The roles of dopamine transport inhibition and dopamine release facilitation in wake enhancement and rebound hypersomnolence induced by dopaminergic agents

Sleep. 2009 Nov;32(11):1425-38. doi: 10.1093/sleep/32.11.1425.


Study objective: Rebound hypersomnolence (RHS: increased sleep following increased wake) is a limiting side-effect of many wake-promoting agents. In particular, RHS in the first few hours following wake appears to be associated with dopamine (DA)-releasing agents, e.g., amphetamine, but whether it can also be produced by DA transporter (DAT) inhibition alone is unknown. In these studies, DA-releasing and DAT-inhibiting agents and their interaction were systematically examined for their ability to increase wake and induce RHS.

Design: Chronically implanted rats were evaluated in a blinded, pseudo-randomized design.

Participants: 237 rats were used in these studies with 1 week between repeat tests.

Interventions: Animals were habituated overnight and dosed the next day, 5 h after lights on, with test agents.

Measurements and results: Sleep/wake activityand RHS were evaluated using EEG/EMG recording up to 22 h post dosing. In vitro dopamine release was evaluated in rat synaptosomes. At doses that produced equal increases in wake, DA-releasing (amphetamine, methamphetamine, phentermine) and several DAT-inhibiting agents (cocaine, bupropion, and methylphenidate) produced RHS during the first few hours after the onset of sleep recovery. However, other DAT-inhibiting agents (mazindol, nomifensine, GBR-12909, and GBR-12935) did not produce RHS. Combination treatment with amphetamine and nomifensine produced waking activity greater than the sum of their individual activities alone while ameliorating the amphetamine-like RHS. In rat synaptosomes, nomifensine reduced the potency of amphetamine to induce DA release approximately 270-fold, potentially explaining its action in ameliorating amphetamine-induced RHS.

Conclusions: All DA releasing agents tested, and some DAT-inhibiting agents, produced RHS at equal wake-promoting doses. Thus amphetamine-like DA release appears sufficient for inducing RHS, but additional properties (pharmacologic and/or pharmacokinetic) evidently underlie RHS of other DAT inhibitors. Enhancing wake while mitigating RHS can be achieved by combining DAT-inhibiting and DA-releasing agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamines / pharmacology*
  • Animals
  • Cell Culture Techniques
  • Disorders of Excessive Somnolence / chemically induced*
  • Disorders of Excessive Somnolence / metabolism
  • Dopamine Plasma Membrane Transport Proteins / drug effects*
  • Dopamine Uptake Inhibitors / pharmacology*
  • Nomifensine / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Sleep Stages / drug effects
  • Synaptosomes / drug effects
  • Wakefulness / drug effects*


  • Amphetamines
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Nomifensine