title: Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents.
abstract: BACKGROUND
  Amphetamine withdrawal and major depression share many behavioral commonalities 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D000661:Amphetamine / Q000009:adverse effects*; D019969:Amphetamine-Related Disorders / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D003863:Depression / Q000139:chemically induced / Q000209:etiology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012653:Self Stimulation; D013375:Substance Withdrawal Syndrome / Q000150:complications*; D013550:Swimming
chemical_list: D000697:Central Nervous System Stimulants; D000661:Amphetamine