The Roles of Dopamine Transport Inhibition and Dopamine Release Facilitation in Wake Enhancement and Rebound Hypersomnolence Induced by Dopaminergic Agents

ALTHOUGH THE REGULATION OF SLEEP AND WAKE STATES IS BELIEVED TO INVOLVE BRAIN DOPAMINE (DA),1–3 ITS ROLE APPEARS COMPLEX. ACTIVATION of dopamine D1 receptors increases wake and reduces rapid eye movement sleep (REMS).4 The effects of activation of dopamine D2 receptors depend on dose and location.5 While D1 and D2 receptor agonists injected into intracerebral ventricles can increase wake,6 microinjection of mixed D1/D2 receptor agonists (e.g., apomorphine) into the ventral tegmental area increases slow wave sleep (SWS) cortical activity.7 This finding is consistent with action on cell body D2 autoreceptors which reduce DA release when activated.8 D2 autoreceptors also appear to regulate extracellular DA concentrations by stimulating DAT activity.9 Thus, activation of D2 autoreceptors can decrease extracellular DA concentration by decreasing DA release and increasing DAT activity. Consequently, antagonists of DA autoreceptors have been shown to increase wake.10 Agents that elevate extracellular DA levels are known to increase arousal.6,11–15 DAT inhibitors, such as cocaine or methylphenidate, constitute a class of agents that indirectly enhance extracellular DA levels by blocking DA reuptake. Agents such as amphetamine and methamphetamine can enhance synaptic DA levels by directly inducing its release from synaptic terminals.16–18 Rebound hypersomnolence (RHS) consisting of “an intense interval of compensatory sleep after drug-induced waking”19 has been demonstrated to occur for several h following the end of waking produced by some dopaminergic agents, in particular methamphetamine and amphetamine.20–22 Non-dopaminergic agents such as caffeine do not appear to demonstrate this property.23 Cocaine has been shown to produce a late hypersomnolence during the dark phase (12–24 h) following administration,24 but the time resolution in that study was insufficient to determine if RHS also occurred immediately after the initial waking period. In contrast to methamphetamine and amphetamine, modafinil did not produce significant RHS after waking.19–22 Thus RHS, particularly immediately following waking, as exhibited following methamphetamine or amphetamine treatment, appears to be distinct from hypersomnolence resulting from a homeostatic increase in sleep propensity following enhanced waking.2,19,25 An ideal wake-promoting profile would preclude RHS since it can limit the therapeutic utility of a wake promoting agent.21 Modafinil, which does not does not produce RHS, also does not induce DA release from synaptosomes,26 but wake enhancement appears to depend at least in part on DAT inhibition.13,15,27 We therefore hypothesized that RHS might be specifically associated with DA release as opposed to DAT inhibition.2,28 To test this hypothesis we first performed a systematic determination of EC50 values for synaptosomal DA release of several known DAT-inhibiting and DA-releasing agents. Throughout this paper, “DA-releasing agent” will specifically refer to agents that induced DA release in the synaptosomal preparation. The in vivo effects of these compounds on specific measures of RHS, primarily within the first 7 h after dosing in rats (up to the time of lights off), were then studied at doses that produced comparable wake activity. These studies revealed that while DA-releasing agents produced RHS, some DAT inhibitors also produced RHS, while others (e.g., nomifensine) did not. Furthermore, the combination of amphetamine and nomifensine ameliorated the amphetamine-induced RHS and surprisingly produced more wake activity than expected from either agent alone. A mechanistic explanation for this interaction supported by the finding that nomifensine inhibits amphetamine-induced DA release in a rat synaptosomal assay is discussed.