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0031-6997/08/6003-358-403$7.00
Pharmacol Rev 60:358-403, 2008

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Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection

Jeffrey A. Lieberman, Frank P. Bymaster, Herbert Y. Meltzer, Ariel Y. Deutch, Gary E. Duncan, Christine E. Marx, June R. Aprille, Donard S. Dwyer, Xin-Min Li, Sahebarao P. Mahadik, Ronald S. Duman, Joseph H. Porter, Josephine S. Modica-Napolitano, Samuel S. Newton and John G. Csernansky

Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, New York (J.A.L.); Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana (F.P.B.); Division of Psychopharmacology, Vanderbilt University Medical Center, Psychiatric Hospital at Vanderbilt, Nashville, Tennessee (H.Y.M); Departments of Psychiatry and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (A.Y.D.); Departments of Psychiatry & Biology, University of North Carolina System–Chapel Hill, Chapel Hill, North Carolina (G.E.D.); Department of Psychiatry and Behavioral Sciences, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, North Carolina (C.E.M.); Department of Biology, Washington and Lee University, Lexington, Virginia (J.R.A.); Louisiana State University Health Sciences Center–Shreveport, Shreveport, Louisiana (D.S.D); Department of Psychiatry and International Medical Graduate Program, University of Manitoba, Winnipeg, Manitoba, Canada (X.-M.L.); Department of Psychiatry and Health Behavior, Medical College of Georgia and Medical Research, Veterans Affairs Medical Center, Augusta, Georgia (S.P.M.); Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (R.S.D., S.S.N.); Department of Psychology, Virginia Commonwealth University, Richmond, Virginia (J.H.P.); Department of Biology, Merrimack College, North Andover, Massachusetts (J.S.M.-N.); and Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois (J.G.C.)

Abstract
I. Introduction
II. Pathophysiology of Schizophrenia
    A. Neurotransmitter Dysregulation
        1. Dopamine.
        2. GABA.
        3. Glutamate.
        4. Other—Serotonin, Acetylcholine, Norepinephrine.
        5. Intracellular Signaling Cascades.
    B. Neuroanatomical Pathology
    C. Apoptosis and N-Methyl-D-aspartate Antagonist-Induced Neurodegeneration
    D. Altered Levels of Neuroactive Steroids
    E. Decreased Mitochondrial Function
    F. Dysfunction of Glucose Metabolism
    G. Elevated Levels of Oxidative Stress
    H. Reduced Neurotrophic Factor Expression
III. Comparison of Antipsychotic Drugs in Animal Models of Antipsychotic Efficacy, Neurotransmitter Regulation, and Neuroprotection
    A. Traditional Animal Models of Antipsychotic Activity
        1. Dopamine Stimulant-Induced Hyperactivity.
        2. Conditioned Avoidance Responding.
        3. Forelimb and Hind Limb Retraction Time (Paw Test).
        4. Drug Discrimination.
        5. Electrophysiology and Brain Activation Patterns.
    B. Neurotransmitter Regulation via Antipsychotic Drugs
        1. Dopamine and Antipsychotic Drugs.
        2. GABA and Antipsychotic Drugs.
        3. Glutamate and Antipsychotic Drugs.
            a. N-Methyl-D-aspartate Antagonists in Animal Models.
        4. Other—Peptides and Antipsychotic Drugs.
        5. Intracellular Signaling Cascades and Antipsychotic Drugs.
        6. Effects of Antipsychotic Drugs on Monoamine and Amino Acid Neurotransmitter Efflux.
            a. Dopamine and Norepinephrine Extracellular Concentrations.
            b. Serotonin Extracellular Concentrations.
            c. Acetylcholine Extracellular Concentrations.
            d. Glutamate and GABA Extracellular Concentrations.
    C. Neuroanatomical Plasticity after Treatment with Antipsychotic Drugs
    D. Apoptosis and N-Methyl-D-aspartate Antagonist-Induced Neurodegeneration
    E. Second-Generation Antipsychotic Drugs Increase Neuroactive Steroids in Animal Models
    F. Effects of Antipsychotic Drugs on Mitochondria and Oxidative Phosphorylation
        1. Impaired Mitochondrial Function and Risk for Tardive Dyskinesia.
        2. Antipsychotic Drugs Differentially Inhibit Complex I Activity.
        3. Compensatory Changes in Mitochondrial Function with Antipsychotic Drug Treatment.
    G. Glucose Transport and Mechanism of Neuroprotection
        1. Antipsychotic Drugs Inhibit Glucose Transport.
        2. SGAs Promote Neurite Outgrowth and Cell Survival—Role of Akt.
    H. Second-Generation Antipsychotic Drugs Demonstrate Antioxidant Properties
    I. Regulation of Neurogenesis and Neurotrophic Factor Expression
        1. Regulation of Neurotrophic Factor Expression.
        2. Regulation of Neurogenesis and Cell Proliferation.
IV. Conclusions
Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D2 receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.

Address correspondence to: Dr. Jeffrey Lieberman, Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, 1051 Riverside Dr., Unit 4, New York, NY 10032. E-mail: jlieberman{at}columbia.edu






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