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Vol. 53, Issue 1, 119-134, March 2001
School of Animal and Microbial Sciences, University of Reading,
Whiteknights, Reading, United Kingdom
I. Introduction
II. Which Dopamine Receptor Isoform Is Important for Antipsychotic
Action?
A. Problems with Ligand Binding Assays for D2 Dopamine
Receptors
B. Comparison of Affinities for Antipsychotic Drugs at Different
D2-Like Receptor Subtypes
C. Use of Radiolabeled Antipsychotic Drugs to Image Dopamine
Synapses In Vivo
D. Calculation of Dopamine Receptor Occupancies Using in Vivo
Scanning Techniques
III. What Is the Mechanistic Basis for the Difference Between
Typical and Atypical Antipsychotics?
A. Blockade of Dopamine Receptors Achieved by Antipsychotic Drugs
B. Kinetics of the Interactions of Dopamine and Antipsychotic Drugs
at Dopamine Receptors
C. Differential Effects of Antipsychotic Drugs in Striatal and
Cortical Brain Regions
D. Occupancy of Dopamine Receptors by Clozapine: Use of Different
Tracer Radioligands
E. Summary of the Differences Between Typical and Atypical
Antipsychotic Drugs
IV. Antagonism or Inverse Agonism in the Mechanism of Antipsychotic
Drugs
V. Pharmacogenetic Studies of the Effects of Antipsychotic Drugs
VI. Appendix
A. Three-Way Competition Between Antipsychotic Drug, Tracer
Radioligand, and Dopamine in Relation to In Vivo Imaging Studies
B. Effect of Synaptic Dopamine Concentration on Inhibition of
Functional Response by Antipsychotic Drugs
C. Effect of Synaptic Dopamine Release on Binding of Radiotracer to
Brain Dopamine Receptors in Vivo
Acknowledgments
References
Interaction of the antipsychotic drugs with dopamine receptors of the D2, D3, or D4 subclasses is thought to be important for their mechanisms of action. Consideration of carefully defined affinities of the drugs for these three receptors suggests that occupancy of the D4 subclass is not mandatory for achieving antipsychotic effects, but actions at D2 or D3 receptors may be important. A major difference between typical and atypical antipsychotic drugs is in the production of extrapyramidal side effects by the typical drugs. Production of extrapyramidal side effects by typical drugs seems to be due to the use of the drugs at doses where striatal D2 receptor occupancy exceeds ~80%. Use of these drugs at doses that do not produce this level of receptor blockade enables them to be used therapeutically without producing these side effects. The antipsychotic drugs have been shown to act as inverse agonists at D2 and D3 dopamine receptors, and this property may be important for the antipsychotic effects of the drugs. It is suggested that the property of inverse agonism leads to a receptor up-regulation upon prolonged treatment, and this alters the properties of dopamine synapses. Several variants of the dopamine receptors exist with different DNA sequences and in some cases different amino acid sequences. These variants may have different properties that alter the effects of dopamine and the antipsychotic drugs. The determination of such variants in patients may help in the prediction of drug responsiveness.
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