT AS A FRAMEWORK FOR MEDICATIONS DEVELOPMENT. COMPULSIVE DRUG SEEKING THAT IS ASSOCIATED WITH ADDICTION IS HYPOTHESIZED TO FOLLOW A HEURISTIC FRAMEWORK THAT INVOLVES THREE STAGES (BINGE/INTOXICATION, WITHDRAWAL/NEGATIVE AFFECT, AND PREOCCUPATION/ANTICIPATION) AND THREE DOMAINS OF DYSFUNCTION (INCENTIVE SALIENCE/PATHOLOGIC HABITS, NEGATIVE EMOTIONAL STATES, AND EXECUTIVE FUNCTION, RESPECTIVELY) VIA CHANGES IN THE BASAL GANGLIA, EXTENDED AMYGDALA/HABENULA, AND FRONTAL CORTEX, RESPECTIVELY. THIS REVIEW FOCUSES ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE ADDICTION CYCLE. HYPERKATIFEIA PROVIDES AN ADDITIONAL SOURCE OF MOTIVATION FOR COMPULSIVE DRUG SEEKING VIA NEGATIVE REINFORCEMENT. NEGATIVE REINFORCEMENT REFLECTS AN INCREASE IN THE PROBABILITY OF A RESPONSE TO REMOVE AN AVERSIVE STIMULUS OR DRUG SEEKING TO REMOVE HYPERKATIFEIA THAT IS AUGMENTED BY GENETIC/EPIGENETIC VULNERABILITY, ENVIRONMENTAL TRAUMA, AND PSYCHIATRIC COMORBIDITY. NEUROBIOLOGICAL TARGETS FOR HYPERKATIFEIA IN ADDICTION INVOLVE NEUROCIRCUITRY OF THE EXTENDED AMYGDALA AND ITS CONNECTIONS VIA WITHIN-SYSTEM NEUROADAPTATIONS IN DOPAMINE, ENKEPHALIN/ENDORPHIN OPIOID PEPTIDE, AND GAMMA-AMINOBUTYRIC ACID/GLUTAMATE SYSTEMS AND BETWEEN-SYSTEM NEUROADAPTATIONS IN PROSTRESS CORTICOTROPIN-RELEASING FACTOR, NOREPINEPHRINE, GLUCOCORTICOID, DYNORPHIN, HYPOCRETIN, AND NEUROIMMUNE SYSTEMS AND ANTISTRESS NEUROPEPTIDE Y, NOCICEPTIN, ENDOCANNABINOID, AND OXYTOCIN SYSTEMS. SUCH NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS ARE HYPOTHESIZED TO MEDIATE A NEGATIVE HEDONIC SET POINT THAT GRADUALLY GAINS ALLOSTATIC LOAD AND SHIFTS FROM A HOMEOSTATIC HEDONIC STATE TO AN ALLOSTATIC HEDONIC STATE. BASED ON PRECLINICAL STUDIES AND TRANSLATIONAL STUDIES TO DATE, MEDICATIONS AND BEHAVIORAL THERAPIES THAT RESET BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURN THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. SIGNIFICANCE STATEMENT: THE FOCUS OF THIS REVIEW IS ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE DRUG ADDICTION CYCLE AND A DRIVING FORCE FOR NEGATIVE REINFORCEMENT IN ADDICTION. MEDICATIONS AND BEHAVIORAL THERAPIES THAT REVERSE HYPERKATIFEIA BY RESETTING BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURNING THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. 2021 9 4930 29 PATERNAL ALCOHOL EXPOSURE REDUCES ACQUISITION OF OPERANT ALCOHOL SELF-ADMINISTRATION AND AFFECTS BDNF DNA METHYLATION IN MALE AND FEMALE OFFSPRING. FAMILIAL TRANSMISSION OF ALCOHOL USE DISORDER REFLECTS GENETIC AND ENVIRONMENTAL FACTORS. PATERNAL ALCOHOL EXPOSURE MAY AFFECT RODENT OFFSPRING VIA EPIGENETIC MODIFICATIONS TRANSMITTED THROUGH THE MALE GERM LINE. WHILE SUCH EXPOSURE ALTERS ALCOHOL SENSITIVITY IN MOUSE OFFSPRING, NO STUDIES EXAMINED IF IT IMPACTS THE DEVELOPMENT OF OPERANT ALCOHOL SELF-ADMINISTRATION IN RATS. WE EXPOSED MALE (SIRES) WISTAR RATS TO CHRONIC INTERMITTENT ETHANOL IN VAPOUR CHAMBERS (16 H/DAY; 5 DAYS/WEEK) OR TO AIR FOR 6 WEEKS. EIGHT WEEKS LATER, RATS WERE MATED WITH ALCOHOL-NAIVE FEMALES. ADULT ALCOHOL- AND CONTROL-SIRED F1 OFFSPRING WERE ASSESSED IN ACQUISITION OF ALCOHOL SELF-ADMINISTRATION IN WHICH INCREASING ALCOHOL CONCENTRATIONS (2.5%, 5% AND 10%, V/V) WERE DELIVERED AFTER ONE LEVER PRESS (FIXED RATIO 1 OR FR1). PRIOR TO ALCOHOL SESSIONS, RATS WERE TRAINED TO LEVER PRESS FOR FOOD DELIVERY UNDER AN FR1 SCHEDULE OF REINFORCEMENT. DNA METHYLATION LEVELS OF THE BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) GENE WERE MEASURED IN SPERM, NUCLEUS ACCUMBENS (NAC) AND MEDIAL PREFRONTAL CORTEX (MPFC) IN SIRES AND IN OFFSPRING. ALCOHOL-EXPOSED SIRES HAD LOWER BDNF DNA METHYLATION LEVELS IN NAC AND GREATER METHYLATION LEVELS IN MPFC. ALTHOUGH THIS PATTERN WAS NOT RECAPITULATED IN OFFSPRING, ALCOHOL-SIRED OFFSPRING OF BOTH SEXES DID SHOW ABERRANT BDNF DNA METHYLATION PATTERNS COMPARED TO CONTROL-SIRED OFFSPRING. ALCOHOL-SIRED OFFSPRING SELF-ADMINISTERED LESS ALCOHOL (5% AND 10%) WITH NO GROUP DIFFERENCES IN FOOD RESPONDING. RESULTS INDICATE THAT PATERNAL ALCOHOL EXPOSURE PRIOR TO CONCEPTION PROTECTS AGAINST ALCOHOL'S INITIAL REINFORCING EFFECTS BUT THE PATTERN OF DYSREGULATED BDNF METHYLATION IN REWARD-RELATED CIRCUITRY DID NOT MIMIC CHANGES SEEN IN SIRES. 2022 10 2670 24 ETHANOL ACTIONS ON THE VENTRAL TEGMENTAL AREA: NOVEL POTENTIAL TARGETS ON REWARD PATHWAY NEURONS. THE VENTRAL TEGMENTAL AREA (VTA) EVALUATES SALIENCE OF ENVIRONMENTAL STIMULI AND PROVIDES DOPAMINERGIC INNERVATION TO MANY BRAIN AREAS AFFECTED BY ACUTE AND CHRONIC ETHANOL EXPOSURE. WHILE PRIMARILY ASSOCIATED WITH REWARDING AND REINFORCING STIMULI, RECENT EVIDENCE INDICATES A ROLE FOR THE VTA IN AVERSION AS WELL. ETHANOL ACTIONS IN THE VTA MAY TRIGGER NEUROADAPTATION RESULTING IN REDUCTION OF THE AVERSIVE RESPONSES TO ALCOHOL AND A RELATIVE INCREASE IN THE REWARDING RESPONSES. IN SEARCHING FOR EFFECTIVE PHARMACOTHERAPIES FOR THE TREATMENT OF ALCOHOL ABUSE AND ALCOHOLISM, RECOGNITION OF THIS IMBALANCE MAY REVEAL NOVEL STRATEGIES. IN ADDITION TO CONVENTIONAL RECEPTOR/ION CHANNEL PHARMACOTHERAPIES, EPIGENETIC FACTORS THAT CONTROL NEUROADAPTATION TO CHRONIC ETHANOL TREATMENT CAN BE TARGETED AS AN AVENUE FOR DEVELOPMENT OF THERAPEUTIC APPROACHES TO RESTORE THE BALANCE. FURTHERMORE, WHEN EXPLORING THERAPIES TO ADDRESS REWARD/AVERSION IMBALANCE IN THE ACTION OF ALCOHOL IN THE VTA, SEX DIFFERENCES HAVE TO BE TAKEN INTO ACCOUNT TO ENSURE EFFECTIVE TREATMENT FOR BOTH MEN AND WOMEN. THESE PRINCIPLES APPLY TO A VTA-CENTRIC APPROACH TO THERAPIES, BUT SHOULD HOLD TRUE WHEN THINKING ABOUT THE OVERALL APPROACH IN THE DEVELOPMENT OF NEUROACTIVE DRUGS TO TREAT ALCOHOL USE DISORDERS. ALTHOUGH THE FUNCTIONS OF THE VTA ITSELF ARE COMPLEX, IT IS A USEFUL MODEL SYSTEM TO EVALUATE THE REWARD/AVERSION IMBALANCE THAT OCCURS WITH ETHANOL EXPOSURE AND COULD BE USED TO PROVIDE NEW LEADS IN THE EFFORTS TO DEVELOP NOVEL DRUGS TO TREAT ALCOHOLISM. 2018 11 2325 38 EPIGENETIC REGULATION OF HIPPOCAMPAL FOSB EXPRESSION CONTROLS BEHAVIORAL RESPONSES TO COCAINE. DRUG ADDICTION RESULTS IN PART FROM MALADAPTIVE LEARNING, INCLUDING THE FORMATION OF STRONG ASSOCIATIONS BETWEEN THE DRUG AND THE CIRCUMSTANCES OF CONSUMPTION. HOWEVER, DRUG-INDUCED CHANGES IN GENE EXPRESSION UNDERLYING THE SALIENCY OF THESE ASSOCIATIONS REMAIN UNDERSTUDIED. CONSOLIDATION OF EXPLICIT MEMORIES OCCURS WITHIN THE HIPPOCAMPUS, AND WE HAVE SHOWN THAT SPATIAL LEARNING INDUCES EXPRESSION OF THE TRANSCRIPTION FACTOR DELTAFOSB IN HIPPOCAMPUS AND THAT THIS INDUCTION IS CRITICAL FOR LEARNING. DRUGS OF ABUSE ALSO UPREGULATE DELTAFOSB IN HIPPOCAMPUS, BUT THE MECHANISM OF ITS INDUCTION BY COCAINE AND ITS ROLE IN HIPPOCAMPUS-DEPENDENT COCAINE RESPONSES IS UNKNOWN. WE INVESTIGATED DIFFERENCES IN MOUSE DORSAL AND VENTRAL HIPPOCAMPAL DELTAFOSB EXPRESSION IN RESPONSE TO CHRONIC COCAINE, BECAUSE THESE REGIONS APPEAR TO REGULATE DISTINCT COCAINE-RELATED BEHAVIORS. WE FOUND THAT COCAINE-MEDIATED INDUCTION OF DELTAFOSB WAS SUBREGION-SPECIFIC, AND THAT DELTAFOSB TRANSCRIPTIONAL ACTIVITY IN BOTH THE DORSAL AND VENTRAL HIPPOCAMPUS IS NECESSARY FOR COCAINE CONDITIONED PLACE PREFERENCE. FURTHER, WE CHARACTERIZE CHANGES IN HISTONE MODIFICATIONS AT THE FOSB PROMOTER IN HIPPOCAMPUS IN RESPONSE TO CHRONIC COCAINE AND FOUND THAT LOCUS-SPECIFIC EPIGENETIC MODIFICATION IS ESSENTIAL FOR FOSB INDUCTION AND MULTIPLE HIPPOCAMPUS-DEPENDENT BEHAVIORS, INCLUDING COCAINE PLACE PREFERENCE. COLLECTIVELY, THESE FINDINGS SUGGEST THAT EXPOSURE TO COCAINE INDUCES HISTONE MODIFICATION AT THE HIPPOCAMPAL FOSB GENE PROMOTER TO CAUSE DELTAFOSB INDUCTION CRITICAL FOR COCAINE-RELATED LEARNING.SIGNIFICANCE STATEMENT ALTHOUGH COCAINE ADDICTION IS DRIVEN IN PART BY THE FORMATION OF INDELIBLE ASSOCIATIONS BETWEEN THE DRUG AND THE ENVIRONMENT, PARAPHERNALIA, AND CIRCUMSTANCES OF USE, AND ALTHOUGH THIS TYPE OF ASSOCIATIVE LEARNING IS DEPENDENT UPON CHANGES IN GENE EXPRESSION IN A BRAIN REGION CALLED THE HIPPOCAMPUS, THE MECHANISMS BY WHICH COCAINE ALTERS HIPPOCAMPAL GENE EXPRESSION TO DRIVE FORMATION OF THESE ASSOCIATIONS IS POORLY UNDERSTOOD. HERE, WE DEMONSTRATE THAT CHRONIC COCAINE ENGAGES LOCUS-SPECIFIC CHANGES IN THE EPIGENETIC PROFILE OF THE FOSB GENE IN THE HIPPOCAMPUS, AND THAT THESE ALTERATIONS ARE REQUIRED FOR COCAINE-DEPENDENT GENE EXPRESSION AND COCAINE-ENVIRONMENT ASSOCIATIONS. THIS WORK PROVIDES NOVEL INSIGHT INTO ADDICTION ETIOLOGY AND POTENTIAL INROADS FOR THERAPEUTIC INTERVENTION IN COCAINE ADDICTION. 2019 12 4937 29 PATERNAL MORPHINE EXPOSURE IN RATS REDUCES SOCIAL PLAY IN ADOLESCENT MALE PROGENY WITHOUT AFFECTING DRUG-TAKING BEHAVIOR IN JUVENILE MALES OR FEMALE OFFSPRING. THE ONGOING OPIOID ADDICTION CRISIS NECESSITATES THE IDENTIFICATION OF NOVEL RISK FACTORS TO IMPROVE PREVENTION AND TREATMENT OF OPIOID USE DISORDER. PARENTAL OPIOID EXPOSURE HAS RECENTLY EMERGED AS A POTENTIAL REGULATOR OF OFFSPRING VULNERABILITY TO OPIOID MISUSE, IN ADDITION TO HERITABLE GENETIC LIABILITY. AN UNDERSTUDIED ASPECT OF THIS "MISSING HERITABILITY" IS THE DEVELOPMENTAL PRESENTATION OF THESE CROSS-GENERATIONAL PHENOTYPES. THIS IS AN ESPECIALLY RELEVANT QUESTION IN THE CONTEXT OF INHERITED ADDICTION-RELATED PHENOTYPES, GIVEN THE PROMINENT ROLE OF DEVELOPMENTAL PROCESSES IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. PATERNAL MORPHINE SELF-ADMINISTRATION WAS PREVIOUSLY SHOWN TO ALTER THE SENSITIVITY TO THE REINFORCING AND ANTINOCICEPTIVE PROPERTIES OF OPIOIDS IN THE NEXT GENERATION. HERE, PHENOTYPING WAS EXPANDED TO INCLUDE THE ADOLESCENT PERIOD, WITH A FOCUS ON ENDOPHENOTYPES RELATED TO OPIOID USE DISORDERS AND PAIN. PATERNAL MORPHINE EXPOSURE DID NOT ALTER HEROIN OR COCAINE SELF-ADMINISTRATION IN MALE AND FEMALE JUVENILE PROGENY. FURTHER, BASELINE SENSORY REFLEXES RELATED TO PAIN WERE UNALTERED IN MORPHINE-SIRED ADOLESCENT RATS OF EITHER SEX. HOWEVER, MORPHINE-SIRED ADOLESCENT MALES EXHIBITED A REDUCTION IN SOCIAL PLAY BEHAVIOR. OUR FINDINGS SUGGEST THAT, IN MORPHINE-SIRED MALE OFFSPRING, PATERNAL OPIOID EXPOSURE DOES NOT AFFECT OPIOID INTAKE DURING ADOLESCENCE, SUGGESTING THAT THIS PHENOTYPE DOES NOT EMERGE UNTIL LATER IN LIFE. ALTERED SOCIAL BEHAVIORS IN MALE MORPHINE-SIRED ADOLESCENTS INDICATE THAT THE CHANGES IN DRUG-TAKING BEHAVIOR IN ADULTS SIRED BY MORPHINE-EXPOSED SIRES MAY BE DUE TO MORE COMPLEX FACTORS NOT YET FULLY ASSESSED. 2023 13 3203 45 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 14 242 39 ADOLESCENT CANNABINOID EXPOSURE MODULATES THE VULNERABILITY TO COCAINE-INDUCED CONDITIONED PLACE PREFERENCE AND DNMT3A EXPRESSION IN THE PREFRONTAL CORTEX IN SWISS MICE. RATIONALE: CANNABIS SATIVA IS THE MOST WIDELY USED DRUG BY ADOLESCENTS GLOBALLY. THE RECREATIONAL USE OF SYNTHETIC CANNABINOIDS BY TEENAGERS HAS ALSO GROWN IN RECENT YEARS. DESPITE THE WRONG PERCEPTION THAT EXPOSURE TO THESE DRUGS DOES NOT CAUSE HARM, REPEATED EXPOSURE TO CANNABINOIDS AT EARLY STAGES OF LIFE COMPROMISES IMPORTANT MATURATION PROCESSES AND BRAIN DEVELOPMENT. CHRONIC EARLY CANNABINOID USE HAS BEEN RELATED TO A HIGHER RISK OF PSYCHIATRIC OUTCOMES, INCLUDING COCAINE ADDICTION. EVIDENCE SUGGESTS THAT EXPOSURE TO NATURAL AND SYNTHETIC CANNABINOIDS DURING ADOLESCENCE MODIFIES MOLECULAR AND BEHAVIORAL EFFECTS OF COCAINE IN ADULTHOOD. RESPONSES TO COCAINE ARE REGULATED BY EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, IN THE BRAIN'S REWARD REGIONS. HOWEVER, THE INVOLVEMENT OF THESE PROCESSES IN MODULATION OF THE VULNERABILITY TO THE EFFECTS OF COCAINE INDUCED BY PRIOR EXPOSURE TO CANNABINOIDS REMAINS POORLY UNDERSTOOD. OBJECTIVES: INVESTIGATE WHETHER EXPOSURE TO THE SYNTHETIC CANNABINOID WIN55,212-2 DURING ADOLESCENCE MODULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIOR, MEMORY, AND COCAINE REWARD IN ADULT MICE. WE ALSO EVALUATED WHETHER EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE MODULATES THE EXPRESSION OF ENZYMES THAT ARE INVOLVED IN DNA METHYLATION. RESULTS: EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE DID NOT ALTER ANXIETY- OR DEPRESSIVE-LIKE BEHAVIOR. HOWEVER, PRIOR EXPOSURE TO CANNABINOIDS INHIBITED COCAINE-INDUCED CONDITIONED PLACE PREFERENCE WITHOUT MODULATING COCAINE-INDUCED HYPERLOCOMOTION, ACCOMPANIED BY AN INCREASE IN EXPRESSION OF THE ENZYME DNA METHYLTRANSFERASE 3A (DNMT3A) IN THE PREFRONTAL CORTEX. CONCLUSIONS: OUR FINDINGS SUGGEST THAT EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE LEADS TO CHANGES IN DNMT3A EXPRESSION, AND THIS PATHWAY APPEARS TO BE RELEVANT TO MODULATING THE REWARDING EFFECTS OF COCAINE. 2021 15 1086 42 COCAINE ADMINISTRATION AND ITS WITHDRAWAL ENHANCE THE EXPRESSION OF GENES ENCODING HISTONE-MODIFYING ENZYMES AND HISTONE ACETYLATION IN THE RAT PREFRONTAL CORTEX. CHRONIC EXPOSURE TO COCAINE, CRAVING, AND RELAPSE ARE ATTRIBUTED TO LONG-LASTING CHANGES IN GENE EXPRESSION ARISING THROUGH EPIGENETIC AND TRANSCRIPTIONAL MECHANISMS. ALTHOUGH SEVERAL BRAIN REGIONS ARE INVOLVED IN THESE PROCESSES, THE PREFRONTAL CORTEX SEEMS TO PLAY A CRUCIAL ROLE NOT ONLY IN MOTIVATION AND DECISION-MAKING BUT ALSO IN EXTINCTION AND SEEKING BEHAVIOR. IN THIS STUDY, WE APPLIED COCAINE SELF-ADMINISTRATION AND EXTINCTION TRAINING PROCEDURES IN RATS WITH A YOKED TRIAD TO DETERMINE DIFFERENTIALLY EXPRESSED GENES IN PREFRONTAL CORTEX. MICROARRAY ANALYSIS SHOWED SIGNIFICANT UPREGULATION OF SEVERAL GENES ENCODING HISTONE MODIFICATION ENZYMES DURING EARLY EXTINCTION TRAINING. SUBSEQUENT REAL-TIME PCR TESTING OF THESE GENES FOLLOWING COCAINE SELF-ADMINISTRATION OR EARLY (THIRD DAY) AND LATE (TENTH DAY) EXTINCTION REVEALED ELEVATED LEVELS OF THEIR TRANSCRIPTS. INTERESTINGLY, WE FOUND THE ENRICHMENT OF BRD1 MESSENGER RNA IN RATS SELF-ADMINISTERING COCAINE THAT LASTED UNTIL EXTINCTION TRAINING DURING COCAINE WITHDRAWAL WITH CONCOMITANT INCREASED ACETYLATION OF H3K9 AND H4K8. HOWEVER, DESPITE ELEVATED LEVELS OF METHYL- AND DEMETHYLTRANSFERASE-ENCODED TRANSCRIPTS, NO CHANGES IN GLOBAL DI- AND TRI-METHYLATION OF HISTONE H3 AT LYSINE 4, 9, 27, AND 79 WERE OBSERVED. SURPRISINGLY, AT THE END OF EXTINCTION TRAINING (10 DAYS OF COCAINE WITHDRAWAL), MOST OF THE ANALYZED GENES IN THE RATS ACTIVELY AND PASSIVELY ADMINISTERING COCAINE RETURNED TO THE CONTROL LEVEL. TOGETHER, THE ALTERATIONS IDENTIFIED IN THE RAT PREFRONTAL CORTEX MAY SUGGEST ENHANCED CHROMATIN REMODELING AND TRANSCRIPTIONAL ACTIVITY INDUCED BY EARLY COCAINE ABSTINENCE; HOWEVER, TO KNOW WHETHER THEY ARE BENEFICIAL OR NOT FOR THE EXTINCTION OF DRUG-SEEKING BEHAVIOR, FURTHER IN VIVO EVALUATION IS REQUIRED. 2017 16 4639 33 NEURONAL EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) ACTIVITY AS MARKER AND MEDIATOR OF ALCOHOL AND OPIOID DEPENDENCE. EARLY PIONEERING WORK IN THE FIELD OF BIOCHEMISTRY IDENTIFIED PHOSPHORYLATION AS A CRUCIAL POST-TRANSLATIONAL MODIFICATION OF PROTEINS WITH THE ABILITY TO BOTH INDICATE AND ARBITRATE COMPLEX PHYSIOLOGICAL PROCESSES. MORE RECENT INVESTIGATIONS HAVE FUNCTIONALLY LINKED PHOSPHORYLATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) TO A VARIETY OF NEUROPHYSIOLOGICAL MECHANISMS RANGING FROM ACUTE NEUROTRANSMITTER ACTION TO LONG-TERM GENE EXPRESSION. ERK PHOSPHORYLATION SERVES AS AN INTRACELLULAR BRIDGING MECHANISM THAT FACILITATES NEURONAL COMMUNICATION AND PLASTICITY. DRUGS OF ABUSE, INCLUDING ALCOHOL AND OPIOIDS, ACT AS ARTIFICIAL YET POWERFUL REWARDS THAT IMPINGE UPON NATURAL REINFORCEMENT PROCESSES CRITICAL FOR SURVIVAL. THE GRADED PROGRESSION FROM INITIAL EXPOSURE TO ADDICTION (OR SUBSTANCE DEPENDENCE) IS BELIEVED TO RESULT FROM DRUG- AND DRUG CONTEXT-INDUCED ADAPTATIONS IN NEURONAL SIGNALING PROCESSES ACROSS BRAIN REWARD AND STRESS CIRCUITS FOLLOWING EXCESSIVE DRUG USE. IN THIS REGARD, COMMONLY ABUSED DRUGS AS WELL AS DRUG-ASSOCIATED EXPERIENCES ARE CAPABLE OF MODIFYING THE PHOSPHORYLATION OF ERK WITHIN CENTRAL REINFORCEMENT SYSTEMS. IN ADDITION, CHRONIC DRUG AND ALCOHOL EXPOSURE MAY DRIVE ERK-REGULATED EPIGENETIC AND STRUCTURAL ALTERATIONS THAT UNDERLIE A LONG-TERM PROPENSITY FOR ESCALATING DRUG USE. UNDER THE INFLUENCE OF SUCH A NEUROBIOLOGICAL VULNERABILITY, ENCOUNTERING DRUG-ASSOCIATED CUES AND CONTEXTS CAN PRODUCE SUBSEQUENT ALTERATIONS IN ERK SIGNALING THAT DRIVE RELAPSE TO DRUG AND ALCOHOL SEEKING. CURRENT STUDIES ARE DETERMINING PRECISELY WHICH MOLECULAR AND REGIONAL ERK PHOSPHORYLATION-ASSOCIATED EVENTS CONTRIBUTE TO THE ADDICTION PROCESS, AS WELL AS WHICH NEUROADAPTATIONS NEED TO BE TARGETED IN ORDER TO RETURN DEPENDENT INDIVIDUALS TO A HEALTHY STATE. 2014 17 4848 25 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 5804 30 STRAIN AND SEX DEPENDENT EFFECTS OF ISOLATION HOUSING RELATIVE TO ENVIRONMENTAL ENRICHMENT ON OPERANT SENSATION SEEKING IN MICE. SENSATION SEEKING IS A MULTIDIMENSIONAL PHENOTYPE THAT PREDICTS THE DEVELOPMENT OF DRUG ADDICTION IN HUMANS AND ADDICTION-LIKE DRUG SEEKING IN RODENTS. SEVERAL LINES OF EVIDENCE SUGGEST THAT CHRONIC STRESS INCREASES SENSATION SEEKING AND ADDICTION-LIKE DRUG SEEKING THROUGH COMMON GENETIC MECHANISMS. DISCOVERY AND CHARACTERIZATION OF THESE MECHANISMS WOULD REVEAL HOW CHRONIC STRESS INTERACTS WITH THE GENOME TO INFLUENCE SENSATION SEEKING AND HOW DRUGS OF ABUSE HIJACK THESE FUNDAMENTAL REWARD MECHANISMS TO DRIVE ADDICTION. TO THIS END, WE TESTED THE HYPOTHESIS THAT CHRONIC ISOLATION HOUSING STRESS (RELATIVE TO ENVIRONMENTAL ENRICHMENT) INFLUENCES OPERANT SENSATION SEEKING AS A FUNCTION OF STRAIN, SEX, OR THEIR INTERACTION. TO DETERMINE IF THE BXD RECOMBINANT INBRED PANEL COULD BE USED TO IDENTIFY GENETIC AND EPIGENETIC MECHANISMS UNDERLYING ANY IDENTIFIED GENE-BY-ENVIRONMENT INTERACTIONS, WE USED MICE FROM THE TWO BXD FOUNDER STRAINS. FOLLOWING 10 WEEKS OF DIFFERENTIAL HOUSING, WE ASSESSED OPERANT SENSATION SEEKING USING SEVERAL REINFORCEMENT SCHEDULES. THE PRIMARY FINDING FROM THIS STUDY WAS THAT DBA/2J BUT NOT C57BL/6J MICE WERE SIGNIFICANTLY VULNERABLE TO AN ISOLATION-INDUCED INCREASE (RELATIVE TO ENVIRONMENTAL ENRICHMENT) IN SENSATION SEEKING DURING EXTINCTION WHEN THE SENSORY REWARD WAS NO LONGER AVAILABLE; THIS EFFECT WAS SIGNIFICANTLY MORE ROBUST IN FEMALES. THESE DATA REVEAL A PREVIOUSLY UNKNOWN ISOLATION-INDUCED EFFECT ON EXTINCTION OF OPERANT SENSATION SEEKING THAT IS SEX-DEPENDENT, ADDICTION-RELEVANT, AND THAT CAN BE DISSECTED USING THE BXD RECOMBINANT INBRED PANEL. 2021 19 5444 39 REPEATED TOLUENE EXPOSURE MODIFIES THE ACETYLATION PATTERN OF HISTONES H3 AND H4 IN THE RAT BRAIN. TOLUENE IS A VOLATILE ORGANIC SOLVENT WITH ADDICTIVE POTENTIAL THAT EXHIBITS SIMILARITIES IN ITS PHYSIOLOGICAL EFFECTS AND MODES OF ACTION TO OTHER ADDICTIVE DRUGS. DESPITE ITS WIDESPREAD ABUSE, THE MOLECULAR MECHANISMS DRIVING THE RESPONSE AND ADAPTATION OF THE ORGANISM TO THIS DRUG ARE NOT FULLY UNDERSTOOD. IN RECENT YEARS, DIFFERENT EPIGENETIC MECHANISMS THAT MODULATE GENE EXPRESSION HAVE BEEN SHOWN TO BE ASSOCIATED TO COCAINE, AMPHETAMINE AND ALCOHOL MISUSE-INDUCED ALTERATIONS IN NEURONAL FUNCTION. FOR EXAMPLE, IT HAS BEEN DEMONSTRATED THAT DRUG CONSUMPTION INDUCES VARIATIONS IN HISTONE ACETYLATION LEVELS IN BRAIN REWARD REGIONS AND THESE PLAY A RELEVANT ROLE ON THE ABUSE-ASSOCIATED BEHAVIORAL PLASTICITY. IN ORDER TO DECIPHER WHETHER REPEATED TOLUENE EXPOSURE COULD MEDIATE EPIGENETIC CHANGES IN THE RAT BRAIN, WE HERE ANALYZED THE ACETYLATION PATTERN OF HISTONES H3 AND H4 IN THREE BRAIN AREAS THAT HAVE BEEN PREVIOUSLY ASSOCIATED TO SUBSTANCE ABUSE REWARD PATHWAYS: THE NUCLEUS ACCUMBENS (NAC), THE VENTRAL TEGMENTAL AREA (VTA) AND THE CENTRAL AMYGDALA (CEA). USING IMMUNOFLUORESCENCE ANALYSIS OF BRAIN SECTIONS WITH SPECIFIC ANTIBODIES THAT RECOGNIZE THE ACETYLATED FORMS OF HISTONES H3 AND H4, WE DEMONSTRATE THAT CHRONIC TOLUENE INHALATION DIFFERENTIALLY MODIFIES HISTONE H3 AND H4 ACETYLATION IN THE NAC AND THE VTA WHILE NO EFFECT IS OBSERVED IN THE CEA. OUR RESULTS SUGGEST THAT THE ACTIVITY OF CHROMATIN-MODIFYING ENZYMES SUCH AS HISTONE DE-ACETYLASES (HDACS) IN CERTAIN BRAIN AREAS ARE RESPONSIVE TO TOLUENE INHALATION AND MIGHT BE CRUCIAL MEDIATORS IN THE ADDICTIVE RESPONSE TO TOLUENE. 2011 20 4938 29 PATERNAL NICOTINE ENHANCES FEAR MEMORY, REDUCES NICOTINE ADMINISTRATION, AND ALTERS HIPPOCAMPAL GENETIC AND NEURAL FUNCTION IN OFFSPRING. NICOTINE USE REMAINS HIGHLY PREVALENT WITH TOBACCO AND E-CIGARETTE PRODUCTS CONSUMED WORLDWIDE. HOWEVER, INCREASING EVIDENCE OF TRANSGENERATIONAL EPIGENETIC INHERITANCE SUGGESTS THAT NICOTINE USE MAY ALTER BEHAVIOR AND NEUROBIOLOGY IN SUBSEQUENT GENERATIONS. WE TESTED THE EFFECTS OF CHRONIC PATERNAL NICOTINE EXPOSURE IN C57BL6/J MICE ON FEAR CONDITIONING IN F1 AND F2 OFFSPRING, AS WELL AS CONDITIONED FEAR EXTINCTION AND SPONTANEOUS RECOVERY, NICOTINE SELF-ADMINISTRATION, HIPPOCAMPAL CHOLINERGIC FUNCTIONING, RNA EXPRESSION, AND DNA METHYLATION IN F1 OFFSPRING. PATERNAL NICOTINE EXPOSURE WAS ASSOCIATED WITH ENHANCED CONTEXTUAL AND CUED FEAR CONDITIONING AND SPONTANEOUS RECOVERY OF EXTINGUISHED FEAR MEMORIES. FURTHER, NICOTINE REINFORCEMENT WAS REDUCED IN NICOTINE-SIRED MICE, AS ASSESSED IN A SELF-ADMINISTRATION PARADIGM. THESE BEHAVIORAL PHENOTYPES WERE COUPLED WITH ALTERED RESPONSE TO NICOTINE, UPREGULATED HIPPOCAMPAL NICOTINIC ACETYLCHOLINE RECEPTOR BINDING, REDUCED EVOKED HIPPOCAMPAL CHOLINERGIC CURRENTS, AND ALTERED METHYLATION AND EXPRESSION OF HIPPOCAMPAL GENES RELATED TO NEURAL DEVELOPMENT AND PLASTICITY. GENE EXPRESSION ANALYSIS SUGGESTS MULTIGENERATIONAL EFFECTS ON BROADER GENE NETWORKS POTENTIALLY INVOLVED IN NEUROPLASTICITY AND MENTAL DISORDERS. THE CHANGES IN FEAR CONDITIONING SIMILARLY SUGGEST PHENOTYPES ANALOGOUS TO ANXIETY DISORDERS SIMILAR TO POST-TRAUMATIC STRESS. 2021