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


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


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


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


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.
Gruner
John A
JA
Cephalon, Inc., West Chester, PA, USA. JGruner@cephalon.com
Marcy
Val R
VR
Lin
Yin-Guo
YG
Bozyczko-Coyne
Donna
D
Marino
Michael J
MJ
Gasior
Maciej
M
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D018929:Cell Culture Techniques; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D009627:Nomifensine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012894:Sleep Stages / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects*
D000662:Amphetamines; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D009627:Nomifensine