The Biology of Marijuana: From Gene to Behavior

041527348xfm.pdf......Page 2
Biology of Marijuana: From gene to behavior......Page 3
Contents......Page 5
Figures......Page 8
Contributors......Page 13
Preface......Page 18
INTRODUCTION......Page 20
Table of Contents......Page 0
Cannabinoid receptor (Cnr) genes......Page 23
Genes encoding human cannabinoid receptors......Page 24
Genes encoding mouse cannabinoid receptors......Page 25
Genes encoding leech cannabinoid receptors......Page 26
Cannabinoid receptor gene expression......Page 27
Molecular characteristics of cannabinoid receptors (Cnrs)......Page 30
Cannabinoid receptor gene knockout mice......Page 37
Other cannabinoid receptor transgenic models......Page 39
Polymorphic structure of cannabinoid receptor genes......Page 40
Chromosomal mapping of the Cnr genes......Page 45
Genes encoding endocannabinoid transporter(s)......Page 47
Neurobiology of cannabinoid modulation of other receptor systems......Page 49
Neurobehavioral and in vitro actions of cannabinoids......Page 50
CONCLUDING REMARKS AND FUTURE DIRECTIONS......Page 54
REFERENCES......Page 55
ABSTRACT......Page 64
Human studies......Page 65
Animal studies......Page 67
Animal studies......Page 69
Human studies......Page 71
Animal studies......Page 72
ALCOHOL DEPENDENCE......Page 73
Animal studies......Page 74
Human studies......Page 79
Animal studies......Page 80
BRAIN DAMAGE FROM HEAD INJURY, EXCITOTOXINS, ISCHEMIA, INFECTION AND POISON......Page 84
CONCLUSION......Page 86
REFERENCES......Page 87
INTRODUCTION......Page 94
CNS REWARD SUBSTRATES......Page 96
The glutamatergic synaptic inputs to the core reward system......Page 97
Additional synaptic inputs to the core reward system......Page 98
Cannabinoid effects on electrically-induced CNS reward......Page 99
Cannabinoid effects on neuronal activity in CNS reward loci......Page 100
Genetic variation in cannabinoid effects on CNS reward substrates......Page 101
ENDOGENOUS CNS OPIOID INVOLVEMENT IN CANNABINOID EFFECTS ON CNS REWARD SUBSTRATES......Page 103
Effects on endogenous CNS opioid neurotransmitters......Page 104
ENDOGENOUS OPIOID MEDIATION OF CANNABINOID EFFECTS ON CNS REWARD SUBSTRATES......Page 105
Sites of cannabinoid action on CNS reward substrates......Page 106
Mechanisms of cannabinoid action on CNS reward substrates......Page 107
Hypothetical models of cannabinoid action on CNS reward substrates......Page 109
Cannabinoid effects on conditioned place preference......Page 110
Cannabinoid effects on naturally rewarding behaviors......Page 111
Cannabinoid self-administration in animals......Page 112
SUMMARY......Page 113
REFERENCES......Page 114
INTRODUCTION......Page 129
Sensory abilities......Page 130
Attentional abilities......Page 131
Cognitive abilities......Page 132
Amotivational syndrome......Page 133
Background......Page 134
Method......Page 135
Results......Page 136
Conclusion......Page 138
CONCLUSION......Page 139
REFERENCES......Page 140
INTRODUCTION......Page 144
Discovery of cannabinoid receptors......Page 145
Discovery of the endocannabinoids: anandamide and 2-arachidonoylglycerol......Page 146
Other cannabimimetic fatty acid amides: before and after 1992......Page 147
QUANTITATIVE ANALYSIS OF ENDOCANNABINOIDS AND OTHER CANNABIMIMETIC FATTY ACID DERIVATIVES......Page 149
Biosynthesis of anandamide and congeners......Page 152
Biosynthesis of 2-arachidonoyl glycerol......Page 155
Biosynthesis of oleamide and of fatty acyl glycines......Page 157
Inactivation of endocannabinoids......Page 159
Fatty acid amide hydrolase – an “enzyme for all seasons”......Page 161
Regulation of endocannabinoid metabolism and activity......Page 162
Central nervous functions and the control of behavior......Page 164
Immune and cardiovascular systems......Page 167
Reproduction......Page 168
NON-MAMMALIAN CANNABIMIMETIC FATTY ACID DERIVATIVES......Page 169
Endocannabinoids in invertebrates......Page 170
Cannabimimetic fatty acid derivatives in plants......Page 172
CANNABIMIMETIC FATTY ACID DERIVATIVES IN FOODS......Page 175
WHAT’S NEXT?......Page 177
REFERENCES......Page 178
ABSTRACT......Page 193
PHARMACOLOGICAL PROFILE OF CANNABINOIDS......Page 194
The mouse tetrad......Page 195
Biphasic effects......Page 196
PHARMACOLOGICAL PROFILE OF CANNABINOID RECEPTOR ANTAGONISTS......Page 198
CB1 KNOCKOUT MICE......Page 199
Tolerance......Page 200
Craving and reinforcement......Page 201
STRESS AND ANXIETY......Page 202
The prefrontal cortex (PFC)......Page 203
FEEDING AND APPETITE......Page 204
SLEEP......Page 205
The cannabinoid system in development......Page 207
EFFECTS OF PERINATAL EXPOSURE TO CANNABINOIDS......Page 208
ACKNOWLEDGEMENTS......Page 211
REFERENCES......Page 212
Marijuana and movement......Page 224
Cannabinoid receptors and cellular actions of cannabinoids......Page 225
Anatomical techniques......Page 226
Basal ganglia......Page 227
Cortex......Page 229
Red nucleus......Page 230
Spinal cord and dorsal root ganglion......Page 232
Within a nucleus......Page 233
Between nuclei......Page 235
Superior colliculus......Page 236
Systemic......Page 237
THERAPEUTIC USE OF CANNABINOIDS ON MOVEMENT DISORDERS......Page 239
Parkinson’s disease......Page 240
Dystonia......Page 241
Huntington’s disease......Page 242
Spasticity......Page 243
REFERENCES......Page 244
ASSESSING THE EFFECTS OF MARIJUANA ON BRAIN......Page 253
Changes in general circulation and respiration......Page 254
Variability of effects......Page 255
The 133Xenon inhalation technique......Page 256
Image registration......Page 257
Partial volume corrections......Page 258
PET data acquisition......Page 259
CHANGES IN MENTAL STATE ASSOCIATED WITH MARIJUANA......Page 260
Depersonalization......Page 261
Subjects......Page 262
Quantification of physiological and behavioral changes......Page 263
CBF changes......Page 264
Physiological and pharmacological changes......Page 265
Changes in time sense and its correlates after marijuana smoking......Page 266
Results......Page 267
Data analysis......Page 268
Regression analyses......Page 269
Canonical correlational analysis......Page 270
Subjects......Page 271
PET scan......Page 272
Results......Page 273
Time sense after tetrahydrocannabinol administration......Page 275
Procedures......Page 276
Results......Page 277
Summary and implications of acute effects......Page 280
Animal studies......Page 281
Human functional studies......Page 282
Potential effects of marijuana use in early adolescence......Page 284
Subjects......Page 285
Brain volumes......Page 286
Height and weight......Page 288
Potential effects on brain morphological development......Page 289
REFERENCES......Page 291
INTRODUCTION......Page 301
Decreased resistance to infection with viruses......Page 302
Decreased resistance to infection with bacteria......Page 304
Relevance of doses used in animal studies......Page 305
Decreased resistance to infection with protozoa......Page 306
Effects on macrophages......Page 308
Effects on lymphocytes, other immunocytes, and cytokines......Page 309
Multiple modes of action......Page 311
Changes effected through cannabinoid receptors......Page 312
Studies reporting minimal effects on immunity and host resistance......Page 318
SUMMARY......Page 319
REFERENCES......Page 320
INTRODUCTION......Page 327
EFFECTS ON THE CENTRAL NERVOUS SYSTEM......Page 328
ANIMAL RESEARCH......Page 329
HUMAN RESEARCH......Page 335
CONCLUSION......Page 342
REFERENCES......Page 343
INTRODUCTION......Page 352
Male......Page 353
Females......Page 354
STRESS HORMONES......Page 355
OTHER HORMONES......Page 357
Brain......Page 358
REFERENCES......Page 359
ABSTRACT......Page 363
EXPRESSION OF CANNABINOID RECEPTORS IN THE PREIMPLANTATION MOUSE UTERUS AND EMBRYO......Page 364
EFFECTS OF CANNABINOID AGONISTS ON PREIMPLANTATION EMBRYO DEVELOPMENT......Page 366
EFFECTS OF THC ON IMPLANTATION......Page 368
DISCUSSION......Page 369
ACKNOWLEDGEMENTS......Page 371
REFERENCES......Page 372
ABSTRACT......Page 375
INTRODUCTION......Page 376
Role of neurotransmitters involved in chemotherapy-induced emesis......Page 377
ANTIEMETIC PROPERTIES OF CLINICALLY-USEFUL CANNABINOIDS......Page 379
Clinical trials with Delta9-THC......Page 380
Clinical trials with nabilone......Page 384
Clinical trials with levonantradol......Page 388
Side effects of cannabinoid antiemetics in clinical trials......Page 391
Animal models of emesis and the established cannabinoid antiemetics......Page 392
Site of action and the role of cannabinoid CB1 receptors in emesis......Page 393
Possible role of other neurotransmitter systems in the antiemetic properties of cannabinoids......Page 398
SUMMARY AND CONCLUSIONS......Page 399
REFERENCES......Page 401
INTRODUCTION......Page 409
Intact cell models......Page 411
Effects of cannabinoids on prostaglandin levels in the CNS......Page 412
Prostaglandins and cannabinoids in peripheral systems......Page 413
Structural and functional comparisons......Page 414
COX-2 substrate......Page 415
Metabolic origin......Page 416
Ajulemic acid: a potent synthetic analog of THC-11-oic acid......Page 417
N-arachidonylglycine (NAGly): a putative endogenous cannabinoid acid......Page 418
CONCLUSIONS......Page 419
REFERENCES......Page 420
INTRODUCTION......Page 426
G-PROTEIN COUPLING......Page 427
Ligand-receptor-G-protein interactions......Page 429
Receptor structure/activity relationships......Page 430
INVERSE AGONISM AT CANNABINOID RECEPTORS......Page 433
CANNABINOID RECEPTOR ACTIVATION OF ION CHANNELS......Page 434
CALCIUM MOBILIZATION AND ACTIVATION OF THE PHOSPHOLIPASE C/INOSITOL PHOSPHATE SYSTEM AND OTHER PATHWAYS......Page 435
MAP KINASE ACTIVATION AND REGULATION OF GENE EXPRESSION......Page 437
ACTIVITY DEPENDENT REGULATION OF CANNABINOID RECEPTORS......Page 438
CONCLUSIONS......Page 441
REFERENCES......Page 442
CANNABINOIDS......Page 450
EFFECTS OF CANNABINOIDS ON NEUROTRANSMITTER RECEPTORS......Page 451
INTERACTION OF THC WITH SPECIFIC RECEPTORS......Page 452
FUNCTIONAL CORRELATES OF THC RECEPTOR BINDING AND SIGNALING ALTERATIONS......Page 453
ENDOGENOUS MEMBRANE-DERIVED LIGANDS OF THE CANNABINOID RECEPTOR......Page 454
EFFECT OF CANNABINOIDS ON PHOSPHOLIPID ENZYMES AND ARACHIDONIC ACID BIOSYNTHESIS......Page 455
MEMBRANE SIGNALING AND VOLUME TRANSMISSION......Page 456
PHYSIOLOGICAL IMPLICATIONS FOR MEDICINE AND THERAPEUTICS......Page 458
“Opiate pathway” (acute pain)......Page 459
Antiemetic effects......Page 460
Neurological disorders......Page 461
CONCLUSIONS......Page 462
REFERENCES......Page 463
THE CANNABINOID RECEPTORS AND THEIR LIGANDS......Page 468
Cannabinoid receptors......Page 469
Cannabinoid receptor agonists......Page 471
Sub-type specific ligands......Page 472
Endothelial receptor for anandamide......Page 473
Multiple affinity states of the CB receptors......Page 474
Cannabinoid receptor selective G-protein coupling......Page 476
Cannabinoid agonist selective G-protein coupling......Page 477
Mutations affecting cannabinoid signaling......Page 478
Inverse agonism produced by cannabinoid antagonists......Page 480
MODELING THE CANNABINOID RECEPTORS......Page 481
Development of preliminary cannabinoid receptor models......Page 483
Creation of cannabinoid R and R* models......Page 487
The inactive/ground (R) form of CB1 and CB2......Page 488
CB RECEPTOR MUTATION/CHIMERA STUDIES: IMPLICATIONS FOR CB RECEPTOR MODELS......Page 489
Mutations suggesting pharmacophore separation......Page 490
Mutations revealing sub-type selectivity......Page 491
Proposed binding sites for classical/non-classical cannabinoids......Page 492
Proposed aminoalkylindole binding sites......Page 493
Mutations of functional importance......Page 494
Activating mutations or peptides of the CB receptors......Page 496
CONCLUSIONS......Page 497
REFERENCES......Page 498
INTRODUCTION......Page 510
ENDOCANNABINOID LIGANDS......Page 511
PHARMACOLOGICAL EFFECTS OF ANANDAMIDE......Page 513
Central nervous system (CNS)......Page 515
Cardiovascular system......Page 516
Anandamide amidase (ANAse)......Page 517
The anandamide transporter (ANT)......Page 518
Anandamide metabolism......Page 519
Oxidative metabolism of anandamide......Page 520
Analgesia (antinociceptive)......Page 522
Antineoplastic......Page 523
SAR OF ENDOCANNABINOIDS FOR CANNABINOID RECEPTORS, ANANDAMIDE AMIDASE AND THE ANANDAMIDE TRANSPORTER......Page 524
Structural modifications of the N-hydroxyethyl group of anandamide......Page 525
Importance of cis-olefinic bonds for cannabimimetic activity......Page 526
Tail n-pentyl group modifications......Page 527
Structural requirements of a substrate for ANAse......Page 528
ANAse inhibitors......Page 529
ANANDAMIDE TRANSPORTER (ANT) SUBSTRATES AND INHIBITORS......Page 530
CONCLUSIONS......Page 531
REFERENCES......Page 532
INTRODUCTION......Page 542
The hippocampal slice......Page 543
Extracellular recordings......Page 544
Excitatory synaptic transmission......Page 545
Inhibitory synaptic transmission......Page 546
Long-term potentiation......Page 547
Formation of endocannabinoids upon neural activity......Page 548
Long-term potentiation......Page 550
K+ Conductances......Page 552
Transduction mechanisms......Page 554
Summary......Page 555
Interaction with the opiate system......Page 556
REFERENCES......Page 557
Actions in vivo......Page 561
Vascular actions of endocannabinoids......Page 563
Endocannabinoids and EDHF......Page 564
Mechanisms of vasorelaxation for endocannabinoids......Page 565
CONCLUDING REMARKS......Page 569
REFERENCES......Page 570
THE CANNABINOID RECEPTORS......Page 573
Endogenous cannabinoids......Page 577
Non-classical cannabinoids and aminoalkylindoles......Page 579
Structural features of the cannabinoid receptors......Page 580
Chimeric CB1/CB2 receptors......Page 582
A model for the interaction between SR 144528 and CB2......Page 583
A model for the interaction between WIN 55212-2 and CB2......Page 584
Other mutational studies......Page 585
CONSTITUTIVELY ACTIVE CANNABINOID RECEPTORS AND INVERSE AGONISM OF SR 141716A AND SR 144528......Page 586
REFERENCES......Page 587
HISTORY......Page 592
CANNABINOIDS AND PAIN......Page 594
Cannabinoid suppression of responses to noxious stimuli in spinal wide dynamic range and nociceptive specific neurons......Page 595
Cannabinoid analgesia or anesthesia?......Page 596
Cannabinoid suppression of nociceptive responses in the ventroposterolateral thalamus......Page 597
Relationship between effects on nociceptive neurons and behavior......Page 598
Role of descending modulation......Page 599
Peripheral cannabinoid action......Page 601
ROLE OF ENDOGENOUS CANNABINOIDS IN PAIN MODULATION......Page 602
SUMMARY AND CLINICAL IMPLICATIONS......Page 604
REFERENCES......Page 606
Cannabinoids and hippocampus......Page 610
Physiological effects of cannabinoids on hippocampal neurons......Page 611
Effects of cannabinoids on short-term memory......Page 612
Effects of cannabinoids on DNMS performance......Page 613
Effects of ibotenate lesions of the hippocampus on DNMS behavior......Page 614
Role of hippocampus in short term memory – DNMS......Page 615
Cannabinoid effects on DNMS information processing......Page 617
Cannabinoids affect encoding strength but not encoding functions......Page 619
CHRONIC EXPOSURE TO CANNABINOIDS ATTENUATES EFFECTS ON SHORT-TERM MEMORY......Page 620
THE MOLECULAR BASIS OF TOLERANCE TO DRUGS OF ABUSE......Page 623
Functional gene changes in drug abuse research......Page 624
DNA array designs and technical implications......Page 625
Application of cDNA microarrays to analyze effects of chronic cannabinoids......Page 626
Verification of large scale cDNA microarray screen by RNA dot blot analyses......Page 631
SUMMARY......Page 632
REFERENCES......Page 633
INTRODUCTION......Page 640
ACUTE ADVERSE EFFECTS OF MARIJUANA......Page 641
Task performance......Page 642
Neuropsychiatric......Page 643
Neuropsychiatric......Page 644
Reproduction system, hormone system and the fetus......Page 645
Cardiovascular system (CVS)......Page 646
Chemical dependence......Page 647
REFERENCES......Page 648