Original article| Volume 54, ISSUE 1, P49-58, July 01, 2003

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Withdrawal from chronic amphetamine induces Depressive-Like behavioral effects in rodents

  • John F. Cryan
    Department of Neuropharmacology (JFC, AM), Scripps Research Institute, La Jolla, California, USA

    Nervous System Research (JFC, DH), Novartis Pharma AG, Basel, Switzerland
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  • Daniel Hoyer
    Nervous System Research (JFC, DH), Novartis Pharma AG, Basel, Switzerland
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  • Athina Markou
    Address reprint requests to John F. Cryan, Ph.D., Neuromodulation Unit, Nervous System Research, Novartis Pharma AG, WSJ 386.344, Basel, CH-4002, Switzerland, or Athina Markou, Ph.D., Department of Neuropharmacology, CVN-7, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, USA.
    Department of Neuropharmacology (JFC, AM), Scripps Research Institute, La Jolla, California, USA
    Search for articles by this author



      Amphetamine withdrawal and major depression share many behavioral commonalties in humans. Therefore, the examination of the behavioral effects of amphetamine withdrawal in rodents may provide insights into the neurobiological mechanisms underlying both disorders and aid in the development of animal models of depression that are sensitive to antidepressant agents.


      We examined the behavioral effects of withdrawal from chronic continuous infusion of amphetamine (via minipump) in three behavioral paradigms: the intracranial self-stimulation (ICSS) procedure in rats, the modified forced swim test in rats, and the tail suspension test in mice.


      Amphetamine withdrawal resulted in a prolonged (5 day) deficit in brain reward function as assessed by elevations in ICSS thresholds. Using a similar regimen of amphetamine administration, we examined the behavioral effects of withdrawal in a modified rat forced swim test. Animals that were treated with the highest dose of amphetamine (10 mg/kg/day) exhibited increased climbing behavior and decreased immobility 24 hours after withdrawal; by the 48-hour testing time point, this effect had dissipated. In contrast, animals that had been pretreated with 5 mg/kg/day amphetamine exhibited a pronounced increase in immobility indicative of an increase in “depressive-like” behavior, coupled with decreases in swimming and climbing. In the mouse tail suspension test, both regimens of amphetamine pretreatment induced increases in immobility scores, also indicative of “depressive-like” behavior, 24 hours following withdrawal.


      Withdrawal from chronic amphetamine administration results in behavioral changes that may be analogous to some aspects of depression in humans, such as reward deficits (i.e., elevations in brain reward thresholds) and behaviors opposite to those seen after treatment with antidepressant drugs, such as decreased immobility in the forced swim test and the tail suspension test.


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