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Effects of the Triple Monoamine Uptake Inhibitor DOV 102,677 on Alcohol-Motivated Responding and Antidepressant Activity in Alcohol-Preferring (P) Rats

Authors

  • Andrew R. S. T. Yang,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Heon S. Yi,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Kaitlin T. Warnock,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Jacek Mamczarz,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Harry L. June Jr.,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Nikhil Mallick,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Philip A. Krieter,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Leonardo Tonelli,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Phil Skolnick,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Anthony S. Basile,

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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  • Harry L. June Sr.

    1. From the Department of Psychiatry and Behavioral Sciences (ARSTY, HSY, KTW, HLJJr, HLJSr), Howard University College of Medicine, Washington, DC; Division of Alcohol and Drug Abuse (JM, NM), Mood and Anxiety Program (LT), Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; and DOV Pharmaceutical, Inc. (PAK, PS, ASB), Somerset, New Jersey.
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Reprint requests: Harry L. June Sr., PhD, Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, 2041 Georgia Ave. NW Suite #5B02, Washington, DC 20060; Tel.: 202-865-6611; Fax: 202-865-3086; E-mail:harry.June@howard.edu

Abstract

Background:  Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats.

Methods:  Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed-ratio 4 (FR4) schedule, DOV (1.56 to 50 mg/kg; PO) was given 25 minutes or 24 hours prior to evaluation. The effects of DOV (12.5 to 50 mg/kg; PO) in the FST were evaluated 25 minutes posttreatment.

Results:  DOV (6.25 to 50 mg/kg) dose-dependently reduced alcohol-maintained responding by 59 to 88% at 25 minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50 mg/kg) was sustained for up to 120 hours after a single dose. Administration of a single dose of DOV (25, 50 mg/kg) 24 hours before testing suppressed alcohol responding for 48 hours by 59 to 62%. DOV (12.5 to 50 mg/kg) also dose-dependently reduced immobility of P rats in the FST.

Conclusions:  DOV produces both prolonged and selective reductions of alcohol-motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD-like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans.

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