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 5519 35 RISK FACTORS FOR ALZHEIMER'S DISEASE: ROLE OF MULTIPLE ANTIOXIDANTS, NON-STEROIDAL ANTI-INFLAMMATORY AND CHOLINERGIC AGENTS ALONE OR IN COMBINATION IN PREVENTION AND TREATMENT. THE ETIOLOGY OF ALZHEIMER'S DISEASE (AD) IS NOT WELL UNDERSTOOD. ETIOLOGIC FACTORS, CHRONIC INFLAMMATORY REACTIONS, OXIDATIVE AND NITROSYLATIVE STRESSES AND HIGH CHOLESTEROL LEVELS ARE THOUGHT TO BE IMPORTANT FOR INITIATING AND PROMOTING NEURODEGENERATIVE CHANGES COMMONLY FOUND IN AD BRAINS. EVEN IN FAMILIAL AD, OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE EARLY ONSET OF THE DISEASE. MITOCHONDRIAL DAMAGE AND PROTEASOME INHIBITION REPRESENT EARLY EVENTS IN THE PATHOGENESIS OF AD, WHEREAS INCREASED PROCESSING OF AMYLOID PRECURSOR PROTEIN (APP) TO BETA-AMYLOID (ABETA) FRAGMENTS (ABETA(40) AND ABETA(42)) AND FORMATION OF SENILE PLAQUES AND NEUROFIBRILLARY TANGLES (NFTS) REPRESENT LATE EVENTS. WE PROPOSE A HYPOTHESIS THAT IN IDIOPATHIC AD, EPIGENETIC COMPONENTS OF NEURONS SUCH AS MITOCHONDRIA, PROTEASOMES AND POST-TRANSLATION PROTEIN MODIFICATIONS (PROCESSING OF AMYLOID PRECURSOR PROTEIN TO BETA-AMYLOID AND HYPERPHOSPHORYLATION OF TAU), RATHER THAN NUCLEAR GENES, ARE THE PRIMARY TARGETS FOR THE ACTION OF DIVERSE GROUPS OF NEUROTOXINS. BASED ON EPIDEMIOLOGIC, LABORATORY AND LIMITED CLINICAL STUDIES, WE PROPOSE THAT A COMBINATION OF NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND APPROPRIATE LEVELS AND TYPES OF MULTIPLE MICRONUTRIENTS, INCLUDING ANTIOXIDANTS, MAY BE MORE EFFECTIVE THAN THE INDIVIDUAL AGENTS IN THE PREVENTION, AND THEY, IN COMBINATION WITH A CHOLINERGIC AGENT, MAY BE MORE EFFECTIVE IN THE TREATMENT OF AD THAN THE INDIVIDUAL AGENTS ALONE. IN ADDITION, AGENTS, WHICH CAN PREVENT FORMATION OF PLAQUES OR DISSOLVE THESE PLAQUES MAY FURTHER ENHANCE THE EFFICACY OF OUR PROPOSED TREATMENT STRATEGY. 2002 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 5837 28 STRESSED MITOCHONDRIA: A TARGET TO INTRUDE ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE INOPERABLE, INCAPACITATING, NEUROPSYCHIATRIC, AND DEGENERATIVE MANIFESTATION THAT DRASTICALLY AFFECTS HUMAN LIFE QUALITY. THE CURRENT MEDICATIONS TARGET EXTRA-NEURONAL SENILE PLAQUES, OXIDATIVE STRESS, NEUROINFLAMMATION, INTRANEURONAL NEUROFIBRILLARY TANGLES, CHOLINERGIC DEFICITS, AND EXCITOTOXICITY. AMONG NOVEL PATHWAYS AND TARGETS, BIOENERGETIC AND RESULTANT MITOCHONDRIAL DYSFUNCTION HAS BEEN RECOGNIZED AS ESSENTIAL FACTORS THAT DECIDE THE NEURONAL FATE AND CONSEQUENT NEURODEGENERATION IN AD. THE CRUCIAL ATTRIBUTES OF MITOCHONDRIA, INCLUDING BIOENERGESIS, SIGNALING, SENSING, INTEGRATING, AND TRANSMITTING BIOLOGICAL SIGNALS CONTRIBUTE TO OPTIMUM NETWORKING OF NEURONAL DYNAMICS AND MAKE THEM INDISPENSABLE FOR CELL SURVIVAL. IN AD, MITOCHONDRIAL DYSFUNCTION AND MITOPHAGY ARE A PRELIMINARY AND CRITICAL EVENT THAT AGGRAVATES THE PATHOLOGICAL CASCADE. STRESS IS KNOWN TO PROMOTE AND EXAGGERATE THE NEUROPATHOLOGICAL ALTERATION DURING NEURODEGENERATION AND METABOLIC IMPAIRMENTS, ESPECIALLY IN THE CORTICO-LIMBIC SYSTEM, BESIDES ADVERSELY AFFECTING THE NORMAL PHYSIOLOGY AND MITOCHONDRIAL DYNAMICS. STRESS INVOLVES THE ALLOCATION OF ENERGY RESOURCES FOR NEURONAL SURVIVAL. CHRONIC AND AGGRAVATED STRESS RESPONSE LEADS TO EXCESSIVE RELEASE OF GLUCOCORTICOIDS BY ACTIVATION OF THE HYPOTHALAMIC-PITUITARYADRENAL (HPA) AXIS. BY ACTING THROUGH THEIR RECEPTORS, GLUCOCORTICOIDS INFLUENCE ADVERSE MITOCHONDRIAL CHANGES AND ALTER MTDNA TRANSCRIPTION, MTRNA EXPRESSION, HIPPOCAMPAL MITOCHONDRIAL NETWORK, AND ULTIMATELY MITOCHONDRIAL PHYSIOLOGY. CHRONIC STRESS ALSO AFFECTS MITOCHONDRIAL DYNAMICS BY CHANGING METABOLIC AND NEURO-ENDOCRINAL SIGNALLING, AGGRAVATING OXIDATIVE STRESS, PROVOKING INFLAMMATORY MEDIATORS, ALTERING TROPIC FACTORS, INFLUENCING GENE EXPRESSION, AND MODIFYING EPIGENETIC PATHWAYS. THUS, EXPLORING CHRONIC STRESS-INDUCED GLUCOCORTICOID DYSREGULATION AND RESULTANT BIO-BEHAVIORAL AND PSYCHOSOMATIC MITOCHONDRIAL ALTERATIONS MAY BE A FEASIBLE NARRATIVE TO INVESTIGATE AND UNRAVEL THE MYSTERIOUS PATHOBIOLOGY OF AD. 2021 5 4938 24 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 6 1091 38 COGNITIVE ENHANCERS AS A TREATMENT FOR HEROIN RELAPSE AND ADDICTION. HEROIN ADDICTION IS A DISORDER THAT STEMS FROM MALADAPTIVE PLASTICITY WITHIN NEURAL CIRCUITS AND PRODUCES BROAD COGNITIVE DEFICITS. DESPITE CONSIDERABLE ADVANCES IN PSYCHOTHERAPY AND PHARMACOTHERAPY FOR HEROIN RELAPSE AND ADDICTION, EFFECTIVE TREATMENTS FOR HEROIN USE DISORDER ARE STILL LACKING. INCREASING PRECLINICAL EVIDENCE INDICATES THAT HEROIN SEEKING BEHAVIOR IS PERSISTENT AFTER WITHDRAWAL, WHILE COGNITIVE DYSFUNCTIONS ASSOCIATED WITH CHRONIC HEROIN USE ARE AN IMPORTANT CONTRIBUTING FACTOR TO RISK OF HEROIN RELAPSE AND ADDICTION. COGNITIVE ENHANCERS MAY BE USED TO STIMULATE TREATMENT SUCCESS AND ENHANCE TREATMENT EFFICACY. THE PURPOSE OF THIS REVIEW IS TO OUTLINE THE LITERATURE THAT DEMONSTRATES THE COGNITIVE DEFICITS DURING THE DEVELOPMENT OF HEROIN ADDICTION AND WITHDRAWAL PROCESS, AND SEVERAL FACTORS THAT UNDERLINE THE EFFICACY OF COGNITIVE ENHANCERS FOR HEROIN USE DISORDERS. THE REVIEW, THEN, EXAMINES THE POTENTIAL USE AND PHARMACOLOGICAL MECHANISMS OF COGNITIVE ENHANCERS THAT ACT ON CHOLINERGIC, GLUTAMATERGIC, DOPAMINERGIC OR ADRENERGIC PATHWAYS. IT ALSO EXAMINES THE EFFECTS OF COMPOUNDS THAT ALTER CREB SIGNALING AND EPIGENETIC MECHANISMS IN ANIMAL MODEL OF HEROIN RELAPSE. THE CURRENT BODY OF RESEARCH REVEALS THE NEW INSIGHTS INTO THE PHARMACOLOGICAL MECHANISMS UNDERLYING HEROIN ADDICTION AND HOLDS A SIGNIFICANT PROMISE FOR COGNITIVE ENHANCERS AS AN IMPROVED APPROACH TO TREAT HEROIN USE DISORDER IN A MORE EFFICIENT AND PERSISTENT WAY. 2019 7 6536 26 TRANSCRIPTIONAL REGULATION OF TYPE-2 METABOTROPIC GLUTAMATE RECEPTORS: AN EPIGENETIC PATH TO NOVEL TREATMENTS FOR CHRONIC PAIN. ACTIVATION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS INHIBITS PAIN TRANSMISSION AT THE SYNAPSES BETWEEN PRIMARY AFFERENT FIBERS AND NEURONS IN THE DORSAL HORN OF THE SPINAL CORD. IN ADDITION, MGLU2 RECEPTORS ARE FOUND IN PERIPHERAL NOCICEPTORS, AND IN PAIN-REGULATORY CENTERS OF THE BRAIN STEM AND FOREBRAIN. MGLU2 RECEPTOR AGONISTS PRODUCE ANALGESIA IN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN, BUT THEIR USE IS LIMITED BY THE DEVELOPMENT OF TOLERANCE. A NEW THERAPEUTIC STRATEGY COULD BE BASED ON THE TRANSCRIPTIONAL REGULATION OF MGLU2 RECEPTORS VIA THE ACETYLATION-PROMOTED ACTIVATION OF THE P65/RELA TRANSCRIPTION FACTOR. "EPIGENETIC" DRUGS THAT INCREASE MGLU2 RECEPTOR EXPRESSION, INCLUDING L-ACETYLCARNITINE AND INHIBITORS OF HISTONE DEACETYLASES, HAVE A DIFFERENT ANALGESIC PROFILE WITH NO TOLERANCE TO THE THERAPEUTIC EFFECT AFTER REPEATED DOSING. 2010 8 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 9 4701 35 NICOTINE AND THE ADOLESCENT BRAIN. ADOLESCENCE ENCOMPASSES A SENSITIVE DEVELOPMENTAL PERIOD OF ENHANCED CLINICAL VULNERABILITY TO NICOTINE, TOBACCO, AND E-CIGARETTES. WHILE THERE ARE SOCIOCULTURAL INFLUENCES, DATA AT PRECLINICAL AND CLINICAL LEVELS INDICATE THAT THIS ADOLESCENT SENSITIVITY HAS STRONG NEUROBIOLOGICAL UNDERPINNINGS. ALTHOUGH DEFINITIONS OF ADOLESCENCE VARY, THE HALLMARK OF THIS PERIOD IS A PROFOUND REORGANIZATION OF BRAIN REGIONS NECESSARY FOR MATURE COGNITIVE AND EXECUTIVE FUNCTION, WORKING MEMORY, REWARD PROCESSING, EMOTIONAL REGULATION, AND MOTIVATED BEHAVIOR. REGULATING CRITICAL FACETS OF BRAIN MATURATION ARE NICOTINIC ACETYLCHOLINE RECEPTORS (NACHRS). HOWEVER, PERTURBATIONS OF CHOLINERGIC SYSTEMS DURING THIS TIME WITH NICOTINE, VIA TOBACCO OR E-CIGARETTES, HAVE UNIQUE CONSEQUENCES ON ADOLESCENT DEVELOPMENT. IN THIS REVIEW, WE HIGHLIGHT RECENT CLINICAL AND PRECLINICAL DATA EXAMINING THE ADOLESCENT BRAIN'S DISTINCT NEUROBIOLOGY AND UNIQUE SENSITIVITY TO NICOTINE. FIRST, WE DISCUSS WHAT DEFINES ADOLESCENCE BEFORE REVIEWING NORMATIVE STRUCTURAL AND NEUROCHEMICAL ALTERATIONS THAT PERSIST UNTIL EARLY ADULTHOOD, WITH AN EMPHASIS ON DOPAMINERGIC SYSTEMS. WE REVIEW HOW ACUTE EXPOSURE TO NICOTINE IMPACTS BRAIN DEVELOPMENT AND HOW DRUG RESPONSES DIFFER FROM THOSE SEEN IN ADULTS. FINALLY, WE DISCUSS THE PERSISTENT ALTERATIONS IN NEURONAL SIGNALING AND COGNITIVE FUNCTION THAT RESULT FROM CHRONIC NICOTINE EXPOSURE, WHILE HIGHLIGHTING A LOW DOSE, SEMI-CHRONIC EXPOSURE PARADIGM THAT MAY BETTER MODEL ADOLESCENT TOBACCO USE. WE ARGUE THAT NICOTINE EXPOSURE, INCREASINGLY OCCURRING AS A RESULT OF E-CIGARETTE USE, MAY INDUCE EPIGENETIC CHANGES THAT SENSITIZE THE BRAIN TO OTHER DRUGS AND PRIME IT FOR FUTURE SUBSTANCE ABUSE. 2015 10 189 34 ACETYL-L-CARNITINE IN CHRONIC PAIN: A NARRATIVE REVIEW. ACETYL-L-CARNITINE (ALC) IS AN ENDOGENOUS MOLECULE THAT NOT ONLY PLAYS A ROLE IN ENERGY METABOLISM, BUT ALSO HAS ANTIOXIDANT PROPERTIES, PROTECTS FROM OXIDATIVE STRESS, MODULATES BRAIN NEUROTRANSMITTERS SUCH AS ACETYLCHOLINE, SEROTONIN AND DOPAMINE, AND ACTS ON NEUROTROPHIC FACTORS SUCH AS NERVE GROWTH FACTOR (NGF) AND METABOTROPIC GLUTAMATE (MGLU) RECEPTORS BY MEANS OF EPIGENETIC MECHANISMS. IMPORTANTLY, IT INDUCES MGLU2 EXPRESSION AT NERVE TERMINALS, THUS GIVING RISE TO ANALGESIA AND PREVENTING SPINAL SENSITISATION. IT HAS ALSO BEEN FOUND TO HAVE EVEN LONG-TERM NEUROTROPHIC AND ANALGESIC ACTIVITY IN EXPERIMENTAL MODELS OF CHRONIC INFLAMMATORY AND NEUROPATHIC PAIN. THE AIM OF THIS NARRATIVE REVIEW IS TO SUMMARISE THE CURRENT EVIDENCE REGARDING THE USE OF ALC IN PATIENTS WITH CHRONIC PAIN, AND COGNITIVE AND MOOD DISORDERS, AND INVESTIGATE THE RATIONALE UNDERLYING ITS USE IN PATIENTS WITH FIBROMYALGIA SYNDROME, WHICH IS CHARACTERISED BY NOCIPLASTIC CHANGES THAT INCREASE THE SENSITIVITY OF THE NERVOUS SYSTEM TO PAIN. 2021 11 191 30 ACETYL-L-CARNITINE: FROM A BIOLOGICAL CURIOSITY TO A DRUG FOR THE PERIPHERAL NERVOUS SYSTEM AND BEYOND. ACETYL-L-CARNITINE (ALC) IS A MOLECULE DERIVED FROM ACETYLATION OF CARNITINE IN THE MITOCHONDRIA. CARNITINE ACETYLATION ENABLES THE FUNCTION OF COA AND FACILITATES ELIMINATION OF OXIDATIVE PRODUCTS. BEYOND THIS METABOLIC ACTIVITY, ALC PROVIDES ACETYL GROUPS FOR ACETYLCHOLINE SYNTHESIS, EXERTS A CHOLINERGIC EFFECT AND OPTIMIZES THE BALANCE OF ENERGY PROCESSES. ACETYLCARNITINE SUPPLEMENTATION INDUCES NEUROPROTECTIVE, NEUROTROPHIC AND ANALGESIC EFFECTS IN THE PERIPHERAL NERVOUS SYSTEM. IN THE RECENT STUDIES, ALC, BY ACTING AS A DONOR OF ACETYL GROUPS TO NF-KB P65/RELA, ENHANCED THE TRANSCRIPTION OF THE GRM2 GENE ENCODING THE MGLU2 RECEPTORS, INDUCING LONG-TERM UPREGULATION OF THE MGLUR2, EVIDENCING THEREFORE THAT ITS LONG-TERM ANALGESIC EFFECTS ARE DEPENDENT ON EPIGENETIC MODIFICATIONS. SEVERAL STUDIES, INCLUDING DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP STUDIES AND FEW OPEN STUDIES SHOWED THE EFFECT OF ALC IN DISEASES CHARACTERIZED BY NEUROPATHIES AND NEUROPATHIC PAIN: THE STUDIES INCLUDED DIABETIC NEUROPATHY, HIV AND ANTIRETROVIRAL THERAPY-INDUCED NEUROPATHIES, NEUROPATHIES DUE TO COMPRESSION AND CHEMOTHERAPEUTIC AGENTS. DOUBLE-BLINDED STUDIES INVOLVED 1773 PATIENTS. STATISTICAL EVALUATIONS EVIDENCED REDUCTION OF PAIN, IMPROVEMENTS OF NERVE FUNCTION AND TROPHISM. IN CONCLUSION, ALC REPRESENTS A CONSISTENT THERAPEUTIC OPTION FOR PERIPHERAL NEUROPATHIES, AND ITS COMPLEX EFFECTS, NEUROTROPHIC AND ANALGESIC, BASED ON EPIGENETIC MECHANISM, OPEN NEW PATHWAYS IN THE STUDY OF PERIPHERAL NERVE DISEASE MANAGEMENT. 2013 12 5580 32 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED. 2021 13 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 14 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 15 6352 31 THE ROLE OF GABA(A) RECEPTORS IN THE DEVELOPMENT OF ALCOHOLISM. ALCOHOLISM IS A COMMON, HERITABLE, CHRONIC RELAPSING DISORDER. GABA(A) RECEPTORS UNDERGO ALLOSTERIC MODULATION BY ETHANOL, ANESTHETICS, BENZODIAZEPINES AND NEUROSTEROIDS AND HAVE BEEN IMPLICATED IN THE ACUTE AS WELL AS THE CHRONIC EFFECTS OF ETHANOL INCLUDING TOLERANCE, DEPENDENCE AND WITHDRAWAL. MEDICATIONS TARGETING GABA(A) RECEPTORS AMELIORATE THE SYMPTOMS OF ACUTE WITHDRAWAL. ETHANOL INDUCES PLASTICITY IN GABA(A) RECEPTORS: TOLERANCE IS ASSOCIATED WITH GENERALLY DECREASED GABA(A) RECEPTOR ACTIVATION AND DIFFERENTIALLY ALTERED SUBUNIT EXPRESSION. THE DOPAMINE (DA) MESOLIMBIC REWARD PATHWAY ORIGINATING IN THE VENTRAL TEGMENTAL AREA (VTA), AND INTERACTING STRESS CIRCUITRY PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ADDICTION. VTA GABAERGIC INTERNEURONS ARE THE PRIMARY INHIBITORY REGULATORS OF DA NEURONS AND A SUBSET OF VTA GABA(A) RECEPTORS MAY BE IMPLICATED IN THE SWITCH FROM HEAVY DRINKING TO DEPENDENCE. GABA(A) RECEPTORS MODULATE ANXIETY AND RESPONSE TO STRESS; IMPORTANT ELEMENTS OF SUSTAINED DRINKING AND RELAPSE. THE GABA(A) RECEPTOR SUBUNIT GENES CLUSTERED ON CHROMOSOME 4 ARE HIGHLY EXPRESSED IN THE REWARD PATHWAY. SEVERAL RECENT STUDIES HAVE PROVIDED STRONG EVIDENCE THAT ONE OF THESE GENES, GABRA2, IS IMPLICATED IN ALCOHOLISM IN HUMANS. THE INFLUENCE OF THE INTERACTION BETWEEN ETHANOL AND GABA(A) RECEPTORS IN THE REWARD PATHWAY ON THE DEVELOPMENT OF ALCOHOLISM TOGETHER WITH GENETIC AND EPIGENETIC VULNERABILITIES WILL BE EXPLORED IN THIS REVIEW. 2008 16 2398 23 EPIGENETIC REPROGRAMMING OF CORTICAL NEURONS THROUGH ALTERATION OF DOPAMINERGIC CIRCUITS. ALTERATIONS OF THE DOPAMINERGIC SYSTEM ARE ASSOCIATED WITH THE COGNITIVE AND FUNCTIONAL DYSFUNCTIONS THAT CHARACTERIZE COMPLEX NEUROPSYCHIATRIC DISORDERS. WE MODELED A DYSFUNCTIONAL DOPAMINERGIC SYSTEM USING MICE WITH TARGETED ABLATION OF DOPAMINE (DA) D2 AUTORECEPTORS IN MESENCEPHALIC DOPAMINERGIC NEURONS. LOSS OF D2 AUTORECEPTORS ABOLISHES D2-MEDIATED CONTROL OF DA SYNTHESIS AND RELEASE. HERE, WE SHOW THAT THIS MUTATION LEADS TO A PROFOUND ALTERATION OF THE GENOMIC LANDSCAPE OF NEURONS RECEIVING DOPAMINERGIC AFFERENTS AT DISTAL SITES, SPECIFICALLY IN THE PREFRONTAL CORTEX. INDEED, WE OBSERVED A REMARKABLE DOWNREGULATION OF GENE EXPRESSION IN THIS AREA OF ~2000 GENES, WHICH INVOLVES A WIDESPREAD INCREASE IN THE HISTONE REPRESSIVE MARK H3K9ME2/3. THIS REPROGRAMMING PROCESS IS COUPLED TO PSYCHOTIC-LIKE BEHAVIORS IN THE MUTANT MICE. IMPORTANTLY, CHRONIC TREATMENT WITH A DA AGONIST CAN REVERT THE GENOMIC PHENOTYPE. THUS, CORTICAL NEURONS UNDERGO A PROFOUND EPIGENETIC REPROGRAMMING IN RESPONSE TO DYSFUNCTIONAL D2 AUTORECEPTOR SIGNALING LEADING TO ALTERED DA LEVELS, A PROCESS THAT MAY UNDERLIE A NUMBER OF NEUROPSYCHIATRIC DISORDERS. 2014 17 265 40 ADVERSE EFFECTS OF RECREATIONAL AND MEDICAL CANNABIS. PURPOSE OF REVIEW: THIS COMPREHENSIVE REVIEW DISCUSSES THE ADVERSE EFFECTS KNOWN TODAY ABOUT MARIJUANA, FOR EITHER MEDICAL OR RECREATIONAL USE. IT REVIEWS THE ROLE OF CANNABIS IN THE TREATMENT OF CHRONIC PAIN, COGNITIVE AND NEUROLOGICAL ADVERSE EFFECTS, SPECIAL CASES AND ADDICTION. RECENT FINDINGS: CANNABINOIDS WORK THROUGH THE ENDOCANNABINOIDS SYSTEM AND INHIBIT THE RELEASE OF GABA AND GLUTAMATE IN THE BRAIN, IMPACT NEUROMODULATION, AS WELL AS DOPAMINE, ACETYLCHOLINE AND NOREPINEPHRINE RELEASE. THEY AFFECT REWARD, LEARNING AND PAIN. THE USE OF CANNABIS IS INCREASING NATIONALLY AND WORLD-WIDE FOR BOTH RECREATIONAL AND MEDICINAL PURPOSES, HOWEVER, THERE IS RELATIVELY ONLY LOW QUALITY EVIDENCE TO THE EFFICACY AND ADVERSE EFFECTS OF THIS. CANNABIS AND ITS DERIVATIVES MAY BE USED FOR TREATMENT OF CHRONIC PAIN. THEY ARE VIA CB1 RECEPTORS THAT ARE THOUGHT TO MODULATE NOCICEPTIVE SIGNALS IN THE BRAIN. CB2 RECEPTORS IN THE DRG LIKELY AFFECT PAIN INTEGRATION IN THE AFFERENT PATHWAYS, AND PERIPHERALLY CB2 ALSO AFFECTS NORADRENERGIC PATHWAYS INFLUENCING PAIN. A LARGE PROPORTION OF USERS MAY SEE MORE THAN 50% OF CHRONIC PAIN ALLEVIATION COMPARED WITH PLACEBO. CANNABIS AFFECTS COGNITION, MOST NOTABLY EXECUTIVE FUNCTION, MEMORY AND ATTENTION, AND MAY DETERIORATE THE BOUNDARY BETWEEN EMOTIONAL AND EXECUTIVE PROCESSING. CANNABIS IMPAIRS MEMORY IN THE SHORT RUN, WHICH BECOME MORE SIGNIFICANT WITH CHRONIC USE, AND MAY ALSO BE ACCOMPANIED BY POORER EFFORT, SLOWER PROCESSING AND IMPACTED ATTENTION. IT IS GENERALLY BELIEVED THAT LONG-TERM USE AND EARLIER AGE ARE RISK FACTOR FOR NEUROCOGNITIVE DEFICITS; NEUROIMAGING STUDIES HAVE SHOWN REDUCED HIPPOCAMPAL VOLUME AND DENSITY. EXECUTIVE FUNCTIONS AND MEMORY ARE WORSE IN ADOLESCENT USERS VERSUS ADULTS. CANNABIS ADDICTION IS DIFFERENT AND LIKELY LESS COMMON THAN OTHER ADDICTIVE SUBSTANCES, BUT UP TO 10% OF USERS MEET CRITERIA FOR LIFETIME CANNABIS DEPENDENCE. ADDICTION PATTERNS MAY BE LINKED TO GENETIC AND EPIGENETIC DIFFERENCES. IT IS STILL UNCLEAR WHETHER ABSTINENCE REVERSES PATTERNS OF ADDICTION, AND MORE RESEARCH IS REQUIRED INTO THIS TOPIC. SUMMARY: CANNABIS USE HAS BECOME MORE ABUNDANT FOR BOTH MEDICAL AND RECREATIONAL USE. IT CARRIES LIKELY BENEFITS IN THE FORM OF ANALGESIA, ANTI-EMESIS AND IMPROVED APPETITE IN CHRONIC PATIENTS. THE EVIDENCE REVIEWING ADVERSE EFFECTS OF THIS USE ARE STILL LIMITED, HOWEVER, EXITING DATA POINTS TO A CLEAR LINK WITH NEUROCOGNITIVE DETERIORATION, BACKED BY LOSS OF BRAIN VOLUME AND DENSITY. ADDICTION IS LIKELY COMPLEX AND VARIABLE, AND NO GOOD DATA EXISTS TO SUPPORT TREATMENT AT THIS POINT. IT IS BECOMING CLEAR THAT USE IN EARLIER AGES CARRIES A HIGHER RISK FOR LONG-TERM DEFICITS. AS WITH ANY OTHER DRUG, THESE RISKS SHOULD BE CONSIDERED ALONGSIDE BENEFITS PRIOR TO A DECISION ON CANNABIS USE. 2021 18 5820 36 STRESS DYNAMICALLY REGULATES BEHAVIOR AND GLUTAMATERGIC GENE EXPRESSION IN HIPPOCAMPUS BY OPENING A WINDOW OF EPIGENETIC PLASTICITY. EXCITATORY AMINO ACIDS PLAY A KEY ROLE IN BOTH ADAPTIVE AND DELETERIOUS EFFECTS OF STRESSORS ON THE BRAIN, AND DYSREGULATED GLUTAMATE HOMEOSTASIS HAS BEEN ASSOCIATED WITH PSYCHIATRIC AND NEUROLOGICAL DISORDERS. HERE, WE ELUCIDATE MECHANISMS OF EPIGENETIC PLASTICITY IN THE HIPPOCAMPUS IN THE INTERACTIONS BETWEEN A HISTORY OF CHRONIC STRESS AND FAMILIAR AND NOVEL ACUTE STRESSORS THAT ALTER EXPRESSION OF ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. WE DEMONSTRATE THAT ACUTE RESTRAINT AND ACUTE FORCED SWIM STRESSORS INDUCE DIFFERENTIAL EFFECTS ON THESE BEHAVIORS IN NAIVE MICE AND IN MICE WITH A HISTORY OF CHRONIC-RESTRAINT STRESS (CRS). THEY REVEAL A KEY ROLE FOR EPIGENETIC UP- AND DOWN-REGULATION OF THE PUTATIVE PRESYNAPTIC TYPE 2 METABOTROPIC GLUTAMATE (MGLU2) RECEPTORS AND THE POSTSYNAPTIC NR1/NMDA RECEPTORS IN THE HIPPOCAMPUS AND PARTICULARLY IN THE DENTATE GYRUS (DG), A REGION OF ACTIVE NEUROGENESIS AND A TARGET OF ANTIDEPRESSANT TREATMENT. WE SHOW CHANGES IN DG LONG-TERM POTENTIATION (LTP) THAT PARALLEL BEHAVIORAL RESPONSES, WITH HABITUATION TO THE SAME ACUTE RESTRAINT STRESSOR AND SENSITIZATION TO A NOVEL FORCED-SWIM STRESSOR. IN WT MICE AFTER CRS AND IN UNSTRESSED MICE WITH A BDNF LOSS-OF-FUNCTION ALLELE (BDNF VAL66MET), WE SHOW THAT THE EPIGENETIC ACTIVATOR OF HISTONE ACETYLATION, P300, PLAYS A PIVOTAL ROLE IN THE DYNAMIC UP- AND DOWN-REGULATION OF MGLU2 IN HIPPOCAMPUS VIA HISTONE-3-LYSINE-27-ACETYLATION (H3K27AC) WHEN ACUTE STRESSORS ARE APPLIED. THESE HIPPOCAMPAL RESPONSES REVEAL A WINDOW OF EPIGENETIC PLASTICITY THAT MAY BE USEFUL FOR TREATMENT OF DISORDERS IN WHICH GLUTAMATERGIC TRANSMISSION IS DYSREGULATED. 2015 19 747 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 20 2772 41 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003