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Brain Norepinephrine
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 (ISBN-13: 9780511271120)




Index




LC=locus coeruleus; NE=norepinephrine

acetylcholine

   effects on LC activity 57–58

   expression and receptor distribution in the LC 18

acetylcholine-containing neurons, inputs to the LC 57–58

addictions, NE gene-linked susceptibility 496

   see also substance abuse

ADHD (attention deficit/hyperactivity disorder) 85–86

    adrenergic receptor agonist treatment 563

   amphetamine treatment 563

   arousal state disorders 179

   catecholamine dysregulation 179

   cognitive disorders 418–420

   effects of mode of LC activity 179

   factors involved in etiology 557

   genetic factors 561–562

   heritability 561–562

   history of descriptions and treatments 557–561

   hypertonic LC activity 219–220

   mechanisms of treatments 418–420

   methylphenidate treatment 563

   NE gene-linked susceptibility 493–494

   prefrontal cortex dysfunction 418–420

   pharmacological regulation of LC activity mode 224–225

   possible genetic effects 419–420

   reboxetine treatment 124,125

   role of compromised NET function 134–135

   role of NE in etiology and treatment 418–420

   role of NE in pathophysiology 563–564

   role of NE in “prefrontal” abnormalities 562–563

   role of NE system abnormalities 301

   role of prefrontal cortex pathology 562–563

   role of the dopamine system 563–564

   role of the LC in pathophysiology 563–564

   sleep disorders associated 176–177,179

   stimulants versus selective NE medications 563

ADHD and NE medications 564–570,573,575–576,578–579,580,581–582,583

    agonists 574,575–576

   atomoxetine 577–582,583,584

   bupropion 574–577,578–579

   monoamine oxidase inhibitors (MAOIs) 572,573

   review of studies 564–565,567–570,573,575–576,578–579,580,581–582

   stimulants versus NE agents 565–566

   tricyclic antidepressants 566–570,572

   venlafaxine 577,580

adrenal medulla 395

adrenergic receptor genes 477–478,479,487–489

adrenergic receptors

   clinical effects of blocking by antidepressants 527–530

   clinical effects of blocking by antipsychotics 527–530

   functions 68

   G protein-coupled receptors 68–69

   historical development of classification 69–71

   in the prefrontal cortex 408–409

   mediation of norepinephrine and epinephrine actions 68

   subtype-selective agents 69–71

   subtypes 68,69–71

   see also adrenergic receptors; adrenergic receptors; adrenergic receptors; noradrenergic receptors

aging

   and LC neuron loss 17,180

   and memory loss 415–416

   effects on LC-NE activity 180

   effects on sleep-wake regulation 180

alcoholism see substance abuse

adrenergic receptors

   activation of CREB-mediated gene transcription 102–103

   blocking effects of antidepressants 525,526, 528

   blocking effects of antipsychotics 525,527,529

   densities in brain tissues 82–83

   desensitization (tachyphylaxis) 74

   G protein activation 79,80

   genes 479,487

   historical development of classification 69–71

   molecular characteristics 72–74

   nonsubtype selective agonists 71–72

   nonsubtype selective antagonists 71–72

   pharmacological characteristics 71–72

   physiological roles 80,82–83

   polymorphisms 83

   regulation 74–75

   role in CNS function 82–83

   signal transduction pathways 79,80

   subtype selective agents 71,72

adrenergic receptors

   blocking effects of antidepressants 525,526,528

   blocking effects of antipsychotics 525,527,529

   densities in brain tissues 83,86

   desensitization (tachyphylaxis) 76–77

   G protein activation 79–81

   genes 479,487–488

   historical development of classification 69–71

   in aetiology and treatment of depression 76–77

   mechanisms of antidepressant drugs 76–77

   mediation of analgesia 80,84

   mediation of anesthesia 80,84

   molecular characteristics 73,76

   nonsubtype selective agonists 73,75–76

   nonsubtype selective antagonists 73,75–76

   pharmacological characteristics 73,75–76

   physiological roles 80,83–86

   polymorphisms 86

   regulation 76–77

   signal transduction pathways 79–81

   subtype selective agents 73,75–76

   subtype-specific functions 80,83–86

agonists, ADHD treatment 574,575–576

Alzheimer’s disease

   cellular changes in the LC 19

   cognitive deficits 416

   degenerative process 416

   inflammatory component 464

   neuron loss in the LC 17,18–19,20,180,223–224

   NE gene-linked susceptibility 493

   postmortem brain research 341–342

   role of compromised NET function 134–135

   specific patterns of LC neuronal loss 463,464

amphetamine

   effects of prolonged use on NET activity 131

   effects on memory consolidation 238–240

   effects on NETs 124,125

   treatment for ADHD 563

   see also substance abuse

amygdala

   axonal projection to the pericoerulear area 53

   basolateral complex role in memory 237

amygdala noradrenergic system

    adrenoceptor mediation of NE effects 247–248,249,250

    adrenoceptor mediation of NE effects 247–248,249,250

   BLA role in memory consolidation 244–245,247–248,249–250,251–254,256,257,259,260,261

   effects on neuroplasticity 249–251,252–253

   electrophysiological events induced by activation 249–251

   influence of NE on memory consolidation 243–246,247,248,250,253

   influence on memory consolidation 243–246,247,248,250,253

   influences on different forms of memory 252–253

   influences on the hippocampus 252–253

   interaction with the cholinergic system 258–260,261

   interactions with other systems on memory consolidation 253–254,256,257,259,260,261

   mediation of epinephrine-induced memory enhancement 243–244

   mediation of GABAergic system effects on memory 258

   mediation of glucocorticoid hormone effects on memory 253–254,256,257

   mediation of opioid peptidergic system effects on memory 256–258,259

   molecular events induced by activation 249–251

   regulation of memory processes in other brain regions 251–253

   role in memory 237

   stress-induced NE release and memory consolidation 245–246,247

   training-induced NE release and memory consolidation 245–246,247

analgesia, mediation by A adrenergic receptors 80,84

anesthesia

   mediation by A adrenergic receptors 80, 84

   role of noradrenergic mechanisms 396–397

animal models of psychopathology

   approach to development of models 325

   benefits and limitations of models 325–326

   construct validity 301–302

   convergent validity 301–302

   criteria for a satisfactory model 301–302

   etiological validity 301–302

   face validity 301–302

   future directions 326–327

   NE system alterations 302–304,325

   predictive validity 301–302

   role of NE in neural development 325

   vulnerability to psychopathologies 325

animal models of psychopathology (animal assay) 303–304,317–320

   benefits and limitations of models 325–326

   elevated plus-maze 318

   forced-swim test 317–318

   open-field test 318–319

   operant conflict test 320

   social interaction test 319

animal models of psychopathology (breeding to phenotype) 303–304,320–322

   benefits and limitations of models 326

   Flinders sensitive line 320–321

   Maudsley line 321

   Roman high- and low-avoidance rats 321–322

animal models of psychopathology (gene manipulation) 303–304,322–325

   B adrenergic receptor knockout and overexpressing mice 323

    adrenergic receptor knockout and overexpressing mice 323–324

   benefits and limitation of models 326

   dopamine β-hydroxylase knockout mice 322

   galanin overexpressing mice 324–325

   NET knockout mice 322–323

animal models of psychopathology (homologous) 302–304,317

   adult models of psychopathology 314–317

   chronic variable stress/chronic mild stress 315–316

   early malnutrition 309–311

   isolation rearing 311–313

   learned helplessness 314–315

   maternal separation and neonatal handling 307–309

   neonatal infection 313

   olfactory bulbectomy 316–317

   perinatal models of psychopathology 302–314

   plasticity of early life effects 313–314

   prenatal glucocorticoid exposure 307

   prenatal stress 306–307

anorexia nervosa

   NE metabolism 597–599

   NE pharmacology in treatment 603

   research on NE and feeding 595–597

anterior cingulate cortex, influence on LC neuronal activity 215,216,217

antidepressant drug research and development

   actions on NE transporter 516–520

   bi-dimensional model of affective illness 517–520

   biogenic amine hypothesis of affective illness 516

   discovery of chlorpromazine 515

   discovery of imipramine 515–517

   discovery of noradrenergic interactions 515

   effects on adrenergic receptors 517–520

   history of reserpine 516

   in the 1950s and 1960s 515–517

   in the 1970s and 1980s 517–520

   introduction of monoamine oxidase inhibitors 515–517

   introduction of the first antidepressants 515

   introduction of tricyclic antidepressants 515

   mechanisms of antidepressant actions 517–520

   NE uptake blockers 516–520

   permissive hypothesis of affective illness 517–520

   receptor desensitization process 517–518

   relationship between serotonin and NE 517–520

   role of NE in antidepressant effects 363–364

   serotonin uptake blockers 516–520

   time lag for onset of activity 517–518

antidepressant drug treatments

    adrenoceptor blocking effects 525,526,528

   antiepileptic effects 462–463

   clinical differences between SSRIs and NRIs 372,374

   clinical effects of blocking NE transporter and receptors 527–530

   discovery and development 372,374

   effects of NE selective reuptake inhibitors 104–106,107,112

   effects of prolonged use on NET activity 131

   effects on adrenergic receptors 79,87

   effects on noradrenergic receptors and signal transduction pathways 104–106,107,112

   imipramine 535

   induction of c-Fos 113–114

   mediation by adrenergic receptors 76–77, 85

   modulation of LC activity 60

   regulation of c-Fos and IEG expression 112–113

   role of CREB 109

   role of CREB in adult neurogenesis 110–111,112

   targeting of noradrenergic neurotransmission 287–290

   therapeutic mechanisms 372,374

   up-regulation of adult neurogenesis 110–111,112

   use in treatment of anxiety disorders 535

antiepileptic drugs, antidepressant effects 462–463

antipsychotic drugs

    adrenoceptor blocking effects 525,527,529

   clinical effects of blocking NE transporter and receptors 527–530

   mechanisms 85–86

anxiety disorders

   antidepressant targeting of noradrenergic neurotransmission 287–290

   antidepressant treatments 535

   genetic component 474

   HPA axis dysregulation 473–474

   insomnia 176–177

   link with LC-norepinephrine dysfunction 60,61,69

   NE gene-linked susceptibility 494–495

   role of genes affecting NE homeostasis 474

   role of NE dysregulation 275,283–284,285,286,288,300–301,473–474

   role of NE neurotransmission in the amygdala 112–113

   role of NE-LC hyperactivity 176–177

   sleep disorders associated 176–177

   treatment with NE reuptake inhibitors 544–547,549–550

AP-1 (activator protein-1) family of transcription factors 98–99

   regulation by noradrenergic receptors 101,103–104

   regulation of AP-1 mediated gene transcription 112

arousal, role of the LC-NE system 157

asthma treatment

    selective agonists 77–78

   NE gene-linked response 498

atomoxetine (selective NE reuptake inhibitor)

   ADHD treatment 577–582,583,584

   effects on NETs 124,125

   see also tomoxetine

attention state

   focused vs. flexible 196–198

   modulation by LC activity 196–198

   selective vs. scanning 196–198

autism, hyperphasic LC activity 220–221

basolateral complex of the amygdala (BLA), role in memory consolidation 244–245,247–248,249–250,251–254,256,257,259,260,261

bed nucleus of the stria terminalis (BNST)

   effects of stress-induced NE release 280–281,282,283

   mediation of substance withdrawal symptoms 617–618

   role in stress-induced drug relapse 618–620

behaviour and psychiatric diseases, NE gene-linked susceptibility 493–496

behavioural flexibility, modulation by LC activity 196–198

benzodiazepines, withdrawal effects on LC activity 56

adrenergic receptors

    physiological roles 80,83,86–87

    polymorphisms 88

    physiological roles 80,83,86–87

    polymorphisms 88

    selective agonists in treatment of asthma 77–78

    physiological roles 88–89

    polymorphisms 89

   densities in brain tissues 83,87

   desensitization (tachyphylaxis) 78–79

   effects of antidepressant drugs 79

   G protein activation 80,81–82

   genes 479,488–489

   historical development of classification 69

   molecular characteristics 73,78

   nonsubtype selective agonists 77–78

   nonsubtype selective antagonists 77,78

   pharmacological characteristics 77–78

   physiological roles 80,83,86–89

   regulation 78–79

   regulation of cAMP-CREB cascade 97,100–102

   signal transduction pathways 80,81–82

   subtype selective agonists 77–78

   subtype selective antagonists 77,78

bipolar disorder

   excessive NE activity 421–422

   prefrontal cortex dysfunction 421–422

   protein kinase C (PKC) activity 421–422

blood pressure

   effects of adrenergic receptors 83–84, 85

   role of adrenergic receptors 80,82

BNST see bed nucleus of the stria terminalis

brain, regulators of gene expression 95

   see also CNS

brain development, primary functions of NE 299

brain function, role of adrenergic receptors 82–83

brain mapping, use of IEGs 112

brain mapping during stress, use of IEGs 113–114

brain tissues, densities of adrenergic receptors 82–83

breast cancer risk, NE gene-linked susceptibility 498

bulimia nervosa

   NE metabolism 599–603

   NE pharmacology in treatment 604–605

   research on NE and feeding 595–597

bupropion, ADHD treatment 574–577,578–579

c-Fos (immediate early gene; IEG) 103–104

   expression regulation by desipramine 112–113

   induction by antidepressants 113–114

   induction by stress 113–114

   NE regulation under stress conditions 113–114

   use for brain mapping 112

   use for brain mapping during stress 113–114

c-Fos mediated gene transcription, regulation by NE 112–114

cAMP-CREB cascade see also CREB

   effects of NE selective reuptake inhibitors 105–106,107,109

   increase in adult neurogenesis 110–111,112

   regulation by noradrenergic receptors 97,100–102

   role in learning and memory 114–115

cAMP signaling pathway 100

cardiovascular disease

   heritability of onset and severity 474–476

   NE gene-linked susceptibility 496–497

   role of compromised NET function 134–135

catechol-O-methyltransferase gene 479, 486–487

catecholamine-containing neurons, classification 436–437,438

catecholamine dysregulation, in ADHD 179

catecholamine neurotransmitters 1

central nucleus of the amygdala, effects of stress-induced NE release 280–281,282, 283

cerebral cortex

   influence of NE on functions 408

   light deprivation-induced loss of NE 173–174

   NE innervation 408–409

   see also prefrontal cortex; posterior and subcortical function

chlorpromazine 515

cholinergic system

   effects on memory 258–260,261

   interaction with the amygdala noradrenergic system 258–260,261

circadian regulation, role of the LC-NE system 157

circadian sleep-wake regulation, role of LC 167–169,171,172,173,174

clonidine, growth hormone response 365–366

CNS disorders, link with LC-norepinephrine dysfunction 60,61,69

CNS function, role of adrenergic receptors 82–83

   see also brain

cocaine, effects on NET activity 124,125,131

   see also substance abuse

cognitive disorders with altered NE 411,415–424

   ADHD 418–420

   Alzheimer’s disease 416

   depression 420–421

   disorders with too little NE 415–421

   disorders with too much NE 411,421–424

   Korsakoff’s amnesia 417

   mania/bipolar disorder 421–422

   normal aging process 415–416

   Parkinson’s disease 417

   PTSD 411,423–424

   role of NE in etiology and treatment 411,415–424

   schizophrenia 422–423

cognitive functions

   effects of stress-induced NE 414–415

   in the prefrontal cortex 409–410,411,412

   influences of NE 408

   mediation by C adrenergic receptors 80,85–86

cold sensitivity, role of adrenergic receptors 88–89

complex diseases

   role of inherited gene variation 472–473

   susceptibility loci 472–473

corticotropin-releasing factor see CRF

CREB (cAMP response element binding protein)

   antidepressant effects in behavioural models 109

   family of transcription factors 98–99

   up-regulation of adult hippocampal neurogenesis 110–111,112

CREB-mediated gene transcription, activation by noradrenergic receptors 102–103

CRF (corticotropin-releasing factor)

   expression and receptors in the LC 21–22

   role in noradrenergic regulation of sleep-wake cycle 166,167,168

   role in stress-related sleep disorders 175–176

CRF system, interactions with the NE system 299–300

decision-related LC neuronal activity in monkeys 211–212,213,214

dementia

   inflammatory component 464

   loss of LC neurons 223–224

   role of NE 463,464

   specific patterns of LC neuronal loss 463,464

depression 85–86

   and insomnia 174–175

   and sleep deprivation 176

   antidepressant drug mechanisms 76–77

   antidepressant effects of antiepileptic drugs 462–463

   antidepressant targeting of noradrenergic neurotransmission 287–290

   cognitive effects 420–421

   compromised NET function 134–135

   effects of stress exposure 420–421

   genetic component 474

   hippocampal cell atrophy and cell loss 110–111,112

   HPA axis dysregulation 473–474

   hypotonic LC activity 206,221–222

   interactions affecting sleep 175–176

   LC cell loss 17

   LC NE receptor imbalance 17–18

   LC role in sleep alterations 174–176

   NE dysregulation 60,61,69,175,275,283–284,285,286,288,300–301,420–421,473–474

   NE gene-linked susceptibility 494–495

   prefrontal cortex dysfunction 420–421

   regulation of adrenergic receptors 76–77

   relationship with epilepsy 462–463

   role of genes affecting NE homeostasis 474

   sleep disorders 174–175

   see also mood disorders

depression postmortem research

    adrenergic receptors 351–352

    adrenergic receptors 352–353

   locus coeruleus studies 346–350,356

   postsynaptic markers in depression 351–353

   presynaptic markers in depression 346–350, 356

   role of the noradrenergic system 344–353

depression treatments

   clinical characteristics of responders 539–542

   comparative efficacy of NE selective antidepressants 538–539

   evidence for use of NE reuptake inhibitors 538

   mechanism of action 536

   NE reuptake inhibitors 536–539,542,543, 544

   reboxetine 536

   second generation NE reuptake inhibitors 536

   secondary or demethylated tricyclic compounds 536

   synergistic effects of NE and 5-HT antidepressants 543–544

   tetracyclic compounds 536

   tomoxetine 536

   tricyclic compounds 536

desipramine (tricyclic antidepressant)

   effects on NETs 124,125

   regulation of c-Fos and IEG expression 112–113

diabetes

   effects on LC neuronal responses 56

   NE gene-linked susceptibility 497–498

   role of adrenergic receptors 88–89

dopamine

   effects on LC activity 55

   role in substance abuse 610–611

   transport by NETs 122

dopamine -hydroxylase gene 479,485

dopamine transporter (DAT) 120–121,124,125

dopaminergic neurons

   activity regulation by NE 59–60

   innervation of the LC 55

   origins of 55

dorsal raphe nucleus

   axonal projection to the pericoerulear area 53

   LC reciprocal noradrenergic innervation 59,60

dorsomedial hypothalamus (DMH), role in sleep-wake regulation 157

drug abuse see substance abuse

DSP4 treatment, effects on sleep-wake regulation 159,162,163–164,165,167

dysphoria and affective disorders, NE gene-linked susceptibility 494–495

   see also depression

eating disorders

   NE metabolism in anorexia nervosa 597–599

   NE metabolism in bulimia nervosa 599–603

   NE pharmacology in treatment of anorexia nervosa 603

   NE pharmacology in treatment of bulimia nervosa 604–605

   research on NE and feeding 595–597

electroconvulsant shock, effects on adrenergic receptors 79

electrotonic coupling among LC neurons 196–198

   regulatory inputs 213–216,217,218

emotional/stress memories, role of NE 114–115

enkephalin expression and receptor subtypes in the LC 19–21

environmental sensitization and NE, stress vulnerability 286–287,288

epilepsy

   antiepileptic effects of antidepressants 462–463

   antiepileptic role of the LC 454

   clinical correlates for NE involvement 462–463

   involvement of NE 441,444,454–463

   kindling and NE activity 454–455

   NE role in breeding to epileptic phenotype models 459

   NE role in experimental limbic status epilepticus 441,456–457

   NE role in modulation of seizures 462–463

   NE role in selective gene manipulation models 444,459–462

   NE system in seizure models of epilepsy 455–456

   plasticity-dependent antiepileptic effects of NE 466

   pro- and anticonvulsant effects of adrenergic receptor agonists 457–459

   pro- and anticonvulsant effects of adrenergic receptor antagonists 457–459

   relationship with depressive disorders 462–463

   vagus nerve stimulation (VNS) treatment 462–463

epinephrine (EPI)

   effects on memory consolidation 238–240

   mediation by adrenergic receptors 68

   transport by NETs 122

epinephrine-induced memory enhancement, mediation by the amygdala 243–244

ERK (extracellular regulated protein kinase) signaling pathway 100

fear, role of NE neurotransmission in the amygdala 112–113

Fos family of AP-1 transcription factors 103–104

frontal cortex, axonal projection to the pericoerulear area 53

G protein-coupled receptor subtypes, NE coupling 100,101

G protein-coupled receptors, adrenergic receptors 68–69

GABA (gamma amino-butyric acid)

   effects on LC neuronal activity 56

   expression and receptors in the LC 18

   receptors on LC neurons 56

   regulation of norepinephrine in the cerebral cortex 56

GABA-containing fibers

   innervation of the LC 56

   origins of 56

GABAergic system, effects on memory 258

galanin expression and receptor types in the LC 18–19,20

gene expression, effects of NE reuptake inhibitors 104–106,107,112

gene expression in the brain, regulation by NE 95

gene transcription mechanisms 96–100

   AP-1 (activator protein-1) family of transcription factors 98–99

   cis-regulatory elements 96–97,98

   CREB family of transcription factors 98–99

   initiation of gene transcription 96–97,98

   messenger RNA synthesis 96–97,98

   posttranscriptional processing of mRNA 98

   RNA editing 98

   RNA half-life modulation 98

   splice variants 98

   TATA box 96–97,98

   transcription factors 98–99,100

   trans-regulatory elements 97

gene variation

   role in common complex diseases 472–473

   susceptibility loci for complex diseases 472–473

generalized anxiety disorder (GAD)

   sleep disorders associated 176–177

   treatment with NE reuptake inhibitors 548–549

genes see noradrenergic genes

genetic evidence for NE regulation of memory consolidation 242–243

genetic factors in ADHD 561–562

genetically variant traits, influence of noradrenergic dysfunction 473–477

genetics tools 472–473

   forward genetics using candidate genes 472–473

   positional cloning (reverse genetics) using linkage to markers 472–473

glucocorticoid hormones, effects on memory 253–254,256,257

glutamate

   effects on noradrenergic neurons in the LC 56–57

   inputs to the LC 56–57

   regulatory effects on LC activity 56–57

   sources of input to the LC 57

   stress-associated activation of the LC 57

growth hormone response to clonidine 365–366

heart

   functions of adrenergic receptors 82

   functions of adrenergic receptors 80, 86–87

hippocampus, memory consolidation 252–253

hippocampus/entorhinal complex, effects of NE on memory consolidation 260–264

HPA (hypothalamic-pituitary-adrenal) axis

   dysregulation in anxiety and depression 473–474

   stress-induced activation 278,279

hypnotizability, NE gene-linked susceptibility 498

hypothermic effects, mediation by adrenergic receptors 80,84

IEG (immediate early gene) transcription factors

   effects of NE 112–114

   effects of NE reuptake inhibitors 112–114

IEGs (immediate early genes)

   c-Fos 103–104

   expression regulation by desipramine 112–113

   use in brain mapping 112

   use in brain mapping during stress 113–114

imipramine 515–517

   actions on the noradrenergic system 535

   discovery of antidepressant action 535

   NE gene-linked susceptibility 493–494

   pharmacology 535

   treatment of panic disorder 544–545

insomnia

   in anxiety disorders 176–177

   in depression 174–175

   mechanisms of sleep disruption 180–181

insular cortex, effects of NE on taste aversion memory 264–265

ischemia, effects on NET function 134–135

Jun family of AP-1 transcription factors 103–104

Korsakoff’s amnesia, cognitive deficits 417

lateral reticular nucleus of the medulla 393

LC (locus coeruleus)

   acetylcholine expression and receptor distribution 18

   alternative names for 9

   attention states regulation (focused vs. flexible) 196–198

   axon collaterals 16

   axon-like plexuses 16

   brain processes affected by 41

   cell loss in Alzheimer’s disease 17,18–19,20,180,223–224

   cell loss in dementia 223–224

   cell loss in depression 17

   cell loss in Parkinson’s disease 223–224

   cell loss with age in humans 17,180

   cell numbers within human LC 13–14

   cell population heterogeneity 15–17

   cellular changes in Alzheimer’s disease 19

   CRF expression and receptors 21–22

   degeneration in neurological disorders 438–439

   enkephalin and receptor subtypes 19–21

   enkephalin coexpression by GABAergic terminals 18

   Falck-Hillarp method of identification 10

   functional anatomy 436–437,438

   fusiform cells 15–16

   GABA expression and receptor types 18

   GABA inhibition during REM sleep 56

   galanin expression and receptor types 18–19, 20

   history of discovery 9–10

   human LC neuronal subtypes 17

   in primates 12–14

   in the cat 11–12

   in the rat 10–11

   indirect projection from the SCN 167–169,170

   lack of pigmentation in lower species 9

   location and extent in humans 10,13–14

   mediation of substance withdrawal symptoms 616–618

   morphology of human LC neurons 17

   morphology of neurons 15–17

   multipolar cells 15–16

   NE provision for the CNS 53

   NE receptor imbalance in depression 17–18

   NE receptor subtypes 17–18

   neuronal activity in sleep-wake regulation 159,160–164,165,167

   neuropeptide Y expression and receptors 19

   neuropeptides 18–20,22

   neurophysin 21

   neurotensin 21

   noradrenergic activation of the amygdala 237

   noradrenergic input to the cortex 408–409

   ontogeny 15

   organizational pattern of catecholamine neurons 13–14

   peri-LC dendritic arrays 16–17

   pigmentation and immunoreactivity 13–14,17

   pigmentation development 12–13

   presynaptic profile subtypes 17

   receptor subtypes and distribution 17–22

   reciprocal relationships with other parts of the brain 60,61,69

   role in ADHD pathophysiology 563–564

   role in arousal 157,161–162,196–198

   role in circadian sleep-wake regulation 159,160–164,165,167–169,171,172,173,174

   role in memory consolidation 237,241–242

   role in noradrenergic pain modulation 393–394

   role in sleep alterations due to clinical pathologies 174–181

   role in sleep alterations in depression 174–176

   role in task performance and selective attention 196–198

   selective actions of NE 40–41

   somatostatin 21

   species comparisons 10–14

   substance P 21

   substance P receptors 58–59

   synchronous activation 41

   transmitter agents 17–22

   ultrastructural features of neurons 16–17

   variable impacts of NE 41

   vasoactive intestinal peptide 21

   vasopressin 21

LC activity

   and task performance 196–198

   circadian rhythm 170,171

   effects of acetylcholine 57–58

   effects of aging 180

   effects of dopamine 55

   effects of GABA 56

   effects of glutamate 56–57

   effects of nicotine 58

   effects of serotonin 54–55

   effects of substance P 58–59

   in sleep-wake regulation in primates 161

   mediation by muscarinic acetylcholine receptors 57–58

   mediation by nicotinic acetylcholine receptors 57–58

   metabotropic glutamate receptor activation 57

   modulation by antidepressants 60

LC activity modes

   clinical implications 206,219–225

   dysregulated phasic activity in schizophrenia 222–223

   electrotonic coupling regulatory inputs 213–216,217,218

   hyperphasic activity in autism 220–221

   hypertonic activity in ADHD 179,219–220

   hypertonic activity in posttraumatic stress disorder 220

   hypoactive mode 218

   hypotonic activity in depression 206,221–222

   implications for new pharmacotherapies 224–225

   LC dysfunction and sleep disorders 224

   link with decision to respond 218–219

   pharmacological regulation 224–225

   phasic LC mode 218

   relationship to attention 218–219

   theory of modes of activity 218

   tonic activity variation with arousal states 160–161,199

   tonic LC mode 218

LC afferent input sources 22–25,26

   acetylcholine-containing neurons 57–58

   anterograde studies 22,23–24

   dopaminergic innervation 55

   glutamate 56–57

   innervation by GABA-containing fibers 56

   innervation by substance P-containing fibers 58–59

   input from other brain regions 53

   input from the PGi 53

   input from the PrH 53

   peri-LC dendritic contacts 24–25,26

   retrograde studies 22–23

   serotonergic innervation 54–55

   ultrastructural examinations 24–25,26

LC chemoarchitecture (neurochemically identified pathways) 31–39,40,61

   adrenergic inputs 33

   afferent inputs 31–38,39,61

   CRF inputs 35–36

   dopaminergic inputs 33

   efferent connections 38–40

   efferent target selectivity 40–41

   enkephalin inputs 36

   excitatory inputs 31–32

   GABA inhibitory inputs 32–33

   glutamate receptors 31–32

   glutamatergic excitatory inputs 31–32

   glycine inhibitory inputs 32–33

   hypocretins 34–35

   inhibitory inputs 32–33

   neuropeptide inputs 34–38,39,61

   noradrenergic inputs 33

   orexin A and B 34–35

   preprohypocretin (hcrt) 34–35

   serotonergic inputs 33

   synchronous activation 41

LC efferent projection 26–28,29,30,31

   axon collateralization 28–29,30,31

   global network of NE neurons 198

   histochemistry and anterograde labeling 26–27

   modulation of target area neuronal activity by NE 198–199

   neuron innervation of more than one structure 28–29,30,31

   reciprocal projection of noradrenergic fibers 59–60

   retrograde labeling 28,29,30

LC lesions

   effects on circadian amplitude of sleep-wake cycle 170–173

   effects on sleep-wake regulation 159,162,163–164,165,167

LC neuronal activity, influence of prefrontal cortex 213–215,216,217

LC neuronal activity and task performance (monkeys) 200–202,204,206

   complexity of relationship with vigilant behaviour 205–206

   hypoactive mode 205–206

   interpretation of results 205–206

   modes of LC activity 205–206

   phasic activation by meaningful stimuli 201,202

   phasic mode 205–206

   relationship of tonic to phasic activity 203–204,205

   target detection task 200

   task difficulty 205

   tonic fluctuations during task performance 202–203,204

   tonic mode 205–206

LC neuronal activity and task performance (simulation model) 206–207,209,210

   components of the model 206–207

   electrotonic coupling 208–209

   interpretation of results 210

   LC model 208,209

   questions addressed 206–207

   simulation results 209–210

   stimulus discrimination network 207–208

LC neuronal activity in decision making (monkeys) 211–212,213,214

   forced-choice task 211

   phasic activation of the LC 211–212,213,214

LC neurons

   activation by stressors 199–200

   activity in relation to task performance 196–198

   circadian fluctuations in activity 157

   disease specific patterns of neuronal loss 463

   electrotonic coupling 196–198

   GABA receptors 56

   modes of functioning 196–198

   phasic and tonic activity 196–198

   phasic responsiveness 199–200

   polymodal sensory responsiveness 199–200

   ultrastructural features 16–17

LC-NE dysregulation

   and depression 175

   hyperactivity in anxiety disorders 176–177

   hyperactivity in PTSD 178–179

   link with depression and anxiety 60,61,69

   role in stress-related sleep disorders 175–176

   see also specific disorders

learning

   role of cAMP-CREB cascade 114–115

   role of NE 114–115,236–237

Lewy body disease 463

light deprivation, loss of cortical NE 173–174

locus coeruleus see LC

long-term memory see memory consolidation

long-term potentiation, role of NE 466

lymphocytes, NE receptors on 364–365

mania

   excessive NE activity 421–422

   prefrontal cortex dysfunction 421–422

   protein kinase C (PKC) activity 421–422

MAP kinase signaling pathway 100,102–103

medial prefrontal cortex, effects of NE on working memory 264

memory

   age-related memory loss 415–416

   brain systems involved in 236–237

   development of chronic stress symptoms 265–266

   effects of activation of the noradrenergic system 265–266

   effects of emotional arousal 265–266

   modulation by central NE function 236–237

   NE role in long-term consolidation 236–237

   noradrenergic activation of the amygdala 237

   role of cAMP-CREB cascade 114–115

   role of NE 114–115

   see also working memory

memory consolidation

   effects of amphetamine 238–240

   effects of epinephrine 238–240

   effects of LC noradrenergic system 241–242

   effects of NE on hippocampus/entorhinal complex 260–264

   effects of NE on insular cortex 264–265

   effects of NE on medial prefrontal cortex 264

   factors affecting strength of memories 238

   genetic evidence for NE regulation 242–243

   influence of amygdala noradrenergic system 243–246,247,248,250,253

   influence of emotional arousal 238

   NE effects on human subjects 265–266

   peripheral epinephrine and norepinephrine effects 240

   pharmacological evidence for NE regulation 242–243

   role of adrenergic catecholamines 238–243

   role of brain stem noradrenergic cell groups 240–242

   role of the basolateral complex of the amygdala 244–245,247–248,249–250,251–254,256,257,259,260,261

   role of the nucleus of the solitary tract 240–242

   see also amygdala noradrenergic system

metabolic disorders, NE gene-linked susceptibility 497–498

methylphenidate treatment for ADHD 563

migraine, NE gene-linked susceptibility 493

monoamine oxidase genes 479,486

monoamine oxidase inhibitors (MAOIs)

   ADHD treatment 572,573

   introduction of 515–517

mood disorders

   antidepressant drug mechanisms 372,374

   biological theories 372,374

   clinical differences between SSRIs and NRIs 372,374

   discovery and development of treatments 372,374

   effects of neurotransmitter depletion challenges 366–372

   research into the role of NE 363–364

   role of NE in illness 374–376

   role of NE in treatment 374–376

   see also depression

movement disorders, NE gene-linked susceptibility 489–493

multiple sclerosis 463,465

multiple systems atrophy (MSA) 463–464

muscarinic acetylcholine receptors, mediation of LC activity 57–58

narcolepsy, NE gene-linked susceptibility 498

NE (norepinephrine)

   age-related decrease in clearance 133–134

   and environmental sensitization 286–287,288

   chemical “switch” 414–415,424

   coupling to G protein-coupled receptor subtypes 100,101

   CRF system interactions 299–300

   discovery of 1

   effects of GABA on levels in LC 56

   effects on IEG transcription factors 112–114

   effects on stress vulnerability 286–287,288

   functional anatomy of central NE system 436–437,439

   influence on the amygdala 112–113,243–246,247,248,250,253

   influence on fear and anxiety states 112–113

   influence via reciprocal projections from the LC 60,61,69

   modulation of activity in LC target areas 198–199

   modulatory effects on brain circuits 275–276

   nicotine-stimulated release 58

   primary functions during brain development 299

   primary functions in the mature CNS 299–300

   provision by the LC 53

   regulation by neurotransmitter inputs to the LC 53

   regulation of AP-1 family of transcription factors 98–99

   regulation of c-Fos gene expression 112–113,114

   regulation of c-Fos under stress conditions 113–114

   regulation of CREB family of transcription factors 98–99

   regulation of neuronal gene expression 95

   regulation of serotonergic raphe nuclei 59,60

   role in clinical anesthesia 396–397

   role in etiology and treatment of cognitive disorders 411,415–424

   role in learning 114–115,236–237

   role in long-term memory consolidation 236–237,240,242–246,247,248,250,253

   role in long-term potentiation 466

   role in memory 114–115,409–410,411,412

   role in mood disorders 300–301,374–376

   role in neural development 325

   role in pathogenesis of neurological disorders 438–439

   role in stress-induced HPA axis activation 279

   role in treatment of mood disorders

   role in vigilance and attention 58

   signal transduction pathway activation 100–101,104

   systemic effects in response to stress 275–276

   widespread innervation and influence 275–276

NE dysregulation

   in ADHD 179

   link with depression and anxiety 60,61,69

   see also neurological disorders and NE

NE gene-linked susceptibilities 489–492,498

   addictions 496

   ADHD 493–494

   Alzheimer’s disease 493

   anxiety 494–495

   asthma treatment response 498

   behaviour and psychiatric diseases 493–496

   breast cancer risk 498

   cardiovascular disorders 496–497

   counterbalancing selective benefits 498–499

   diabetes 497–498

   dysphoria and affective disorders 494–495

   hypnotizability 498

   impulsivity 493–494

   metabolic disorders 497–498

   migraine 493

   movement disorders 489–493

   narcolepsy 498

   neurodegenerative disease 493

   neurological disorders 489–493

   obesity 497–498

   pain 493

   Parkinson’s disease 489–493

   prefrontal cortex dysfunction 495–496

   schizophrenia 495–496

NE genetic factors

   in anxiety disorders 474

   in cardiovascular disease 474–476

   in depression 474

   in pain processing

   in respiratory diseases 474–476

NE metabolic pathways

   MHPG marker 364

   peripheral and central markers 364

   see also LC chemoarchitecture

NE receptors

   on lymphocytes 364–365

   on platelets 364–365

   see also adrenergic receptors; noradrenergic receptors

NE reuptake

   termination of action 119

   uptake-1 (neuronal uptake) 119

   uptake-2 (nonneuronal uptake) 119

NE reuptake inhibitors 287–290

   anxiety disorder treatments 544–547,549–550

   clinical characteristics of responders 539–542

   clinical comparison with SSRIs 372,374

   comparative efficacy of NE selective antidepressants 538–539

   effects on cAMP-CREB cascade 105–106,107,109

   effects on gene expression 104–106,107,112

   effects on IEG transcription factors 112–114

   effects on NETs 124,125

   effects on transcription factors 104–106,107,112

   evidence for use in depression 538

   generalized anxiety disorder treatment 548–549

   imipramine 535

   mechanism of action 536

   obsessive-compulsive disorder treatment 546–547

   panic disorder treatment 544–545

   PTSD treatment 549

   reboxetine 536

   second generation compounds 536

   secondary or demethylated tricyclic compounds 536

   social anxiety disorder treatment 549

   synergistic effects of NE and 5-HT antidepressants 543–544

   tetracyclic compounds 536

   tomoxetine 536

   treatment of depression 536–539,542,543,544

   tricyclic compounds 536

   up-regulation of hippocampal neurogenesis 110–111,112

NE selective reuptake inhibitors see NE reuptake inhibitors

NE transcription

   mediation by AP-1 family of transcription factors 98–99

   mediation by CREB family of transcription factors 98–99

NET (norepinephrine transporter) 119

   active transport function 122–123

   acute regulation of neuronal NE uptake 127–130

   age-related alterations in function 133–134

   alternating-access mode 125–126

   blocking effects of psychotropic drugs 520–522,523,524,525

   channel mode 125–126

   chronic regulation of neuronal NE uptake 127–128,131

   clinical effects of blocking by antidepressants 527–530

   clinical effects of blocking by antipsychotics 527–530

   control of NE homeostasis 123

   distribution of NETs 121–122

   effects of prolonged exposure to psychoactive agents 131

   effects of psychoactive drugs 124,125

   effects on NE function 122–123

   factors affecting NET activity 127–128,131

   gateway for NE metabolism and recycling 123

   human NET (hNET) 120–121

   identification in various species 120–121

   mechanism of NE uptake 124–126,127

   molecular structure 120–121

   NE reuptake into presynaptic neurons 122–123

   regional variations in extent of NE recapture 123

   regulation of NE uptake 127–128,131

   role in synaptic plasticity 123

   role of compromised function in disease 134–135

   targets for drugs 124,125

   transmembrane topology 120–121

   transport of other catecholamine neurotransmitters 122

NET-associated proteins 131–132

NET genes 477–478,479,485–486

   polymorphisms (coding and noncoding) 133

   splice variants 132–133

neurodegenerative disease, NE gene-linked susceptibility 493

neuroendocrine challenges, growth hormone response to clonidine 365–366

neurogenesis, up-regulation by NE selective reuptake inhibitors 110–111,112

neurological disorder modelling

   markers to assess damage to NE pathways 441–442,444,445

   tools to damage central NE pathways 437,439–441,442,443

neurological disorders and NE 441,444,445–466

   Alzheimer’s disease 463,464

   dementia 463,464

   disease specific patterns of LC neuronal loss 463

   epilepsy 441,444,454–463

   functional anatomy of central NE system 436–437,439

   Lewy body disease 463

   multiple sclerosis 463,465

   multiple systems atrophy (MSA) 463–464

   NE gene-linked susceptibility 489–493

   Parkinson’s disease 445–454

   Pick’s disease 463

   protective role of NE 466

   role of NE in pathogenesis 438–439

   sleep disorders 465–466

neurophysin, in the LC 21

neurotensin, in the LC 21

neurotransmitter depletion challenges

   AMPT inhibitor 366–367,368–372

   catecholamine depletion 366–372

   effects on mood disorders 366–372

   results 368–372

   synthesis inhibition by dietary means 367–368

   synthesis inhibition by pharmacological means 366–367

neurotransmitter depletion studies 363–364

nicotine

   effects on LC activity 58

   stimulation of norepinephrine release 58

   see also substance abuse

nicotinic acetylcholine receptors, mediation of LC activity 57–58

noradrenergic dysfunction

   and HPA axis dysregulation 473–474

   cardiovascular and respiratory effects 474–476

   influence in anxiety/dysphoria domain 473–474

   influence on genetically variant traits 473–477

   influence on pain processing 476–477

   underlying influence of stress 473

noradrenergic genes

    adrenergic receptors 479,487

    adrenergic receptors 479,487–488

    adrenergic receptors 479,488–489

   biosynthetic genes 477–485

   catechol-O-methyltransferase 479,486–487

   counterbalancing positive effects 498–499

   dopamine -hydroxylase 479,485

   identification in the human genome 477–478

   metabolizing genes 477–478,479,485–487

   missense substitutions 477–478,480–484

   monoamine oxidase 479,486

   NE receptor genes 477–478,479,487–489

   NET genes 477–478,479,485–486

   structural variations 477–484,489

   tyrosine hydroxylase 478–485

noradrenergic neurons

   acetylcholine receptors 57–58

   effects of acetylcholine 57–58

   effects of dopamine 55

   effects of GABA 56

   effects of glutamate 56–57

   effects of substance P 58–59

   functional relationship with serotonergic neurons 54–55

   innervation by GABA axon terminals 56

   projection from the LC 59–60

   regulation of dopaminergic output of the ventral tegmental area 59–60

   regulation of serotonin release in the raphe 59,60

noradrenergic neurotransmission

   effects of chronic NE reuptake blockade 287–290

   effects of selective pharmacological enhancement 287–290

   pharmacological effects on tonic and phasic activity 287–290

   phasic activation in response to stress 277–279

   regulatory target of antidepressants 287–290

   tonic elevation with arousal 276–277

noradrenergic neurotransmitter system

   modulatory effects on brain circuits 275–276

   potential substrate for stress vulnerability 283–284,285,286,288

   systemic effects in response to stress 275–276

   widespread innervation and influence 275–276

noradrenergic pain modulation, interactions with other neurotransmitters 395–396

noradrenergic pain modulation (peripheral mechanisms) 385–387

   conflicting evidence 387

   pain facilitation by peripheral adrenoceptors 386,387

   pain inhibition by peripheral adrenoceptors 386–387

   plasticity following injury or inflammation 385–386

noradrenergic pain modulation (spinal mechanisms) 387–392

   activation of pain inhibitory interneurons 392

   in inflammatory pain 389

   in neuropathic pain 389–390

   in pathological conditions 389–390

   mechanisms underlying noradrenergic analgesia 390–392

   nociception suppression by spinal NE 387–388

   noradrenergic pain inhibitory feedback loop 388

   postsynaptic pain inhibition 391

   presynaptic pain inhibition 390–391

noradrenergic pain modulation (supraspinal mechanisms) 392–394

   lateral reticular nucleus of the medulla 393

   locus coeruleus 393–394

   periaqueductal gray 392

   rostroventromedial medulla

   thalamus 394

noradrenergic pain modulation (sympatho-adrenal mechanisms) 395

   adrenal medulla 395

   in nerve injury 395

   postganglionic sympathetic nerve fibers 395

noradrenergic receptors

   activation of CREB-mediated gene transcription 102–103

   activation of signal transduction pathways 100–101,104

   effects of antidepressants 104–106,107,112

   regulation of AP-1 family transcription factors 101,103–104

   regulation of cAMP-CREB cascade 97, 100–102

   subtypes in the LC 17–18

   see also adrenergic receptors

norepinephrine see NE

NRIs see NE reuptake inhibitors

nucleus of the solitary tract (NTS), role in memory consolidation 240–242

nucleus paragigantocellularis (PGi), input to the LC 53

nucleus prepositus hypoglossi (PrH)

   input to the LC 53

   origin of GABA-containing fibers 56

obesity

   NE gene-linked susceptibility 497–498

   role of adrenergic receptors 88–89

obsessive-compulsive disorder (OCD)

   sleep disorders associated 176–177

   treatment with NE reuptake inhibitors 546–547

opiate abuse see substance abuse

opioid peptidergic system, effects on memory 256–258,259

orbital frontal cortex, influence on LC neuronal activity 213–215,216,217

pain, NE gene-linked susceptibility 493

pain processing

   genetic factors

   influence of noradrenergic dysfunction 476–477

   mechanisms of analgesia

   see also noradrenergic pain modulation

panic disorder

   role of NE system abnormalities 300–301

   sleep disorders associated 176–177

   treatment with NE reuptake inhibitors 544–545

paradoxical sleep 157–158

   see also REM sleep

Parkinson’s disease

   cognitive deficits 417

   differential LC pathology in subgroups 463

   effects of NE depletion 453–454

   effects on the LC 445–446

   involvement of NE 445–454

   involvement of NE neurons (anatomical evidence) 446–447

   involvement of NE neurons (clinical evidence) 448–450

   involvement of NE neurons (neurochemical evidence) 447–448

   involvement of NE neurons in experimental parkinsonism 450

   LC neuron loss 223–224,447,453–454

   NE and progression of parkinsonism 450–453

   NE gene-linked susceptibility 489–493

   postmortem brain research 341–342

   role of compromised NET function 134–135

peri-LC dendrites, afferent input sources 24–25,26

periaqueductal gray 392

pericoerulear area

   axonal projection from other brain areas 53

   dendritic projection from LC neurons 53

PFC see prefrontal cortex

PGi see nucleus paragigantocellularis

phasic noradrenergic neurotransmission

   activation in response to stress 277–279

   pharmacological effects on activity 287–290

Pick’s disease, specific pattern of LC neuronal loss 463

platelets, NE receptors on 364–365

posterior and subcortical function

   arousal state modulation by NE 412–413

   long-term memory consolidation 413–414

   NE modulation of plasticity 414

   NE regulation 410,411,412–414

   stimulus processing enhancement by NE 413–414

postmortem human brain research

   Alzheimer’s disease neuropathy 341–342

   Parkinson’s disease neuropathy 341–342

   postsynaptic NE markers 343–344

   presynaptic NE markers 343–344

   role of NE in CNS disorders 341–343

   shortcomings 342–343

   strengths 343

   tool to study CNS disease 341–343

postmortem research on depression

    adrenergic receptors 351–352

    adrenergic receptors 352–353

   locus coeruleus studies 346–350, 356

   postsynaptic markers in depression 351–353

   presynaptic markers in depression 346–350,356

   role of the noradrenergic system 344–353

postmortem research on schizophrenia

   postsynaptic markers in schizophrenia 354–355

   presynaptic markers in schizophrenia 353–354

   role of the noradrenergic system 353–355

posttraumatic stress disorder (PTSD) 85–86

   and LC-NE hyperactivity 178–179

   cognitive disorders 411,423–424

   effects of NE hyperactivity 411,423–424

   hypertonic LC activity 220

   prefrontal cortex dysfunction 411,423–424

   role of NE 114–115

   role of NE dysregulation 275,283–284,285,286,288,300–301

   role of NE in etiology and treatment 411,423–424

   sleep disorders 176–177,178–179

   treatment with NE reuptake inhibitors 549

prefrontal cortex (PFC)

   adrenergic receptor types and distribution 408–409

   cognitive functions 409–410,411,412

   influence on LC neuronal activity 213–215,216,217

   LC reciprocal innervation 408–409

   NE input 408–409

   NE regulation 409–410,411,412

prefrontal cortex dysfunction

   in psychiatric illnesses 408

   in PTSD 411,423–424

   NE gene-linked susceptibility 495–496

   role in ADHD 562–563

   see also cognitive disorders with altered NE

PrH see nucleus prepositus hypoglossi

prostatic hypertrophy (benign), treatment 82

protein kinase C (PKC) activity

   in mania/bipolar disorder 421–422

   signaling pathway 100,102–103

psychotropic drugs, NET blocking effects 520–522,523,524,525

PTSD see posttraumatic stress disorder

reboxetine (selective NRI) 536

   effects on NETs 124,125

REM (rapid eye movement) sleep

   LC inhibition by GABA 56

   see also paradoxical sleep

reserpine, history of 516

respiratory diseases, heritability of onset and severity 474–476

rostroventromedial medulla

schizophrenia

   cognitive disorders 422–423

   dysregulated LC phasic activity 222–223

   importance of NE hyperactivity 422–423

   mechanisms of antipsychotic drugs 85–86

   NE gene-linked susceptibility 495–496

   prefrontal cortex dysfunction 422–423

   role of compromised NET function 134–135

schizophrenia postmortem research

   postsynaptic markers in schizophrenia 354–355

   presynaptic markers in schizophrenia 353–354

   role of the noradrenergic system 353–355

SCN see suprachiasmatic nucleus

sedation, mediation by A adrenergic receptors 80,84

selective NE reuptake inhibitors (SNRIs) see NE reuptake inhibitors

serotonergic activity

   modulation of GABAergic input to the LC 56

   regulation by NE 59,60

serotonergic neurons

   functional relationship with noradrenergic neurons 54–55

   innervation of the noradrenergic LC 54–55

   origins of 54

serotonin (5-HT)

   effects on LC activity 54–55

   transport by NETs 122

serotonin (5-HT) transporter (SERT) 120–121,124,125

signal transduction pathways

    adrenergic receptors 79,80

    adrenergic receptors 79–81

    adrenergic receptors 80,81–82

   NE activation 100–101,104

sleep deprivation, and depression 176

sleep disorders

   and LC dysfunction 224

   in depression 174–175

sleep disorders (neurological disorders), and NE 465–466

sleep disruption, in insomnia 180–181

sleep rebound effect after sleep deprivation 163–164,165,167

sleep-wake regulation

   alteration due to clinical pathologies 174–181

   brain systems involved 157–159,160

   effects of aging 180

   effects of DSP4 treatment 159,162,163–164,165,167

   effects of LC lesions 159,162,163–164,165, 167

   effects of LC lesions on circadian amplitude 170–173

   effects of light deprivation on cortical NE 173–174

   effects of stress response 166,167,168, 175–176

   in ADHD 179

   in anxiety disorders 176–177

   in depression 174–176

   in PTSD 178–179

   LC activity and cortical arousal 161–162

   LC involvement 159,160–164,165,167

   LC neuronal activity 159,160–164,165, 167

   LC tonic activity variation with arousal states 160–161

   mechanisms of stage transitions 159,160

   networks involved 158–159,160

   neuronal groups involved 158–159

   paradoxical sleep 157–158

   primate LC activity 161

   role of CRF in noradrenergic regulation 166,167,168

   role of LC in circadian regulation 167–169,171,172,173,174

   role of LC-NE system 157

   role of the dorsomedial hypothalamus (DMH) 157

   role of the suprachiasmatic nucleus (SCN) 157,167

   sleep rebound effect after deprivation 163–164,165,167

   slow wave sleep 157–158

   spontaneous sleep 159,162

   wakefulness 157–158

slow wave sleep 157–158

SNRIs see NE reuptake inhibitors

social anxiety disorder, treatment with NE reuptake inhibitors 549

somatostatin, in the LC 21

SSRIs

   clinical comparison with NRIs 372,374

   mechanism of therapeutic effects 363–364

steroid hormone receptor superfamily (transcription factors) 99–100

stress

   development of chronic stress symptoms in humans 265–266

   effects on NE regulation of c-Fos 113–114

   effects on serotonergic input to the LC 54–55

   hippocampal cell atrophy and cell loss 110–111,112

   HPA axis activation 278,279

   induction of c-Fos 113–114

   responses of the noradrenergic neurotransmitter system 275–276

stress-associated activation of the LC

   by glutamate 57

   by substance P 58–59

stress-dependent depression 85–86

stress exposure

   and depression 420–421

   and NE dysregulation 420–421

   and prefrontal cortex dysfunction 420–421

stress-induced drug relapse and NE 618–620

stress-induced NE release

   chemical “switch” 414–415,424

   effects on cognitive function 414–415

   modulatory effects on stress responses 280–281,282,283

stress-induced working memory deficits 412

stress-related interactions, and sleep disorders 175–176

stress-related memories, role of NE 114–115

stress-related psychiatric disorders

   antidepressant targeting of noradrenergic neurotransmission 287–290

   role of NE dysregulation 275,283–284,285,286,288

stress response

   effects on sleep-wake regulation 166,167,168

   modulatory effects of stress-induced NE release 280–281,282,283

   phasic activation of noradrenergic neurotransmission 277–279

   role of brain NE 275

stress vulnerability

   individual vulnerability factors 283–284,285,286,288

   interaction of NE and environmental sensitization 286–287,288

   noradrenergic system as potential substrate 283–284,285,286,288

stressors

   activation of LC neurons 199–200

   processive (psychogenic) 277–279

   range of 277–279

   systemic (physiologic) 277–279

substance abuse

   BNST mediation of withdrawal symptoms 617–618

   BNST role in stress-induced drug relapse 618–620

   definition 610–611

   LC mediation of withdrawal symptoms 616–618

   NE and stress-induced relapse 618–620

   NE markers for predisposition to alcoholism 615

   NE markers for reward dependence personality trait 615

   NE treatment 620–622

   role of dopamine 610–611

   role of NE in dependence 616–618

   role of NE in reward 611–612,616

   role of NE in withdrawal symptoms 616–618

substance P

   effects on LC activity 58–59

   in the LC 21

substance P antagonists, antidepressant properties 58–59

substance P-containing fibers, innervation of the LC 58–59

suicide, role of compromised NET function 134–135

suprachiasmatic nucleus (SCN)

   indirect projection to the LC 167–169,170

   role in sleep-wake regulation 157,167

synaptic plasticity, role of NET 123

task performance, and LC activity 196–198

thalamus 394

tomoxetine 536

   see also atomoxetine

tonic noradrenergic neurotransmission

   elevation with arousal 276–277

   pharmacological effects on activity 287–290

transcription factors, effects of NE selective reuptake inhibitors 104–106,107,112

tricyclic antidepressants

   ADHD treatment 566–570,572

   effects on NETs 124,125

   introduction of 515

   targeting of noradrenergic neurotransmission 287–290

tyrosine hydroxylase gene 478–485

vasoactive intestinal peptide, in the LC 21

vasopressin, in the LC 21

venlafaxine, ADHD treatment 577,580

ventral tegmental area

   axonal projection to the pericoerulear area 53

   LC reciprocal noradrenergic innervation 59–60

   origin of dopaminergic fibers 55

   regulation of dopaminergic output 59–60

wakefulness 157–158

working memory

   effects of stress exposure 412

   in the prefrontal cortex 409–410,411,412

   influences of NE 409–410,411,41

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