Antipsychotic drugs were first discovered in 1953, and not since the late 1970s has the Handbook of Experimental Pharmacology taken up this topic. A new treatment of this topic would be due under any circumstances; however, this is now particularly true, since remarkable progress has been made on several fronts in furthering our understanding of the mechanisms of antipsychotic drug action. First, we have learned that schizophrenia is an illness with particu lar neuroanatomical abnormalities, many of which suggest that the illness is caused by errors in neurodevelopment. These findings have helped to form a context for understanding neurochemical aberrations in the illness and suggest new approaches for pharmacological treatment. Propelled forward by rapid advances in neurochemical anatomy, current pathophysiological hypotheses of schizophrenia and antipsychotic drug action have taken on the appearance of complex electrical circuit diagrams. Second, molecular biology studies have now revealed that there is a multiplicity of dopamine receptors (i. e. , D , DZshort' j DZlong, D , D , and D ), some of which may become entirely new targets for 3 4 s antipsychotic drug action. Ironically, the development of drugs that are selec tive for these receptors and that can be used to investigate their function lags behind; yet the discovery of these new receptors offers unparalleled opportu nities for developing drugs with improved efficacy and fewer side effects.
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1 Classification Schemes for Antipsychotic Drugs.- A. Introduction.- I. Historical Perspective.- B. Classification by Patterns of Efficacy and Neurological Side Effects.- C. Classification by Chemical Structure.- I. Phenothiazines.- II. Thioxanthenes.- III. Butyrophenones.- IV. Diphenylbutylpiperidines.- V. Indoles.- VI. Benzamides.- VII. Dibenzapines.- VIII. Others.- D. Classification by Potency and Nonneurologic Side-Effect Profile.- E. Classification by Pharmacological Mechanism.- I. Selective Dopamine Receptor D2 Antagonists.- II. Combined D2/D3 Antagonists.- III. Combined D2/D1 Antagonists.- IV. Combined 5-HT2-D2 Antagonists.- F. Future Classification Schemes.- I. Selective Serotonin Receptor Antagonists.- II. Partial D2 Agonists.- III. Sigma Site Antagonists and Excitatory Amino Acid Agonists.- IV. GABA-Mimetics and Partial Benzodiazepine Agonists.- G. Conclusions.- References.- 2 Molecular Models and Structure-Activity Relationships.- A. Introduction.- B. Structure-Activity Relationships of Antipsychotic Drugs.- C. Neurotransmitter Receptor Models.- D. Molecular Modelling of Drug-Receptor Interactions.- I. Electrostatic Fields Around Drug and Receptor Molecules.- II. Molecular Dynamics of Drug-Receptor Interactions.- E. Conclusions.- References.- 3 Interaction of Antipsychotic Drugs with Dopamine Receptor Subtypes.- A. Introduction.- B. Molecular Biology of Dopamine Receptor Subtypes.- I. General Structural Features of Dopamine Receptors.- II. The D1 Family of Dopamine Receptors.- 1. The Dopamine D1 Receptor.- 2. The Dopamine D5 Receptor.- III. The D2 Family of Dopamine Receptors.- 1. The Dopamine D2 Receptor.- 2. The Dopamine D3 Receptor.- 3. The Dopamine D4 Receptor.- C. Pharmacology of Neuroleptics at Recombinant Dopamine Receptors.- I. Traditional Neuroleptics and Related Compounds.- II. Clozapine and the Atypical Neuroleptics.- III. New Antipsychotics.- 1. Olanzapine: A Second-Generation Clozapine-Like Compound.- 2. Remoxipride: A D2 Receptor-Selective Substituted Benzamide.- 3. Risperidone: A D2/5-HT2 Receptor Antagonist.- D. Future Outlook and Hopes for Subtype-Specific Drugs.- References.- 4 Atypical Antipsychotic Drugs: Clinical and Preclinical Studies.- A. Introduction.- B. Glutamate.- I. Glutamate Receptors.- II. Glutamate Hypothesis of Schizophrenia.- III. Glutamatergic Drugs.- 1. Glycine and Milacemide.- 2. Umespirone.- 3. Others.- C. ?-Aminobutyric Acid (GABA).- I. GABA Receptors.- II. GABA Hypothesis of Schizophrenia and Clinical Studies of GABA-ergic Drugs.- D. Acetylcholine.- I. Acetylcholine Receptors.- II. Muscarinic Hyperactivity in Schizophrenia? ..- E. Norepinephrine.- I. ?1-Adrenergic Receptor Involvement in Atypical Antipsychotic Drug Actions.- F. Cholecystokinin (CCK).- I. CCK-ergic Drugs.- 1. LY262691.- 2. Caerulin.- 3. Others.- G. Neurotensin.- I. Neurotensin and Schizophrenia.- II. Effects of Atypical Antipsychotic Drugs on Neurotensin Systems.- H. Sigma Receptors.- I. Sigma Receptors.- II. Preclinical Studies.- III. Specific Agents.- I. Opioids.- J. Serotonin.- I. 5-HT Receptors and Schizophrenia.- II. Selective 5-HT2A/2C Antagonists.- 1. Ritanserin.- 2. ICI169369 and MDL100907.- 3. Mianserin.- III. Mixed 5-HT2/D2 Antagonists.- 1. Clozapine.- 2. Risperidone.- 3. Melperone.- 4. Olanzapine.- 5. Amperozide.- 6. Fluperlapine.- 7. Tiosperone.- 8. Zotepine.- 9. Others.- IV. 5-HT3 Antagonists.- V. Nonselective 5-HT Receptor Antagonists.- VI. 5-HT Reuptake Inhibitors.- K. Conclusions.- References.- 5 Sites and Mechanisms of Action of Antipsychotic Drugs as Revealed by Immediate-Early Gene Expression.- A. Introduction.- B. Immediate-Early Gene Expression as a Method to Assess the Sites and Mechanisms of Action of Antipsychotic Drugs (APDs).- C. Effects of APDs on Immediate-Early Gene Induction in the Striatal Complex.- I. Effects of APDs on Regionally Specific Striatal Immediate-Early Gene Expression.- 1. Dorsal Striatum.- 2. Ventral Striatum.- II. Striatal Immediate-Early Gene Induction: Fos, Fos-Related Antigens, and Others.- 1. Fos Versus Fras.- 2. Other Immediate-Early Genes.- III. Mechanisms of Antipsychotic Drug-Elicited Striatal Fos Expression.- 1. Dopamine Receptors and APD-Elicited Increases in Striatal Fos.- a) D2 Dopamine Receptors.- b) D1 Dopamine Receptors.- c) Concurrent D2/D1 Receptor Occupancy and Striatal Fos Expression.- 2. Involvement of Excitatory Amino Acid Receptors in Neuroleptic-Elicited Striatal Fos Expression.- 3. Cholinergic and Adenosine Receptors.- a) Muscarinic Cholinergic Receptors.- b) Adenosine A2 Receptors.- IV. Acute Versus Chronic Effects of APDs on Striatal Fos Expression.- V. What Is the Transcriptional Target of APD-Elicited Striatal Fos Expression?.- 1. Neurotensin.- 2. Enkephalin.- 3. Glutamic Acid Decarboxylase.- D. Preferential Induction of Fos in the Prefrontal Cortex (PFC) by Clozapine.- I. Regional Effects of APDs on Fos Expression in the PFC.- 1. Effects of APDs on Fos Expression in the Medial PFC.- 2. Correlations Between PFC Expression and Clinical Status.- II. Receptor Mechanisms of Clozapine-Elicited Increase in PFC Fos Expression.- 1. D1 and D2 Dopamine (DA) Receptors and Clozapine-Elicited Fos Expression.- 2. Nondopaminergic Receptors and the PFC Fos Response to Clozapine.- 3. Mechanisms of Clozapine-Elicited Increases in PFC Fos Expression.- a) Possible Role of a Novel DA Receptor in Mediating Clozapine-Elicited Effects.- b) Targeting of Multiple Receptors.- c) Transsynaptic Events as a Possible Determinant of Clozapine-Induced Changes.- III. Transcriptional Targets of Clozapine's Actions in the PFC.- E. Effects of APDs on Immediate-Early Gene Expression in Other CNS Sites.- I. Thalamic Paraventricular Nucleus.- II. Lateral Septal Nucleus.- III. Other CNS Regions.- F. Conclusions.- I. Methodological Issues.- II. Validity of Fos Expression as a Model of the Actions of APDs.- III. Future Directions.- References.- 6 Basic Neurophysiology of Antipsychotic Drug Action.- A. Introduction.- B. The Dopamine Hypothesis of Schizophrenia.- I. Antipsychotic Drugs as D2 Blockers.- II. Shortcomings of the Dopamine Hypothesis.- C. Acute Physiology of Antipsychotic Drug Action.- I. Dopamine Cell Identification and Physiology.- II. Acute Actions of Antipsychotic Drugs on Dopamine Cell Physiology.- 1. Acute Antipsychotic Drugs Increase Firing Rate.- 2. Acute Antipsychotic Drug Administration Increases Dopamine Cell Burst Firing.- 3. Acute Antipsychotic Drug Treatment Increase the Number of Dopamine Cells Firing Sponta…