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.

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-Rel