Handbook of Psychopharmacology

1 Neuropathological and Neurochemical Aspects of Alzheimer’s Disease.- 1. Introduction.- 2. The Neuropathology of Alzheimer’s Disease.- 2.1. The Gross Changes of Alzheimer’s Disease.- 2.2. Nerve Cell Loss in Alzheimer’s Disease.- 2.3. Degenerative Changes in Nerve Cells in Alzheimer’s Disease.- 2.4. The Senile Plaque.- 2.5. The Neurofibrillary Tangle.- 2.6. Granulovacuolar Degeneration.- 2.7. The Hirano Body.- 2.8. Lewy Bodies and Alzheimer’s Disease.- 2.9. Changes in Glial Cells.- 2.10. Changes in Blood Vessels.- 2.11. The Relationship between Senile Plaques, Neurofibrillary Tangles, and Cerebrovascular Amyloid.- 3. Alzheimer-Type Changes in Conditions Other than Alzheimer’s Disease.- 3.1. Nondemented Individuals of All Ages.- 3.2. Down’s Syndrome at Middle Age.- 3.3. Parkinson’s Disease.- 3.4. Boxer’s Encephalopathy and Other Conditions.- 4. Alzheimer’s Disease and Patient Age.- 5. Biochemical Correlates of Pathological Changes.- 5.1. Neurotransmitter Changes.- 5.2. Changes in Protein Synthesis.- 6. Relationship between Plaques and Tangles and Nerve Cell Atrophy and Loss.- 7. Relationship between Extent of Pathological Changes and Degree of Dementia.- 7.1. Gross and Light Microscopic Relationships.- 7.2. Relationships to Dementia at Ultrastructural Level.- 8. Pathogenetic Considerations.- 8.1. Where Is the Site of the Primary Lesion in Alzheimer’s Disease? Is It in the Cerebral Cortex or in the Subcortex?.- 8.2. Is the SP or the NFT the Site of Primary Damage to Nerve Cells in Alzheimer’s Disease?.- 8.3. How Are SP Formed?.- 8.4. Where Does the Process of Alzheimer’s Disease Begin?.- 9. Concluding Remarks.- 10. References.- 2 Basal Forebrain Cholinergic Neurons and Alzheimer’s Disease.- 1. Introduction.- 2. Basal Forebrain Cholinergic Systems.- 3. Cholinergic Alterations in AD.- 3.1. Cortex.- 3.2. Basal Forebrain.- 3.3. Cerebral Spinal Fluid AChE and Other Peripheral Changes.- 4. Cholinergic Physiology.- 4.1. Behavioral Experiments.- 4.2. Electrophysiological Studies.- 4.3. Transsynaptic Consequences of Basal Forebrain Cholinergic Lesions in Experimental Animals.- 4.4. Cholinergic Pharmacotherapy in AD.- 5. Conclusion.- 6. References.- 3 Neurochemical Studies in Dementia.- 1. Introduction.- 1.1. Definition of Dementia.- 1.2. Methodology of Human Neurochemistry.- 2. Alzheimer’s Disease.- 2.1. Acetylcholine.- 2.2. Correlations of Cholinergic Deficit with Cognitive Impairment.- 2.3. Norepinephrine and Dopamine.- 2.4. Serotonin.- 2.5. Amino Acids.- 2.6. Neuropeptides.- 3. Other Cortical Dementias.- 4. Subcortical Dementias.- 4.1. Parkinson’s Disease and Progressive Supranuclear Palsy.- 4.2. Huntington’s Disease.- 4.3. Depression.- 5. Alcohol Dementia.- 6. Confusional States.- 7. Summary.- 8. References.- 4 Chemical Neuroanatomy of Alzheimer’s Disease.- 1. Introduction: Relationship of Neural Connections and Neurotransmitters with Alzheimer Pathology.- 2. Limbic and Cortical Connections and Neurotransmitters in Alzheimer’s Disease.- 2.1. Distribution of Lesions in the Hippocampal Formation.- 2.2. Distribution of Lesions in the Amygdala.- 2.3. Distribution of Neocortical Lesions.- 2.4. Neurotransmitters in Affected Limbic and Corticocortical Connections.- 3. Brain Stem and Basal Forebrain-Cortical Connections and Neurotransmitters in Alzheimer’s Disease.- 3.1. Magnocellular Basal Nucleus.- 3.2. Thalamic Intralaminar Nuclei.- 3.3. Hypothalamus.- 3.4. Brain Stem Monoamine Cell Groups.- 3.5. Brain Stem Cholinergic Cell Groups.- 4. Implications for the Pathogenesis and Treatment of Alzheimer’s Disease.- 5. References.- 5 Dementia in Parkinson’s Disease.- 1. Introduction.- 2. Brain Lesions in Patients with Parkinson’s Disease.- 3. Dementia and Lesions.- 3.1. Neuropathology.- 3.2. Neurochemistry.- 4. Parkinsonian Dementia.- 4.1. Prevalence.- 4.2. Characteristics of Parkinsonian Psychopathology.- 5. Symptoms and Lesions.- 5.1. Dopamine-Dependent Symptoms?.- 5.2. Norepinephrine-Dependent Symptoms?.- 5.3. Serotonin-Dependent Symptoms?.- 5.4. Acetylcholine-Dependent Symptoms?.- 5.5. Somatostatin-Dependent Symptoms?.- 6. Conclusion.- 7. References.- 6 Alzheimer’s Disease: Genetic Theories of Etiology.- 1. Introduction.- 2. The Genetic Hypothesis.- 2.1. Pedigree Studies of Presenile Disease.- 2.2. Studies of Pooled Proband Relatives.- 3. Critical Methodological Issues.- 3.1. Diagnostic Heterogeneity.- 3.2. Age-Dependent Onset.- 3.3. Resulting Ambiguity in Classical Twin and Linkage Studies.- 4. Predicted Characteristics of Genetically Caused AD.- 4.1. Gene Expression May Be Described by a Probability Distribution.- 4.2. Expected Familial Incidence in a Rare Dominant Disorder.- 4.3. Expected Familial Incidence When a Dominant Predisposing Gene Is Common.- 4.4. Effect of Gene Frequency on Relative Risks for Proband versus Control Relatives.- 4.5. Effects of Phenocopies in the Index Case Series.- 5. Review of Previous Studies.- 5.1. Approach.- 5.2. Studies before 1955.- 5.3. Studies after 1955.- 6. Current Studies.- 6.1. The Minnesota State Hospital Studies.- 6.2. The Duke Collaborative Studies.- 6.3. The Baltimore Nursing Home Study.- 6.4. The New York Studies.- 6.5. Autosomal Dominant Inheritance Suggested by Both the Baltimore and New York Studies.- 7. Implications and Strategies for Future Research.- 7.1. Status of the Genetic Hypothesis.- 7.2. Implications of Age-Dependent Expression of AD.- 7.3. Additional Research Strategies.- 8. References.- 7 The Cholinergic Hypothesis of Memory: A Review of Animal Experiments.- 1. Introduction.- 2. Conceptual Issues.- 3. Methodological Issues.- 4. Anatomy of Forebrain Cholinergic Pathways.- 5. Pharmacology of Central Cholinergic Neurons.- 6. Pharmacological Evidence for Cholinergic Involvement in Sensory, Attentional, and Motor Functions.- 7. Pharmacological Studies of Rodent Learning and Memory.- 7.1. Discrimination Learning.- 7.2. Avoidance Learning.- 7.3. Spontaneous and Rewarded Alternation Behavior.- 7.4. Maze Learning.- 7.5. Intracerebral Injections.- 8. Lesion Studies.- 8.1. Lesions of Ascending Cholinergic Projections.- 8.2. Recovery of Function after Lesions.- 8.3. Tissue Transplants.- 9. Pharmacological Studies of Primate Memory.- 9.1. Delayed Matching to Sample.- 9.2. Primate Studies: Delayed Responding.- 9.3. Other Behavioral Tasks.- 9.4. Primate Studies: Conclusions.- 10. Summary and Concluding Remarks.- 11. References.- 8 Behavioral Models of Aging in Nonhuman Primates.- 1. Introduction.- 2. Some Characteristics of Age-Related Behavioral Deficits in Nonhuman Primates.- 2.1. Behavioral Test Paradigms.- 2.2. Recent Memory Impairment.- 2.3. Hypersensitivity to Visual Interference.- 2.4. Discrimination Learning.- 2.5. Impairment in Reversal Learning.- 2.6. Synopsis.- 3. Relationship of Age-Related Behavioral Deficits in Nonhuman Primates to Humans.- 3.1. Impairments in Recent Memory.- 3.2. Hypersensitivity to Interfering Stimuli.- 3.3. Increased Perseveration/Behavioral Rigidity.- 3.4. Development of Human Memory Tests Based on Nonhuman Primate Tasks.- 4. Relationship of Age-Related Behavioral Deficits in Nonhuman Primates to Rodents.- 4.1. Recent Memory.- 4.2. Hypersensitivity to Interference.- 4.3. Increased Perseveration/Behavioral Rigidity.- 4.4. Summary.- 5. Possible Insights from Comparisons with Nonhuman Primates Given Discrete Brain Lesions.- 5.1. Frontal Cortex Lesions.- 5.2. Nucleus Basalis of Meynert Lesions.- 5.3. Hippocampal Lesions.- 5.4. Amygdala Lesions.- 5.5. Combined Lesions of Different Brain Regions.- 5.6. Summary.- 6. Possible Insights from Drugs That Impair Performance on Memory Tasks in Young Subjects.- 6.1. Scopolamine and Other Anticholinergics.- 6.2. Diazepam and Benzodiazepines.- 6.3. Tetrahydrocannabinol.- 7. Drugs for Improving Age-Related Cognitive Losses: Current Status and Future Prospects.- 7.1. Neurotransmitter Modulation.- 7.2. Nootropics.- 7.3. Neuropeptides.- 8. Synthesis and Discussion.- 9. References.- 9 Cholinergic Drugs and Human Cognitive Performance.- 1. Introduction.- 2. The Effects of Cholinergic Agents on Processes Involved in Learning and Memory in Experimental Animals.- 3. The Effects of Cholinergic Agents on Processes Involved in Learning and Memory in Young Adult Human Subjects.- 4. Clinical Trials of Cholinergic Agents in Patients with Dementia of the Alzheimer Type or Aged Volunteers.- 5. Implications and New Directions.- 6. References.- 10 Treatment of Dementia with Vasoactive Drugs.- 1. Background and Rationale.- 1.1. Multiinfarct Dementia.- 1.2. Degenerative Dementias.- 2. Traditional Vasodilators.- 3. Recent Developments and Future Prospects.- 3.1. Calcium Channel Blockers.- 3.2. Excitatory Amino Acid Antagonists.- 4. References.- 11 New Pharmacological Perspectives on Nootropic Drugs.- 1. Introduction.- 2. Known Compounds.- 3. Goals of This Chapter.- 4. Distribution of Drugs in Brain.- 5. Neuropsychopharmacological Studies.- 5.1. Aged Rat Quantitative EEG.- 5.2. Therapeutic Window Discovered in Quantitative EEG Studies.- 5.3. Effects on New Learning and the Therapeutic Window.- 5.4. Effects on Firing Rate of Neurons of the Medial Septal Nucleus and the Area Ventral to the Globus Pallidus.- 5.5. Therapeutic Window Shown in Single-Neuron Firing Rate.- 5.6. Cerebral Intraventricular Administration of Pramiracetam and Piracetam and Effects on Single-Neuron Firing Rates.- 5.7. Functional Hippocampal Lesions and the Therapeutic Window.- 6. Neurochemical Studies.- 7. Relationship to Endogenous Substances.- 8. Nootropic Drugs and Arguments for Supplementary Choline.- 9. Clues to the Mode of Action of Nootropic Drugs.- 10. Some Thoughts on Clinical Trials.- 11. Summary and Conclusion.- 12. References.