1 1460 147 DISORDERS OF CONSCIOUSNESS AND PHARMACEUTICALS THAT ACT ON OXYGEN BASED AMINO ACID AND MONOAMINE NEUROTRANSMITTER PATHWAYS OF THE BRAIN. OXYGEN BASED NEUROTRANSMITTERS IN THE SYNAPSES OF THE BRAIN ARE PROPOSED TO PLAY AN IMPORTANT ROLE IN THE GENERATION OF CONSCIOUSNESS. THEY INCLUDE THE AMINO ACIDS GLUTAMATE AND GABA WHICH USE KREBS CYCLE PRECURSORS FOR THEIR SYNTHESIS, AND THE MONOAMINES DOPAMINE, NORADRENALIN, ADRENALIN AND SEROTONIN, WHICH ARE DERIVED FROM TYROSINE AND TRYPTOPHAN. DURING ISCHEMIA AFTER AN ACUTE BRAIN INJURY, A GABA SURGE OFTEN INITIATES BRAIN SUPPRESSION. IT HAS BEEN PROPOSED THAT WITH CHRONIC ISCHEMIA, A SECONDARY, POSSIBLY EPIGENETIC RESPONSE OCCURS WHEN NEUROTRANSMITTERS DEPLETE, A GLUCOSE AND OXYGEN SAVING MECHANISM TERMED NEURODORMANCY THAT MAY INVOKE ALTERNATIVE LONG TERM LOW ENERGY METABOLIC PATHWAYS IN THE BRAIN, ENCOUNTERED IN DISORDERS OF CONSCIOUSNESS. SOME MEDICATIONS CAN REVERSE DISORDERS OF CONSCIOUSNESS IN SOME PATIENTS. VIRTUALLY ALL OF THEM ACT ON NEUROTRANSMITTER SYSTEMS THAT USE OXYGEN AS A BUILDING BLOCK OR AS AN ENERGY SOURCE WITHIN THE BRAIN. PHARMACEUTICALS THAT ACT IN THE OXYGEN BASED AMINO ACID SYSTEMS OF THE BRAIN INCLUDE THE GABAERGIC MEDICATIONS ZOLPIDEM AND BACLOFEN, WHILE THOSE THAT ACT IN THE MONOAMINE AXES INCLUDE THE DOPAMINERGIC MEDICATIONS L DOPA, AMANTADINE, BROMOCRIPTINE, APOMORPHINE AND METHYLPHENIDATE, AND THE NORADRENERGIC AND SEROTONERGIC MEDICATIONS DESIPRAMINE, AMITRIPTYLINE, PROTRIPTYLINE AND FLUOXETINE. ANOTHER GROUP ARE THE CHOLINESTERASE INHIBITORS, RESPONSIBLE FOR INCREASING ACETYLCHOLINE, WHICH IS SYNTHESIZED FROM THE KREBS CYCLE INITIATOR, ACETYL COA. IT APPEARS THAT PHARMACEUTICALS THAT ARE ACTIVE IN THE OXYGEN BASED NEUROTRANSMITTER PATHWAYS OF THE BRAIN ARE SUCCESSFUL TO AROUSE TO CONSCIOUSNESS PATIENTS THAT SUFFER FROM ITS DISORDERS. RESEARCH NEEDS TO BE SUPPORTED AS FOUNDATION TO UNDERSTAND THE BIOCHEMICAL MECHANISMS THAT ARE INVOLVED IN CONSCIOUSNESS DISORDERS AND TO EXPLORE FURTHER THE PHARMACOLOGICAL TREATMENT POSSIBILITIES FOR THESE DEVASTATING NEUROLOGICAL CONDITIONS. 2014 2 3774 23 INTERACTION OF GONADAL HORMONES, DOPAMINERGIC SYSTEM, AND EPIGENETIC REGULATION IN THE GENERATION OF SEX DIFFERENCES IN SUBSTANCE USE DISORDERS: A SYSTEMATIC REVIEW. SUBSTANCE USE DISORDER (SUD) IS A CHRONIC CONDITION CHARACTERIZED BY PATHOLOGICAL DRUG-TAKING AND SEEKING BEHAVIORS. REMARKABLY DIFFERENT BETWEEN MALES AND FEMALES, SUGGESTING THAT DRUG ADDICTION IS A SEXUALLY DIFFERENTIATED DISORDER. THE NEUROBIOLOGICAL BASES OF SEX DIFFERENCES IN SUD INCLUDE SEX-SPECIFIC REWARD SYSTEM ACTIVATION, INFLUENCED BY INTERACTIONS BETWEEN GONADAL HORMONE LEVEL CHANGES, DOPAMINERGIC REWARD CIRCUITS, AND EPIGENETIC MODIFICATIONS OF KEY REWARD SYSTEM GENES. THIS SYSTEMATIC REVIEW, ADHERING TO PICOS AND PRISMA-P 2015 GUIDELINES, HIGHLIGHTS THE SEX-DEPENDENT ROLES OF ESTROGENS, PROGESTERONE, AND TESTOSTERONE IN SUD. IN PARTICULAR, ESTRADIOL ELEVATES AND PROGESTERONE REDUCES DOPAMINERGIC ACTIVITY IN SUD FEMALES, WHILST TESTOSTERONE AND PROGESTERONE AUGMENT SUD BEHAVIOR IN MALES. FINALLY, SUD IS ASSOCIATED WITH A SEX-SPECIFIC INCREASE IN THE RATE OF OPIOID AND MONOAMINERGIC GENE METHYLATION. THE STUDY REVEALS THE NEED FOR DETAILED RESEARCH ON GONADAL HORMONE LEVELS, DOPAMINERGIC OR REWARD SYSTEM ACTIVITY, AND EPIGENETIC LANDSCAPES IN BOTH SEXES FOR EFFICIENT SUD THERAPY DEVELOPMENT. 2023 3 4848 28 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 4 4647 43 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 5 747 25 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 6 6775 31 [ALCOHOL DEPENDENCE MEDIATED BY MONOAMINE NEUROTRANSMITTERS IN THE CENTRAL NERVOUS SYSTEM]. ALCOHOL DEPENDENCE, A CHRONIC RELAPSING BRAIN DISEASE WITH THE CHARACTERISTICS OF DRINKING ALCOHOL OUT OF CONTROL, HAS BECOME A SERIOUS SOCIAL PROBLEM. MONOAMINE NEUROTRANSMITTERS, MAINLY INCLUDING DOPAMINE AND 5-HYDROXYTRYP NOTTAMINE, PLAY IMPORTANT ROLES IN THE OCCURRENCE, DEVELOPMENT AND NEURAL DYSFUNCTION OF ALCOHOL DEPENDENCE SYNDROME. IN THIS REVIEW, THE ROLES OF KEY FACTORS OF THE MONOAMINE SYSTEM (DOPAMINE RECEPTOR GENES, 5-HYDROXYTRYPTAMINE RECEPTOR GENES, TRANSPORTER GENES, TYROSINE HYDROXYLASE GENE, TRYPTOPHANHYDROXYLASE GENE AND MONOAMINE OXIDASE GENE) IN ALCOHOL DEPENDENCE WERE DISCUSSED, AND STRATEGIES FOR FURTHER STUDIES OF MOLECULAR MECHANISMS WERE PROPOSED BASED ON GENE KNOCKOUT MICE MODELS GENERATED IN OUR LABORATORY. THEN, COMBINING WITH STUDIES ON TYROSINE HYDROXYLASE ACTIVATOR CAMKII IN OUR LAB, THERAPEUTIC TARGETS WERE DISCUSSED. BESIDES, EPIGENETIC STRATEGIES FOR PREVENTION AND TREATMENT OF ALCOHOL DEPENDENCE SYNDROME WERE PROPOSED. FURTHERMORE, MANIPULATING METHYLATION LEVELS IN GENE REGULATORY REGIONS AND ALTERNATIVE SPLICING OF PRE-MRNAS MIGHT ALSO HAVE CLINICAL IMPLICATIONS. FINALLY, BASED ON NEW FINDINGS ON GENETIC POLYMORPHISM, IT IS OF GREAT POTENTIAL TO CARRY OUT INDIVIDUAL PREVENTION AND TREATMENT FOR PATIENTS SUFFERING FROM ALCOHOL DEPENDENCE. 2014 7 4632 26 NEUROIMAGING GENETIC APPROACHES TO POSTTRAUMATIC STRESS DISORDER. NEUROIMAGING GENETIC STUDIES THAT ASSOCIATE GENETIC AND EPIGENETIC VARIATION WITH NEURAL ACTIVITY OR STRUCTURE PROVIDE AN OPPORTUNITY TO LINK GENES TO PSYCHIATRIC DISORDERS, OFTEN BEFORE PSYCHOPATHOLOGY IS DISCERNABLE IN BEHAVIOR. HERE WE REVIEW NEUROIMAGING GENETICS STUDIES WITH PARTICIPANTS WHO HAVE POSTTRAUMATIC STRESS DISORDER (PTSD). RESULTS SHOW THAT GENES RELATED TO THE PHYSIOLOGICAL STRESS RESPONSE (E.G., GLUCOCORTICOID RECEPTOR AND ACTIVITY, NEUROENDOCRINE RELEASE), LEARNING AND MEMORY (E.G., PLASTICITY), MOOD, AND PAIN PERCEPTION ARE TIED TO NEURAL INTERMEDIATE PHENOTYPES ASSOCIATED WITH PTSD. THESE GENES ARE ASSOCIATED WITH AND SOMETIMES PREDICT NEURAL STRUCTURE AND FUNCTION IN AREAS INVOLVED IN ATTENTION, EXECUTIVE FUNCTION, MEMORY, DECISION-MAKING, EMOTION REGULATION, SALIENCE OF POTENTIAL THREATS, AND PAIN PERCEPTION. EVIDENCE SUGGESTS THESE RISK POLYMORPHISMS AND NEURAL INTERMEDIATE PHENOTYPES ARE VULNERABILITIES TOWARD DEVELOPING PTSD IN THE AFTERMATH OF TRAUMA, OR VULNERABILITIES TOWARD PARTICULAR SYMPTOMS ONCE PTSD HAS DEVELOPED. WORK DISTINGUISHING BETWEEN THE RE-EXPERIENCING AND DISSOCIATIVE SUB-TYPES OF PTSD, AND EXAMINING OTHER PTSD SYMPTOM CLUSTERS IN ADDITION TO THE RE-EXPERIENCING AND HYPERAROUSAL SYMPTOMS, WILL FURTHER CLARIFY NEUROBIOLOGICAL MECHANISMS AND INCONSISTENT FINDINGS. FURTHERMORE, AN EXCITING POSSIBILITY IS THAT GENETIC ASSOCIATIONS WITH PTSD MAY EVENTUALLY BE UNDERSTOOD THROUGH DIFFERENTIAL INTERMEDIATE PHENOTYPES OF NEURAL CIRCUIT STRUCTURE AND FUNCTION, POSSIBLY UNDERLYING THE DIFFERENT SYMPTOM CLUSTERS SEEN WITHIN PTSD. 2016 8 6266 23 THE NEUROBIOLOGY OF SUICIDE. THE STRESS-DIATHESIS MODEL POSITS THAT SUICIDE IS THE RESULT OF AN INTERACTION BETWEEN STATE-DEPENDENT (ENVIRONMENTAL) STRESSORS AND A TRAIT-LIKE DIATHESIS OR SUSCEPTIBILITY TO SUICIDAL BEHAVIOUR, INDEPENDENT OF PSYCHIATRIC DISORDERS. FINDINGS FROM POST-MORTEM STUDIES OF THE BRAIN AND FROM GENOMIC AND IN-VIVO NEUROIMAGING STUDIES INDICATE A BIOLOGICAL BASIS FOR THIS DIATHESIS, INDICATING THE IMPORTANCE OF NEUROBIOLOGICAL SCREENING AND INTERVENTIONS, IN ADDITION TO COGNITIVE AND MOOD INTERVENTIONS, IN THE PREVENTION OF SUICIDE. EARLY-LIFE ADVERSITY AND EPIGENETIC MECHANISMS MIGHT EXPLAIN SOME OF THE LINK BETWEEN SUICIDE RISK AND BRAIN CIRCUITRY AND NEUROCHEMISTRY ABNORMALITIES. RESULTS FROM A RANGE OF STUDIES USING DIVERSE DESIGNS AND POST-MORTEM AND IN-VIVO TECHNIQUES SHOW IMPAIRMENTS OF THE SEROTONIN NEUROTRANSMITTER SYSTEM AND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS STRESS-RESPONSE SYSTEM IN THE DIATHESIS FOR SUICIDAL BEHAVIOUR. THESE IMPAIRMENTS MANIFEST AS IMPAIRED COGNITIVE CONTROL OF MOOD, PESSIMISM, REACTIVE AGGRESSIVE TRAITS, IMPAIRED PROBLEM SOLVING, OVER-REACTIVITY TO NEGATIVE SOCIAL SIGNS, EXCESSIVE EMOTIONAL PAIN, AND SUICIDAL IDEATION, LEADING TO SUICIDAL BEHAVIOUR. BIOMARKERS RELATED TO THE DIATHESIS MIGHT HELP TO INFORM RISK-ASSESSMENT PROCEDURES AND TREATMENT CHOICE IN THE PREVENTION OF SUICIDE. 2014 9 6174 41 THE HIPPOCAMPUS, NEUROTROPHIC FACTORS AND DEPRESSION: POSSIBLE IMPLICATIONS FOR THE PHARMACOTHERAPY OF DEPRESSION. DEPRESSION IS A PREVALENT, HIGHLY DEBILITATING MENTAL DISORDER AFFECTING UP TO 15% OF THE POPULATION AT LEAST ONCE IN THEIR LIFETIME, WITH HUGE COSTS FOR SOCIETY. NEUROBIOLOGICAL MECHANISMS OF DEPRESSION ARE STILL NOT WELL KNOWN, ALTHOUGH THERE IS CONSENSUS ABOUT INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ANTIDEPRESSANT MEDICATIONS ARE FREQUENTLY USED IN DEPRESSION, BUT AT LEAST 50% OF PATIENTS ARE POOR RESPONDERS, EVEN TO MORE RECENTLY DISCOVERED MEDICATIONS. FURTHERMORE, CLINICAL RESPONSE ONLY OCCURS FOLLOWING WEEKS TO MONTHS OF TREATMENT AND ONLY CHRONIC TREATMENT IS EFFECTIVE, SUGGESTING THAT ACTIONS BEYOND THE RAPIDLY OCCURRING EFFECT OF ENHANCING MONOAMINERGIC SYSTEMS, SUCH AS ADAPTATION OF THESE SYSTEMS, ARE RESPONSIBLE FOR THE EFFECTS OF ANTIDEPRESSANTS. RECENT STUDIES INDICATE THAT AN IMPAIRMENT OF SYNAPTIC PLASTICITY (NEUROGENESIS, AXON BRANCHING, DENDRITOGENESIS AND SYNAPTOGENESIS) IN SPECIFIC AREAS OF THE CNS, PARTICULARLY THE HIPPOCAMPUS, MAY BE A CORE FACTOR IN THE PATHOPHYSIOLOGY OF DEPRESSION. THE ABNORMAL NEURAL PLASTICITY MAY BE RELATED TO ALTERATIONS IN THE LEVELS OF NEUROTROPHIC FACTORS, NAMELY BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WHICH PLAY A CENTRAL ROLE IN PLASTICITY. AS BDNF IS REPRESSED BY STRESS, EPIGENETIC REGULATION OF THE BDNF GENE MAY PLAY AN IMPORTANT ROLE IN DEPRESSION. THE HIPPOCAMPUS IS SMALLER IN DEPRESSED PATIENTS, ALTHOUGH IT IS UNCLEAR WHETHER SMALLER SIZE IS A CONSEQUENCE OF DEPRESSION OR A PRE-EXISTING, VULNERABILITY MARKER FOR DEPRESSION. ENVIRONMENTAL STRESSORS TRIGGERING ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS CAUSE THE BRAIN TO BE EXPOSED TO CORTICOSTEROIDS, AFFECTING NEUROBEHAVIOURAL FUNCTIONS WITH A STRONG DOWNREGULATION OF HIPPOCAMPAL NEUROGENESIS, AND ARE A MAJOR RISK FACTOR FOR DEPRESSION. ANTIDEPRESSANT TREATMENT INCREASES BDNF LEVELS, STIMULATES NEUROGENESIS AND REVERSES THE INHIBITORY EFFECTS OF STRESS, BUT THIS EFFECT IS EVIDENT ONLY AFTER 3-4 WEEKS OF ADMINISTRATION, THE TIME COURSE FOR MATURATION OF NEW NEURONS. THE ABLATION OF HIPPOCAMPAL NEUROGENESIS BLOCKS THE BEHAVIOURAL EFFECTS OF ANTIDEPRESSANTS IN ANIMAL MODELS. THE ABOVE FINDINGS SUGGEST NEW POSSIBLE TARGETS FOR THE PHARMACOTHERAPY OF DEPRESSION SUCH AS NEUROTROPHIC FACTORS, THEIR RECEPTORS AND RELATED INTRACELLULAR SIGNALLING CASCADES; AGENTS COUNTERACTING THE EFFECTS OF STRESS ON HIPPOCAMPAL NEUROGENESIS (INCLUDING ANTAGONISTS OF CORTICOSTEROIDS, INFLAMMATORY CYTOKINES AND THEIR RECEPTORS); AND AGENTS FACILITATING THE ACTIVATION OF GENE EXPRESSION AND INCREASING THE TRANSCRIPTION OF NEUROTROPHINS IN THE BRAIN. 2011 10 3092 28 GENOMIC AND EPIGENOMIC MECHANISMS OF GLUCOCORTICOIDS IN THE BRAIN. FOLLOWING THE DISCOVERY OF GLUCOCORTICOID RECEPTORS IN THE HIPPOCAMPUS AND OTHER BRAIN REGIONS, RESEARCH HAS FOCUSED ON UNDERSTANDING THE EFFECTS OF GLUCOCORTICOIDS IN THE BRAIN AND THEIR ROLE IN REGULATING EMOTION AND COGNITION. GLUCOCORTICOIDS ARE ESSENTIAL FOR ADAPTATION TO STRESSORS (ALLOSTASIS) AND IN MALADAPTATION RESULTING FROM ALLOSTATIC LOAD AND OVERLOAD. ALLOSTATIC OVERLOAD, WHICH CAN OCCUR DURING CHRONIC STRESS, CAN RESHAPE THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS THROUGH EPIGENETIC MODIFICATION OF GENES IN THE HIPPOCAMPUS, HYPOTHALAMUS AND OTHER STRESS-RESPONSIVE BRAIN REGIONS. GLUCOCORTICOIDS EXERT THEIR EFFECTS ON THE BRAIN THROUGH GENOMIC MECHANISMS THAT INVOLVE BOTH GLUCOCORTICOID RECEPTORS AND MINERALOCORTICOID RECEPTORS DIRECTLY BINDING TO DNA, AS WELL AS BY NON-GENOMIC MECHANISMS. FURTHERMORE, GLUCOCORTICOIDS SYNERGIZE BOTH GENOMICALLY AND NON-GENOMICALLY WITH NEUROTRANSMITTERS, NEUROTROPHIC FACTORS, SEX HORMONES AND OTHER STRESS MEDIATORS TO SHAPE AN ORGANISM'S PRESENT AND FUTURE RESPONSES TO A STRESSFUL ENVIRONMENT. HERE, WE DISCUSS THE MECHANISMS OF GLUCOCORTICOID ACTION IN THE BRAIN AND REVIEW HOW GLUCOCORTICOIDS INTERACT WITH STRESS MEDIATORS IN THE CONTEXT OF ALLOSTASIS, ALLOSTATIC LOAD AND STRESS-INDUCED NEUROPLASTICITY. 2017 11 2092 20 EPIGENETIC EFFECT OF CHRONIC STRESS ON DOPAMINE SIGNALING AND DEPRESSION. BECAUSE OF THE COMPLEX CAUSAL FACTORS LEADING TO DEPRESSION, EPIGENETICS IS OF CONSIDERABLE INTEREST FOR THE UNDERSTANDING EFFECT OF STRESS IN DEPRESSION. DOPAMINE IS A KEY NEUROTRANSMITTER IMPORTANT IN MANY PHYSIOLOGICAL FUNCTIONS, INCLUDING MOTOR CONTROL, MOOD, AND THE REWARD PATHWAY. THESE FACTORS LEAD MANY DRUGS TO TARGET DOPAMINE RECEPTORS IN TREATING DEPRESSIVE DISORDERS. IN THIS REVIEW, WE TRY TO PORTRAY HOW CHRONIC STRESS AS AN EPIGENETIC FACTOR CHANGES THE GENE REGULATION PATTERN BY INTERRUPTING DOPAMINE SIGNALING MECHANISM. 2013 12 4649 45 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 13 6139 35 THE ETIOLOGICAL CONTRIBUTION OF GABAERGIC PLASTICITY TO THE PATHOGENESIS OF NEUROPATHIC PAIN. NEUROPATHIC PAIN DEVELOPING AFTER PERIPHERAL OR CENTRAL NERVE INJURY IS THE RESULT OF PATHOLOGICAL CHANGES GENERATED THROUGH COMPLEX MECHANISMS. DISRUPTION IN THE HOMEOSTASIS OF EXCITATORY AND INHIBITORY NEURONS WITHIN THE CENTRAL NERVOUS SYSTEM IS A CRUCIAL FACTOR IN THE FORMATION OF HYPERALGESIA OR ALLODYNIA OCCURRING WITH NEUROPATHIC PAIN. THE CENTRAL GABAERGIC PATHWAY HAS RECEIVED ATTENTION FOR ITS EXTENSIVE DISTRIBUTION AND FUNCTION IN NEURAL CIRCUITS, INCLUDING THE GENERATION AND DEVELOPMENT OF NEUROPATHIC PAIN. GABAERGIC INHIBITORY CHANGES THAT OCCUR IN THE INTERNEURONS ALONG DESCENDING MODULATORY AND NOCICEPTIVE PATHWAYS IN THE CENTRAL NERVOUS SYSTEM ARE BELIEVED TO GENERATE NEURONAL PLASTICITY, SUCH AS SYNAPTIC PLASTICITY OR FUNCTIONAL PLASTICITY OF THE RELATED GENES OR PROTEINS, THAT IS THE FOUNDATION OF PERSISTENT NEUROPATHIC PAIN. THE PRIMARY GABAERGIC PLASTICITY OBSERVED IN NEUROPATHIC PAIN INCLUDES GABAERGIC SYNAPSE HOMO- AND HETEROSYNAPTIC PLASTICITY, DECREASED SYNTHESIS OF GABA, DOWN-EXPRESSION OF GLUTAMIC ACID DECARBOXYLASE AND GABA TRANSPORTER, ABNORMAL EXPRESSION OF NKCC1 OR KCC2, AND DISTURBED FUNCTION OF GABA RECEPTORS. IN THIS REVIEW, WE DESCRIBE POSSIBLE MECHANISMS ASSOCIATED WITH GABAERGIC PLASTICITY, SUCH AS CENTRAL SENSITIZATION AND GABAERGIC INTERNEURON APOPTOSIS, AND THE EPIGENETIC ETIOLOGIES OF GABAERGIC PLASTICITY IN NEUROPATHIC PAIN. MOREOVER, WE SUMMARIZE POTENTIAL THERAPEUTIC TARGETS OF GABAERGIC PLASTICITY THAT MAY ALLOW FOR SUCCESSFUL RELIEF OF HYPERALGESIA FROM NERVE INJURY. FINALLY, WE COMPARE THE EFFECTS OF THE GABAERGIC SYSTEM IN NEUROPATHIC PAIN TO OTHER TYPES OF CHRONIC PAIN TO UNDERSTAND THE CONTRIBUTION OF GABAERGIC PLASTICITY TO NEUROPATHIC PAIN. 2019 14 1327 35 DEPRESSION AND ANTIDEPRESSANTS: INSIGHTS FROM KNOCKOUT OF DOPAMINE, SEROTONIN OR NORADRENALINE RE-UPTAKE TRANSPORTERS. MAJOR DEPRESSIVE DISORDER (MDD) WHICH IS SUPPOSED TO RESULT FROM A COMPLEX INTERACTION OF GENETIC AND EPIGENETIC, ENVIRONMENTAL AND DEVELOPMENTAL FACTORS IS ONE OF THE MOST COMMON DEBILITATING PUBLIC HEALTH PROBLEMS. THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE ARE STILL LARGELY UNCLEAR. IDENTIFYING COMMON PATHWAYS FOR DIVERSE ANTIDEPRESSANTS (ADS) AS WELL AS NEW DRUG TARGETS AND THEREBY DEVELOPING MORE EFFECTIVE TREATMENTS ARE PRIMARY GOALS OF RESEARCH IN THIS FIELD. MAJOR TARGETS OF ADS ARE THE SEROTONIN TRANSPORTER (SERT), THE NORADRENALINE TRANSPORTER (NAT) AND ALSO THE DOPAMINE TRANSPORTER (DAT) LOCATED IN THE PLASMA MEMBRANE OF CORRESPONDING NEURONS. THESE MONOAMINE TRANSPORTERS (MATS) ARE IMPORTANT REGULATORS OF THE EXTRACELLULAR NEUROTRANSMITTER CONCENTRATION. AMONG THE CLINICALLY IMPORTANT ADS ARE TRICYCLIC ADS (E.G. IMIPRAMINE), SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIS, E.G. FLUOXETINE), SELECTIVE NORADRENALINE (NA) RE-UPTAKE INHIBITORS (SNRIS, E.G. REBOXETINE) AND NAT/DAT INHIBITORS LIKE BUPROPION. THIS REVIEW IS FOCUSSING ON BRAIN CHANGES IN MONOAMINE NEUROTRANSMITTER SYSTEMS, DOWNSTREAM TARGETS OF MONOAMINERGIC NEUROTRANSMISSION AS WELL AS OF BEHAVIOURS OF MICE WITH A CONVENTIONAL KNOCKOUT (KO) OF EITHER THE SERT, DAT OR NAT. MAT KNOCKOUT INDUCES CHANGES IN BEHAVIOUR AND BRAIN NEUROCHEMISTRY. ALTHOUGH AT LEAST NATKO AND SERTKO MICE WERE EXPECTED TO SHOW A PHENOTYPE LIKE AD-TREATED WILD-TYPE MICE, THIS HOLDS TRUE ONLY FOR THE NATKO MICE WHEREAS SERTKO MICE SHOW AN ANXIETY-LIKE PHENOTYPE. CHRONIC SOCIAL OR RESTRAINT STRESS-INDUCED DEPRESSION-LIKE BEHAVIOUR AND CONCOMITANT CHANGES IN BRAIN NEUROTROPHINS ARE PREVENTED BY PHARMACOLOGICALLY DIVERSE ADS AND BY NATKO. THUS, NATKO MICE ARE AN INTERESTING TOOL TO INVESTIGATE THE MECHANISMS BEYOND MONOAMINES RESPONSIBLE FOR DEPRESSION AS WELL AS FOR AD ACTIONS. 2011 15 5165 22 PRECLINICAL RESERPINE MODELS RECAPITULATING MOTOR AND NON-MOTOR FEATURES OF PARKINSON'S DISEASE: ROLES OF EPIGENETIC UPREGULATION OF ALPHA-SYNUCLEIN AND AUTOPHAGY IMPAIRMENT. RESERPINE IS AN EFFECTIVE DRUG FOR THE CLINICAL TREATMENT OF HYPERTENSION. IT ALSO INDUCES PARKINSON'S DISEASE (PD)-LIKE SYMPTOMS IN HUMANS AND ANIMALS POSSIBLE THROUGH THE INHIBITION OF MONOAMINE VESICULAR TRANSPORTERS, THUS DECREASING THE LEVELS OF MONOAMINE NEUROTRANSMITTERS IN THE BRAIN. HOWEVER, THE PRECISE MECHANISMS REMAIN UNCLEAR. HEREIN, WE AIMED TO DEVELOP A PRECLINICAL RESERPINE MODEL RECAPITULATING THE NON-MOTOR AND MOTOR SYMPTOMS OF PD AND INVESTIGATE THE UNDERLYING POTENTIAL CELLULAR MECHANISMS. INCUBATION OF RESERPINE INDUCED APOPTOSIS, LED TO THE ACCUMULATION OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS), LOWERED DNA METHYLATION OF ALPHA-SYNUCLEIN GENE, RESULTED IN ALPHA-SYNUCLEIN PROTEIN DEPOSITION, AND ELEVATED THE RATIO OF LC3-II/LC3-I AND P62 IN CULTURED SH-SY5Y CELLS. FEEDING RESERPINE DOSE-DEPENDENTLY SHORTENED THE LIFESPAN AND CAUSED IMPAIRMENT OF MOTOR FUNCTIONS IN MALE AND FEMALE DROSOPHILA. MOREOVER, LONG-TERM ORAL ADMINISTRATION OF RESERPINE LED TO MULTIPLE MOTOR AND NON-MOTOR SYMPTOMS, INCLUDING CONSTIPATION, PAIN HYPERSENSITIVITY, OLFACTORY IMPAIRMENT, AND DEPRESSION-LIKE BEHAVIORS IN MICE. THE MECHANISTIC STUDIES SHOWED THAT CHRONIC RESERPINE EXPOSURE CAUSED HYPOMETHYLATION OF THE ALPHA-SYNUCLEIN GENE AND UP-REGULATED ITS EXPRESSION AND ELEVATED THE RATIO OF LC3-II/LC3-I AND EXPRESSION OF P62 IN THE SUBSTANTIA NIGRA OF MICE. THUS, WE ESTABLISHED PRECLINICAL ANIMAL MODELS USING RESERPINE TO RECAPITULATE THE MOTOR AND NON-MOTOR SYMPTOMS OF PD. CHRONIC RESERPINE EXPOSURE EPIGENETICALLY ELEVATED THE LEVELS OF ALPHA-SYNUCLEIN EXPRESSION POSSIBLE BY LOWERING THE DNA METHYLATION STATUS AND INDUCING AUTOPHAGIC IMPAIRMENT IN VITRO AND IN VIVO. 2022 16 3313 24 HIPPOCAMPAL BDNF IN PHYSIOLOGICAL CONDITIONS AND SOCIAL ISOLATION. EXPOSURE OF AN ORGANISM TO CHRONIC PSYCHOSOCIAL STRESS MAY AFFECT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION THAT HAS BEEN IMPLICATED IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS, SUCH AS DEPRESSION. GIVEN THAT DEPRESSION IN HUMANS HAS BEEN LINKED WITH SOCIAL STRESS, THE CHRONIC SOCIAL STRESS PARADIGMS FOR MODELING PSYCHIATRIC DISORDERS IN ANIMALS HAVE THUS BEEN DEVELOPED. CHRONIC SOCIAL ISOLATION IN ANIMAL MODELS GENERALLY CAUSES CHANGES IN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTIONING, ASSOCIATED WITH ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. ALSO, THIS CHRONIC STRESS CAUSES DOWNREGULATION OF BDNF PROTEIN AND MRNA IN THE HIPPOCAMPUS, A STRESS-SENSITIVE BRAIN REGION CLOSELY RELATED TO THE PATHOPHYSIOLOGY OF DEPRESSION. IN THIS REVIEW, WE DISCUSS THE CURRENT KNOWLEDGE REGARDING THE STRUCTURE, FUNCTION, INTRACELLULAR SIGNALING, INTER-INDIVIDUAL DIFFERENCES AND EPIGENETIC REGULATION OF BDNF IN BOTH PHYSIOLOGICAL CONDITIONS AND DEPRESSION AND CHANGES IN CORTICOSTERONE LEVELS, AS A MARKER OF STRESS RESPONSE. SINCE BDNF LEVELS ARE AGE DEPENDENT IN HUMANS AND RODENTS, THIS REVIEW WILL ALSO HIGHLIGHT THE EFFECTS OF ADOLESCENT AND ADULT CHRONIC SOCIAL ISOLATION MODELS OF BOTH GENDERS ON THE BDNF EXPRESSION. 2017 17 3463 32 HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-GONADAL AXES: SEX DIFFERENCES IN REGULATION OF STRESS RESPONSIVITY. GONADAL HORMONES PLAY A KEY ROLE IN THE ESTABLISHMENT, ACTIVATION, AND REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. BY INFLUENCING THE RESPONSE AND SENSITIVITY TO RELEASING FACTORS, NEUROTRANSMITTERS, AND HORMONES, GONADAL STEROIDS HELP ORCHESTRATE THE GAIN OF THE HPA AXIS TO FINE-TUNE THE LEVELS OF STRESS HORMONES IN THE GENERAL CIRCULATION. FROM EARLY LIFE TO ADULTHOOD, GONADAL STEROIDS CAN DIFFERENTIALLY AFFECT THE HPA AXIS, RESULTING IN SEX DIFFERENCES IN THE RESPONSIVITY OF THIS AXIS. THE HPA AXIS INFLUENCES MANY PHYSIOLOGICAL FUNCTIONS MAKING AN ORGANISM'S RESPONSE TO CHANGES IN THE ENVIRONMENT APPROPRIATE FOR ITS REPRODUCTIVE STATUS. ALTHOUGH THE ACUTE HPA RESPONSE TO STRESSORS IS A BENEFICIAL RESPONSE, CONSTANT ACTIVATION OF THIS CIRCUITRY BY CHRONIC OR TRAUMATIC STRESSFUL EPISODES MAY LEAD TO A DYSREGULATION OF THE HPA AXIS AND CAUSE PATHOLOGY. COMPARED TO MALES, FEMALE MICE AND RATS SHOW A MORE ROBUST HPA AXIS RESPONSE, AS A RESULT OF CIRCULATING ESTRADIOL LEVELS WHICH ELEVATE STRESS HORMONE LEVELS DURING NON-THREATENING SITUATIONS, AND DURING AND AFTER STRESSORS. FLUCTUATING LEVELS OF GONADAL STEROIDS IN FEMALES ACROSS THE ESTROUS CYCLE ARE A MAJOR FACTOR CONTRIBUTING TO SEX DIFFERENCES IN THE ROBUSTNESS OF HPA ACTIVITY IN FEMALES COMPARED TO MALES. MOREOVER, GONADAL STEROIDS MAY ALSO CONTRIBUTE TO EPIGENETIC AND ORGANIZATIONAL INFLUENCES ON THE HPA AXIS EVEN BEFORE PUBERTY. CORRESPONDINGLY, CROSSTALK BETWEEN THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AND HPA AXES COULD LEAD TO ABNORMALITIES OF STRESS RESPONSES. IN HUMANS, A DYSREGULATED STRESS RESPONSE IS ONE OF THE MOST COMMON SYMPTOMS SEEN ACROSS MANY NEUROPSYCHIATRIC DISORDERS, AND AS A RESULT, SUCH INTERACTIONS MAY EXACERBATE PERIPHERAL PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE HPA AND HPG AXES AND REVIEW HOW GONADAL STEROIDS INTERACT WITH THE HPA AXIS TO REGULATE THE STRESS CIRCUITRY DURING ALL STAGES IN LIFE. 2017 18 3534 31 IMMEDIATE-EARLY GENES MODULATION BY ANTIPSYCHOTICS: TRANSLATIONAL IMPLICATIONS FOR A PUTATIVE GATEWAY TO DRUG-INDUCED LONG-TERM BRAIN CHANGES. AN INCREASING AMOUNT OF RESEARCH AIMS AT RECOGNIZING THE MOLECULAR MECHANISMS INVOLVED IN LONG-LASTING BRAIN ARCHITECTURAL CHANGES INDUCED BY ANTIPSYCHOTIC TREATMENTS. ALTHOUGH BOTH STRUCTURAL AND FUNCTIONAL MODIFICATIONS HAVE BEEN IDENTIFIED FOLLOWING ACUTE ANTIPSYCHOTIC ADMINISTRATION IN HUMANS, CURRENTLY THERE IS SCARCE KNOWLEDGE ON THE ENDURING CONSEQUENCES OF THESE ACUTE CHANGES. NEW INSIGHTS IN IMMEDIATE-EARLY GENES (IEGS) MODULATION FOLLOWING ACUTE OR CHRONIC ANTIPSYCHOTIC ADMINISTRATION MAY HELP TO FILL THE GAP BETWEEN PRIMARY MOLECULAR RESPONSE AND PUTATIVE LONG-TERM CHANGES. MOREOVER, A CRITICAL APPRAISAL OF THE SPATIAL AND TEMPORAL PATTERNS OF IEGS EXPRESSION MAY SHED LIGHT ON THE FUNCTIONAL "SIGNATURE" OF ANTIPSYCHOTICS, SUCH AS THE PROPENSITY TO INDUCE MOTOR SIDE EFFECTS, THE POTENTIAL NEUROBIOLOGICAL MECHANISMS UNDERLYING THE DIFFERENCES BETWEEN ANTIPSYCHOTICS BEYOND D2 DOPAMINE RECEPTOR AFFINITY, AS WELL AS THE RELEVANT EFFECTS OF BRAIN REGION-SPECIFICITY IN THEIR MECHANISMS OF ACTION. THE INTEREST FOR BRAIN IEGS MODULATION AFTER ANTIPSYCHOTIC TREATMENTS HAS BEEN REVITALIZED BY BREAKTHROUGH FINDINGS SUCH AS THE ROLE OF EARLY GENES IN SCHIZOPHRENIA PATHOPHYSIOLOGY, THE INVOLVEMENT OF IEGS IN EPIGENETIC MECHANISMS RELEVANT FOR COGNITION, AND IN NEURONAL MAPPING BY MEANS OF IEGS EXPRESSION PROFILING. HERE WE CRITICALLY REVIEW THE EVIDENCE ON THE DIFFERENTIAL MODULATION OF IEGS BY ANTIPSYCHOTICS, HIGHLIGHTING THE ASSOCIATION BETWEEN IEGS EXPRESSION AND NEUROPLASTICITY CHANGES IN BRAIN REGIONS IMPACTED BY ANTIPSYCHOTICS, TRYING TO ELUCIDATE THE MOLECULAR MECHANISMS UNDERPINNING THE EFFECTS OF THIS CLASS OF DRUGS ON PSYCHOTIC, COGNITIVE AND BEHAVIORAL SYMPTOMS. 2017 19 23 36 60 YEARS OF NEUROENDOCRINOLOGY: REDEFINING NEUROENDOCRINOLOGY: STRESS, SEX AND COGNITIVE AND EMOTIONAL REGULATION. THE DISCOVERY OF STEROID HORMONE RECEPTORS IN BRAIN REGIONS THAT MEDIATE EVERY ASPECT OF BRAIN FUNCTION HAS BROADENED THE DEFINITION OF 'NEUROENDOCRINOLOGY' TO INCLUDE THE RECIPROCAL COMMUNICATION BETWEEN THE BRAIN AND THE BODY VIA HORMONAL AND NEURAL PATHWAYS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT AND DEVELOPING BRAIN POSSESS REMARKABLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESS, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. STRESS CAUSES AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION-MAKING, ANXIETY AND MOOD THAT CAN ALTER EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE. BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC ANXIETY AND DEPRESSION. THERE ARE IMPORTANT SEX DIFFERENCES IN THE BRAIN RESPONSES TO STRESSORS THAT ARE IN URGENT NEED OF FURTHER EXPLORATION. MOREOVER, ADVERSE EARLY-LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCE LASTING EFFECTS ON BRAIN AND BODY OVER THE LIFE-COURSE VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS MOST IMPORTANT, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT TAKE INTO CONSIDERATION BRAIN-BODY INTERACTIONS. 2015 20 1722 28 DYSREGULATION OF BRAIN DOPAMINE SYSTEMS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD OR DEPRESSION) IS A DEBILITATING NEUROPSYCHIATRIC SYNDROME WITH GENETIC, EPIGENETIC, AND ENVIRONMENTAL CONTRIBUTIONS. DEPRESSION IS ONE OF THE LARGEST CONTRIBUTORS TO CHRONIC DISEASE BURDEN; IT AFFECTS MORE THAN ONE IN SIX INDIVIDUALS IN THE UNITED STATES. A WIDE ARRAY OF CELLULAR AND MOLECULAR MODIFICATIONS DISTRIBUTED ACROSS A VARIETY OF NEURONAL PROCESSES AND CIRCUITS UNDERLIE THE PATHOPHYSIOLOGY OF DEPRESSION-NO ESTABLISHED MECHANISM CAN EXPLAIN ALL ASPECTS OF THE DISEASE. MDD SUFFERS FROM A VAST TREATMENT GAP WORLDWIDE, AND LARGE NUMBERS OF INDIVIDUALS WHO REQUIRE TREATMENT DO NOT RECEIVE ADEQUATE CARE. THIS MINI-REVIEW FOCUSES ON DYSREGULATION OF BRAIN DOPAMINE (DA) SYSTEMS IN THE PATHOPHYSIOLOGY OF MDD AND DESCRIBING NEW CELLULAR TARGETS FOR POTENTIAL MEDICATION DEVELOPMENT FOCUSED ON DA-MODULATED MICRO-CIRCUITS. WE ALSO EXPLORE HOW NEURODEVELOPMENTAL FACTORS MAY MODIFY RISK FOR LATER EMERGENCE OF MDD, POSSIBLY THROUGH DOPAMINERGIC SUBSTRATES IN THE BRAIN. 2021