ISBN: 3-540-66123-9
TITLE: Neuronal Nicotinic Receptors
AUTHOR: Clementi, F.; Fornasari, D.; Gotti, C. (Eds.)
TOC:

Section I: Introduction to Neuronal Nicotinic Receptors
CHAPTER 1
The History of the Neuronal Nicotinic Receptors
D.A. Brown 3
A. The Autonomic Ganglion: The Archetypical Neuronal Nicotinic Receptor 3
B. Nicotinic Acetylcholine Receptors in the Central Nervous System 5
C. Presynaptic Nicotinic Receptors 7
References 8
CHAPTER 2
Distribution of Cholinergic Neurons in the Mammalian Brain with Special Reference to their Relationship with Neuronal Nicotinic Acetylcholine Receptors
M. Zoli. With 1 Figure 13
A. Distribution of Cholinergic Neurons in Neural Tissues 13
I. The Basal Telencephalic System 13
II. Striatal Interneurons 15
III. The Habenulo-Interpeduncular System 15
IV. The Mesopontine Tegmental System 16
V. Brainstem and Spinal Cord Motor Nuclei 16
VI. Medullary Tegmentum 16
VII. Peripheral Ganglia and Retina 17
VIII. Putative Cholinergic Systems 17
IX. Comparative Aspects 17
B. Distribution of Nicotinic Receptors with Respect to Cholinergic Neurons 20
I. Location of nAChRs in Cholinergic and Cholinoceptive Cells 20
1. Heteroreceptors 21
2. Subunit Composition of Heteroreceptors 22
3. Autoreceptors 23
4. Subunit Composition of Autoreceptors 24
II. Wiring Vs Volume Transmission in Cholinergic Systems 24
References 26
Section II: Genes, Structure, and Distribution of Neuronal Nicotinic Receptors
CHAPTER 3
Gene Structure and Transcriptional Regulation of the Neuronal Nicotinic Acetylcholine Receptors
J.-M. Matter and M. Ballivet. With 4 Figures 33
A. Background 33
B. Functional Groupings and Gene Structure 34
I. Function and Sequence Homology Scores 35
II. Function and Gene Structure 36
C. Expression and Regulation of the Neuronal nAChR Genes 39
I. nAChRs in the Adult Retina 39
II. nAChRs in the Developing Retina 40
III. Role of Innervation and Target Tissues on nAChR Expression 41
D. Identification of Cis-acting Regulatory Elements 43
I. nAChR Genes as a Model for Neuron-Specific Gene Transcription 43
II. Technical Tools to Investigate Transcriptional Regulation 43
III. Identification of Cis-acting Elements that Regulate Transcription 44
1. The beta2 Gene  The Role of Silencing Elements 44
2. The alpha7 Gene 45
3. alpha3 and beta4  The Role of Ubiquitous Transcription Factors 46
IV. A Network of Neuronal bHLH Transcription Factors Regulates beta3 in Retina 47
References 49
CHAPTER 4
Transcriptional Regulation of Neuronal nAChR Subunit Genes
E.S. Deneris. With 3 Figures 57
A. Introduction 57
B. Cell-Type Specific Transcription 59
C. DNA Regulatory Elements and Transcription Factors 60
I. alpha2 Gene 60
1. Avian alpha2 Regulatory Region 60
2. alpha2 Silencer Region 60
II. alpha7 Gene 61
1. Chicken alpha7 Promoter 61
2. Bovine alpha7 Promoter 61
III. beta2 Gene 63
1. Mouse beta2 Promoter 63
2. Transgenic Analysis of the beta2 Promoter 63
3. beta2 Neuron Restrictive Silencer Element 64
IV. beta4, alpha3, alpha5 Gene Cluster 64
1. Rat beta4 Promoter 65
2. Rat and Human alpha3 Promoters 66
3. Activation of the Rat alpha3 Promoter by the POU Factor, SCIP 68
4. Transgenic Analysis of Rat alpha3 Upstream Region 69
5. Rat beta43' Enhancer 69
D. Conclusions and Future Directions 73
References 73
CHAPTER 5
Contributions of Studies of the Nicotinic Receptor from Muscle to Defining Structural and Functional Properties of Ligand-Gated Ion Channels
P. Taylor, H. Osaka, B. Molles, S.H. Keller, and S. Malany. With 4 Figures 79
A. Introduction 79
B. Functional Aspects of the Nicotinic Receptor in Skeletal Muscle 81
C. Isolation and Characterization of Nicotinic Receptors 82
D. Structure of the Muscle Nicotinic Receptor 83
E. Biophysical Properties of Muscle Receptors 88
F. Natural Toxins that Block Motor Activity 89
G. Congenital Myasthenia Syndromes from Receptor Mutations 91
H. Biosynthesis and Assembly of the Receptor Subunits 93
I. Regulation of Nicotinic Acetylcholine Receptor Expression 95
References 96
CHAPTER 6
The Structures of Neuronal Nicotinic Receptors
J. Lindstrom. With 3 Figures 101
A. Muscle AChRs Provide the Model for Neuronal AChRs 101
I. Subunits Which Comprise Muscle AChRs 102
II. Structures of the Muscle AChR Subunits 103
III. Organization of Subunits Around the Central Cation Channel 110
IV. Acetylcholine Binding Sites in the Extracellular Domain 110
V. The Main Immunogenic Region in the Extracellular Domain and Myasthenia Gravis 112
VI. Cation-Specific Channel and Its Gate 123
VII. Large Cytoplasmic Domain 123
VIII. AChR Mutations in Congenital Myasthenic Syndromes 124
B. Neuronal AChRs Which Can Function as Homomers 124
I. Subunits Which Comprise Homomeric Neuronal AChRs 125
II. Structures of the Homomeric Neuronal AChR Subunits 127
III. Organization of Subunits Around the Central Channel 128
IV. Special Properties of Homomeric Neuronal AChRs 131
V. Involvement of Homomeric Neuronal AChRs in Diseases 133
C. Heteromeric Neuronal AChRs 134
I. Structures of the Subunits of Heteromeric Neuronal AChRs 137
II. Organization of Subunits Around the Central Channel 139
III. Special Properties of Heteromeric Neuronal AChRs 140
IV. Involvement of Heteromeric Neuronal AChRs in Diseases 144
D. Conclusions and Current Problems 146
References 147
CHAPTER 7
The Distribution of Neuronal Nicotinic Acetylcholine Receptors
P.B. Sargent. With 3 Figures 163
A. Introduction 163
B. Nicotinic AChRs in Non-neuronal Cells 164
C. Regional Distribution of AChRs Within the Peripheral Nervous System 164
I. Autonomic Ganglia 164
II. Sensory Ganglia 165
D. Regional Distribution of AChRs Within the Central Nervous System 165
I. Mapping Studies with [^3H]Nicotine and with Ligands for alpha4 and beta2 166
II. Mapping Studies with ^125I-alpha-Bgt and with Ligands for alpha7 173
III. Mapping Studies with Ligands for alpha3 174
IV. Mapping Studies with Ligands for beta4 174
V. Mapping Studies with Ligands for a alpha 2, a alpha 5, a alpha 6, and beta3 174
VI. Species Differences among Mammals 175
VII. AChR Mapping in Chicken Brain 176
E. Distribution of AChRs on the Neuronal Surface 176
I. Peripheral Nervous System (see also Chap. 10, this volume) 176
II. Central Nervous System 180
F. Presynaptic AChRs/Extrasynaptic AChRs 182
G. Regulation of AChR Distribution 182
H. Conclusion 184
References 184
CHAPTER 8
Presynaptic Neuronal Nicotinic Receptors: Pharmacology, Heterogeneity, and Cellular Mechanisms
S. Kaiser, L. Soliakov, and S. Wonnacott. With 2 Figures 193
A. Introduction 193
B. Pharmacology and Heterogeneity of Presynaptic Nicotinic Receptors 195
I. Acetylcholine 195
II. Dopamine 196
III. Noradrenaline 197
IV. 5-Hydroxytryptamine 198
V. gamma-Aminobutyric Acid 199
VI. Glutamate 199
VII. Adenosine Triphosphate 200
VIII. Summary 200
C. Molecular and Cellular Mechanisms Underlying the Nicotinic Modulation of Transmitter Release 201
I. Na^+ Dependence and Tetrodotoxin Sensitivity 201
II. Ca^{2+} Dependence and Involvement of Voltage Operated Ca^{2+} Channels 201
III. The Involvement of Second Messengers in the Nicotinic Modulation of Neurotransmission 203
1. Protein Kinase C 203
2. CaM Kinase II 205
3. Tyrosine Kinase Signalling Pathways 205
D. Concluding Remarks 206
References 206
CHAPTER 9
Neuronal Nicotinic Acetylcholine Receptors in Development and Aging
M. Zoli. With 4 Figures 213
A. Development of Neuronal Nicotinic Acetylcholine Receptors 213
I. Development of Neuronal Nicotinic Acetylcholine Receptors in the Peripheral Nervous System 214
1. Phenomenological Aspects 214
2. Mechanistic Aspects 215
3. Conclusions 216
II. Development of Neuronal Nicotinic Acetylcholine Receptors in the Central Nervous System 217
1. Avian Central Nervous System 218
2. Rodent Central Nervous System 218
3. Human Central Nervous System 223
4. Conclusions 224
III. Role of Neuronal Nicotinic Acetylcholine Eeceptors in the Development of Nicotinoceptive Cells 224
1. Effects of Nicotine Exposure on the Development of the Central Nervous System 225
2. Mechanistic Aspects of the Morphogenetic Actions of Neuronal Nicotinic Acetylcholine Receptors 227
3. Conclusions 228
B. Neuronal Nicotinic Acetylcholine Receptors During Aging 229
I. Neuronal Nicotinic Acetylcholine Receptors During Normal Aging 229
II. Neuronal Nicotinic Acetylcholine Receptors During Pathological Aging 231
III. Role of Neuronal Nicotinic Receptors in Normal and Pathological Aging 232
1. Neuronal Nicotinic Acetylcholine Receptors and Amyloid 233
2. Neuronal Nicotinic Acetylcholine Receptors and Apolipoprotein E 234
3. Neuronal Nicotinic Acetylcholine Receptors and Cell Loss 234
4. Conclusions 235
C. General Conclusions 236
References 237
CHAPTER 10
Nicotinic Acetylcholine Receptors in Ganglionic Transmission
D.K. Berg, R.D. Shoop, K.T. Chang, and J. Cuevas. With 4 Figures 247
A. Introduction 247
B. Nicotinic Receptor Composition in Ganglia 248
I. Immunological Identification 248
II. Electrophysiological Features 249
C. Subcellular Locations and Postsynaptic Roles 250
I. Synaptic Currents 250
II. Somatic Spines Versus Postsynaptic Densities 252
III. Functional Significance 254
D. Presynaptic Nicotinic Receptors in Ganglia 257
E. Regulation of Ganglionic Nicotinic Receptors 258
I. Receptor Regulation by Cell-Cell Interactions 258
II. Developmental Regulation 259
III. Molecular Controls 260
F. Future Challenges 262
G. References 262
Section III: Functional Properties
CHAPTER 11
Neuronal Nicotinic Acetylcholine Receptors: From Biophysical Properties to Human Diseases
B. Buisson, F. Picard, and D. Bertrand. With 7 Figures 271
A. Introduction 271
B. Reconstitution and Recording of Neuronal nAChRs 274
C. The Allosteric Model 275
D. Functional Domains of the Neuronal nAChR 277
E. The Agonist Binding Site: Structure and Modulations 278
I. Structural Determinants for Acetylcholine Binding 278
II. Allosteric Modulation of the nAChR Pharmacological Profile 279
F. The nAChR Ion Channel: Stratification, Permeability, Conductance, Rectification and Blockade 282
I. Structure of the Ionic Pore at the Amino Acid Level 282
II. The Ionic Selectivity 284
III. Single Channels Properties of nAChRs 285
IV. Mechanisms Governing the Neuronal nAChR Rectification 288
V. Channel Mutations in Neurological Diseases 289
VI. Open Channel Blockers 290
G. Conclusion 292
References 293
CHAPTER 12
The Functional Diversity of Nicotinic Receptors in the Nervous System: Perspectives on Receptor Subtypes and Receptor Specialization
M.M. Francis and R.L. Papke. With 2 Figures 301
A. Introduction 301
B. Functional Domains of Single Subunits 304
C. Calcium and Neuronal nAChR 305
D. Neuronal nAChR Pharmacology 306
E. Changes in Gene Expression with Development 308
F. Functions Served by Neuronal nAChR in the PNS 310
G. Ganglionic Blockers 312
H. Functions Served by Neuronal nAChR in the CNS 315
I. Presynaptic Receptors 317
J. Special Properties of alpha7 Receptors 323
K. Neuronal nAChR and Developing Therapeutics 325
L. Future Perspectives 329
References 329 
CHAPTER 13
Neuronal Nicotinic Receptors and Synaptic Transmission in the Mammalian Central Nervous System
E.X. Albuquerque, E.F.R. Pereira, M. Alkondon, H.M. Eisenberg, and A. Maelicke. With 6 Figures 337
A. Introduction 337
B. Experimental Requirements to Monitor Functional Nicotinic Receptors 338
C. Neuronal Nicotinic Receptors Present in Hippocampal Neurons in Culture and in Conventional Slices: Pharmacological and Kinetic Properties 339
I. Nicotinic Receptors in Cultured Hippocampal Neurons 339
II. Nicotinic Receptors in Hippocampal Neurons in Conventional Slices 343
D. Neuronal Nicotinic Receptors Control GABAergic and Glutamatergic Synaptic Transmission in the Hippocampus 345
E. Neuronal Nicotinic Receptors Bearing the alpha7 Subunit Mediate Synaptic Transmission in the CA1 Field of the Hippocampus 348
F. The Role of Choline in Controlling the Function of Nicotinic Receptors Bearing the alpha7 Subunit  Physiological Relevance 350
G. Concluding Remarks 351
References 353
CHAPTER 14
Properties of Heterologously and Lipid Bilayer Reconstituted Nicotinic Acetylcholine Receptors
C. Gotti, W. Hanke, and F. Clementi. With 4 Figures 359
A. Introduction 359
B. Experimental Requirements for Bilayer Reconstitution 360
I. Formation of Lipid Bilayers 360
II. Purification of nAChR Subtypes for Reconstitution 360
III. Functional Channel Reconstitution 362
C. Reconstitution of nAChRs 363
I. Muscle-Type Receptor 363
1. alpha_2 beta gamma delta nAChR Channels Expressed in Various Cell Systems 364
a) Calf and Torpedo alpha_2 beta gamma delta nAChR Channel 364
b) Mouse alpha_2 beta gamma delta nAChR Channel 365
2. alpha_2 beta gamma delta nAChR Channel Reconstituted in Lipid Bilayer 365
3. alpha_2 beta gamma delta nAChR Reconstituted in Oocytes 366
4. Desensitisation and Phosphorylation of alpha_2 beta gamma delta nAChR Reconstituted in Lipid Bilayers 367
II. Neuronal-Type Receptor 367
1. Insect alpha-Bgt Receptors 368
2. Chick alpha7, alpha8, and alpha7-alpha8 Subtypes 368
3. Chick alpha6 Subtype 370
D. Concluding Remarks 372
References 375
CHAPTER 15
Comparison of Native and Recombinant Neuronal Nicotinic Receptors: Problems of Measurement and Expression
L.G. Sivilotti, D. Colquhoun, and N.S. Millar. With 3 Figures 379
A. Introduction 379
B. Methods for Comparing Native and Recombinant Receptors 381
I. Measurements of the Relative Potency of Agonists 381
II. Measurements of the Relative Effectiveness of Antagonists 382
III. Single Channel Measurements 383
IV. Species Differences 384
C. Heterogeneity of Native Receptors 385
I. The Chick Ciliary Ganglion 385
II. Intracardiac Ganglia 388
III. The Rat Superior Cervical Ganglion  Macroscopic Currents 389
IV. Single Channel Studies of Native Ganglionic Receptors 390
V. Antisense Methods on Embryonic Chick Sympathetic Ganglion Neurones 392
D. Heterologous Expression of Recombinant Receptors 393
I. Muscle Nicotinic Receptors 394
II. Glutamate (NMDA-Type) Receptors 395
III. Neuronal Nicotinic Receptors 395
1. Potency Ratios 396
2. Single Channel Properties 397
IV. Receptors with More Than Two Types of Subunit 401
E. Folding, Assembly and Posttranslational Modification 403
F. Conclusions and Prospects 407
References 407
Section IV: Pharmacological Properties
CHAPTER 16
Agonists and Antagonists of Nicotinic Acetylcholine Receptors
S.P. Arneric and M.W. Holladay. With 2 Figures 419
A. Introduction 419
B. nAChR Subtype Classification 421
I. Historical Perspective 421
II. Molecular Biology of nAChR Subunits 423
III. Radioligands Used to Identify nAChR Subtypes 424
C. Sites and Modulation of nAChR  Ligand Interaction 425
I. Transition States 425
II. The Nicotinic Pharmacophore 425
III. The ACh Binding Site 426
IV. Channel "Activator" Sites 427
V. Ligand-binding Sites that Inhibit nAChR Function 427
1. Noncompetitive (Negative Allosteric Modulators) Blockers 427
2. Steroid Binding Sites 428
3. Dihydropyridine Binding Site 429
4. Arachidonic Acid Site 430
5. Persistent Modulation of the nAChR Complex 430
D. Pharmacologic Properties of Neuronal nAChRs 431
I. Biochemical and Biophysical Properties of nAChRs Contributing to Pharmacology 431
II. Selective Responsivity of nAChR Subunit Combinations 432
E. SAR of Key Small Molecules Leading to Activation or Inhibition of nAChRs 434
I. Inhibitors 434
1. Peptide Toxins 434
2. Methyllycaconitine (MLA) 435
3. 4-Oxystilbenes 435
4. Other Natural Products 435
II. Positive Allosteric Modulators 436
III. Activators 436
1. ACh 436
2. Nicotine 437
a) Pyridine Ring Modified Analogs 437
b) Pyrrolidine Ring Modified Analogs 438
c) Conformationally Restricted Analogs 438
3. Anabasine and Anabaseine 439
4. Trans-meta-nicotine 439
5. Epibatidine 440
6. Anatoxin 440
7. Pyridyl Ethers: Hybrid Compounds of ACh and Nicotine 441
F. Cholinergic Channel Modulators: Rational for an Alternative Nomenclature 441
G. Perspectives on the Future of Neuronal nAChR Pharmacology 442
References 443
CHAPTER 17
Toxin Antagonists of the Neuronal Nicotinic Acetylcholine Receptor
J.M. Mcintosh. With 1 Figure 455
A. General Introduction 455
B. Cautionary Note Regarding Species Differences 455
C. Small Molecule Toxins 456
I. General Background 456
II. Plant Toxins 457
1. d-Tuborcurarine 457
2. Dihydro-beta-erythroidine 458
3. Methyllycaconitine 459
4. Strychnine 459
III. Marine Toxins 460
1. Neosurugatoxin 460
2. Lophotoxin 460
D. Snake Venom Polypeptides 461
I. General Background 461
II. Snake alpha-Neurotoxins 461
alpha-Bungarotoxin 461
III. Snake kappa-Neurotoxins 462
kappa-Bungarotoxin 462
E. Conus Venom Peptides 464
I. General Background 464
II. alpha-Conotoxins 465
1. alpha-Conotoxin MII 465
2. alpha-Conotoxin ImI 467
3. alpha-Conotoxin AuIB 469
4. alpha-Conotoxins PnIA/PnIB and Analogs 469
5. alpha-Conotoxin EpI 469
6. alpha-Conotoxin MI 470
F. Conclusion and Future Prospects 470
References 470
CHAPTER 18
Neuronal Nicotinic Acetylcholine Receptors in Non-neuronal Cells, Expression and Renaturation of Ligand Binding Domain, and Modulatory Control by Allosterically Acting Ligands
A. Maelicke, A. Schrattenholz, and E.X. Albuquerque. With 4 Figures 477
A. Introduction 477
B. Expression of Neuronal Nicotinic Receptors in Mammalian Muscle and Tegumental Cells 478
C. Ectopically Expressed N-terminal Extracellular Domain of nAChR alpha Subunit 481
D. Modulatory Control of Nicotinic Receptors by Allosterically Acting Ligands 483
E. Allosteric Modulators as Drug Candidates 487
F. Concluding Remarks 490
References 490
CHAPTER 19
Insect Nicotinic Acetylcholine Receptors: Genes, Structure, Physiological and Pharmacological Properties
E.D. Gundelfinger and R. Schulz. With 4 Figures 497
A. Introduction 497
B. Identified Subunits of Insect nAChRs 498
I. Molecular Cloning of Insect nAChR Genes and cDNAs 498
II. Distribution Pattern of Identified nAChR Subunits in the CNS 504
III. Efforts to Study Subunit Assembly 506
1. Purification of a-Bgt-Binding Receptor Complexes 506
2. Correlation of Cloned Subunits with alpha-Bgt Binding Sites 507
3. Characterization of Cloned Subunits by Functional Expression in Heterologous Systems 508
C. Physiology and Pharmacology of Native Insect nAChRs 510
I. Electrophysiological Characterization of Insect Neuronal Receptors 511
II. Nicotinic Receptors as Targets for Insecticides 512
D. Nicotinic Receptors of Other Invertebrates 513
E. Conclusions and Perspectives 515
References 516
Section V: The Role of Nicotinic Acetylcholine Receptors in Neuronal Functions
CHAPTER 20
Knockout Mice as Animal Models for Studying Nicotinic Acetylcholine Receptor Function
L.M. Marubio and J.-P. Changeux 525
A. Introduction 525
B. Using Knockout Mice as Models 525
C. Knockout of Muscle nAChR Subunits 526
D. The Pharmacology of Neuronal nAChRs Revealed Using Knockout Mice: The Incomplete Story 530
E. Behavioural Analysis of Knockout Mice 533
F. Conclusions and Future Directions 534
References 535
CHAPTER 21
Noninvasive Exploration of Nicotinic Acetylcholine Receptors In Vivo
A. Nordberg. With 8 Figures 539
A. Introduction 539
I. In Vitro Receptor Binding Studies 539
II. In Vivo and Ex Vivo Studies 540
III. Functional Brain Imaging 540
B. nAChR Ligands for PET and SPECT Studies 541
C. In Vivo [^11C]Nicotine Binding in Human Brain 545
I. Quantification of Nicotine Binding Using k*_2 Rate Constant 546
D. [^11C]Nicotine Binding in the Brain of Smokers 549
E. PET Studies of nAChRs in Alzheimer's Disease 549
I. Visualization of nAChRs in Alzheimer Patients 549
II. Effect of Drug Treatment on nAChRs in Alzheimer Patients as Studied by PET 550
1. Growth Factors 551
2. Ondansetron 552
3. Cholinesterase Inhibitors 553
F. Conclusions 554
References 555
CHAPTER 22
Genetic Regulation of Nicotine-Related Behaviors and Brain Nicotinic Receptors
J.A. Stitzel, S.S. Leonard, and A.C. Collins 563
A. Introduction 563
B. Human Tobacco Use 563
I. Genetics of Smoking 563
II. Potential Mechanisms for Genetic Influences on Smoking 564
C. Animal Studies of Acute Nicotine Sensitivity 566
I. Genetics of Acute Sensitivity 566
1. Inbred Strain Analyses of Acute Sensitivity to Nicotine 566
2. Analysis of Acute Sensitivity to Nicotine Using Genetic Crosses 567
3. Potential Role for nAChRs in Regulating Acute Sensitivity to Nicotine 568
II. Genetic Influences on the Development of Tolerance to Nicotine 569
1. Comparisons of Tolerance Development Using Inbred Mouse Strains 569
2. Role of Changes in nAChR Numbers in Tolerance Development 570
III. Animal Studies of Reinforcing Effects of Nicotine 571
1. Genetics of Oral Self-administration 571
2. Genetic Influences on Conditioned Place Preference 572
D. Tobacco Use and Psychopathology 572
I. Prevalence of Tobacco Use Among the Mentally Ill 572
II. Brain nAChR Binding in Schizophrenics 574
III. Animal Models of Auditory Gating 574
E. Genetics of Nicotinic Receptors and Seizure Disorders 575
I. Human Studies 575
1. The alpha4 nAChR and Seizure Disorders 575
2. The alpha7 Gene and Seizure Disorders 576
II. Animal Studies 576
1. Naturally Occurring Seizures 576
2. Nicotine-Induced Seizures 577
F. Summary and Conclusions 579
References 579
CHAPTER 23
The Role of Nicotinic Acetylcholine Receptors in Cognitive Function
E.D. Levin. With 3 Figures 587
A. Introduction 587
I. Effects in Humans 587
II. Laboratory Animals 588
III. The Neural Basis of Nicotinic Effects on Cognition 589
IV. Neurotransmitter Interactions 592
B. Therapeutic Possibilities 593
I. Alzheimer's Disease 594
II. Attention Deficit/Hyperactivity Disorder 594
III. Schizophrenia 594
C. Summary and Conclusions 594
References 595
CHAPTER 24
Behavioural Pharmacology and Neurobiology of Nicotine Reward and Dependence
G. Di Chiara. With 12 Figures 603
A. Introduction 603
I. Defining Dependence and Addiction 603
B. Behavioural Stimulus Effects of Nicotine 606
I. Discriminative Stimulus Effects of Nicotine 607
1. Animal Studies 607
2. Intracerebral Site of the Discriminative Stimulus Effects of Nicotine 610
3. Role of Dopamine in the Discriminative Stimulus Effects of Nicotine 611
4. Nicotine as a Discriminative Stimulus in Humans 614
5. Tolerance to the Discriminative Stimulus Effects of Nicotine 616
6. Summary 617
II. Motivational Stimulus Effects of Nicotine 618
III. Aversive Properties of Nicotine 618
1. Animal Studies 619
2. Human Studies 621
3. Summary 622
IV. Effects of Nicotine on Operant Behaviour 622
1. Intracranial Self-Stimulation 623
2. Effect of Nicotine on Operant Behaviour Maintained by Conventional Reinforcers 624
V. Nicotine Self-Administration 625
1. Pharmacokinetic Factors 625
2. Intravenous Self-Administration 626
3. Nicotine Antagonists on Nicotine Self-Administration in Animals 632
4. Extinction of Nicotine Self-Administration 632
5. Role of Dopamine in Nicotine Self-Administration 636
6. Human Studies 639
7. Reinstatement of Drug Self-Administration as a Model of Craving 639
8. Reinstatement of Intravenous Nicotine Self-Administration 640
9. Oral Nicotine Self-Administration 643
10. Smoking in Animals 644
11. Nicotine Intravenous Self-Administration in Humans 645
12. Nicotine Self-Administration by Nasal Spray in Humans 646
13. Nicotine as the Reinforcing Principle of Tobacco Smoke 648
14. Role of Peripheral and Non-Nicotine Factors in Tobacco Smoking 649
15. Nicotine Self-Administration in Animals as a Model of Human Nicotine Addiction 650
VI. Conditioned Place-Preference 654
C. Locomotion 656
I. Neural Mechanism 659
D. Latent Inhibition and Pre-Pulse Inhibition 660
E. Adaptation to Nicotine 661
I. Tolerance and Sensitization 662
1. Acute Tolerance 662
2. Chronic Tolerance and Sensitization 663
3. Cellular Basis of Adaptation to Nicotine 664
4. Nicotine Receptor Upregulation 665
5. Biochemical Correlates of Nicotine Tolerance in Humans 667
6. Behavioural Tolerance 667
7. Acute and Chronic Tolerance to Nicotine in Humans 668
8. Role of Tolerance to Nicotine in Tobacco Smoking 670
9. Role of Sensitization 672
II. Physiological Dependence on and Withdrawal from Nicotine 672
1. Animal Studies 673
2. Withdrawal from Nicotine in Humans 676
3. Role of Physiological Dependence in Tobacco Smoking 678
F. Neurochemical and Neurophysiological Actions of Nicotine Related to Addiction 680
I. Dopamine 680
1. Expression of nAChRs by Dopamine Neurons 681
2. In Vitro Dopamine Release Studies 682
3. In Vivo and Ex Vivo Studies 684
4. Electrophysiological Effects of Nicotine on Dopamine Neurons 688
5. Role of alpha7-Containing nAChRs and of Glutamate 689
6. Adaptive Changes of Dopamine Transmission After Nicotine Exposure 690
7. Desensitization 691
8. Desensitization of Somato-Dendritic nAChRs on Dopamine Neurons 692
9. Inactivation of Somato-Dendritic nAChRs on Dopamine Neurons 692
10. Tolerance and Dependence of Dopamine Transmission 693
11. Sensitization of Dopamine Transmission to Nicotine 698
12. Relationship Between Stimulation of In Vivo Dopamine Transmission by Nicotine and Behaviour 701
II. Noradrenaline 704
III. Serotonin 706
IV. Opioid Peptides 706
V. Amino Acid Transmitters 708
VI. Immediate/Early Genes 708
G. A Model of Nicotine Dependence by Tobacco Smoking 710
References 715
CHAPTER 25
Involvement of Neuronal Nicotinic Receptors In Disease
F. Clementi, J. Court, and E. Perry 751
A. Introduction 751
B. Diseases Affecting the Nervous System 751
I. Developmental Disorders 751
1. Tourette's Syndrome 751
2. Schizophrenia 752
II. Age-Independent Disorders 753
1. Epilepsy 753
2. Head Injury 754
3. Depression 754
4. Alcoholism 754
III. Age-Related Degenerative Diseases of the Brain 754
1. Aging 754
2. Alzheimer's and Parkinson's Diseases  Cortical Involvement 755
3. Dementia with Lewy Bodies and Parkinson's Disease  Subcortical Involvement 757
4. Evidence for an Aetiopathological Role for nAChR in Alzheimer's and Parlcinson's Diseases Based on Human Pathology and Tobacco Use 758
5. Symptomatic Benefit of Nicotinic Agonists 760
IV. Pathologies in Non-neuronal Tissues and Cells 761
1. Lung Cells 761
a) Small Cell Lung Carcinoma 761
b) Other Lung Cells 762
2. Vascular Smooth Muscle and Endothelial Cells 762
3. Hypertension 763
4. Keratinocytes 764
5. Intestinal Epithelium 765
6. Lymphocytes 765
C. Conclusion 766
References 767
CHAPTER 26
Clinical Aspects of Nicotinic Agents: Therapeutic Applications in Central Nervous System Disorders
P.A. Newhouse and M. Kelton 779
A. Introduction 779
B. Pharmacokinetics and Pharmacodynamics 781
C. Cognitive and Behavioral Effects of Nicotine in Humans 782
D. Potential Clinical Applications 783
I. Movement Disorders 783
1. Parkinson's Disease 783
2. Tourette's Syndrome 785
3. Other Movement Disorders 786
II. Cognitive Disorders 787
1. Nicotinic Involvement in the Regulation of Cognitive Processes 787
2. Alzheimer's Disease 788
a) Studies of Nicotinic Antagonists in Alzheimer's Disease 790
b) Studies of Nicotinic Agonists in Alzheimer's Disease 791
3. Parkinson's Disease 793
4. Nicotinic System Involvement in the Cognitive Disorders of the Cortical Dementias: Synthesis and Therapeutic Model 795
5. Schizophrenia 796
6. Attention Deficit Hyperactivity Disorder 798
III. Other Potential Clinical Applications 799
1. Analgesia 799
2. Cytoprotection 800
3. Smoking Cessation 802
4. Anxiety/Depression 802
5. Epilepsy 803
E. Further Directions 803
References 804
Subject Index 813
END
