Wake-promoting Actions Research Articles

The central nucleus of the amygdala and the wake-promoting effects of modafinil

Modafinil, a novel non-amphetamine stimulant recently approved for the treatment of narcolepsy, has been shown to increase waking in both animals and humans. However, its mechanism of action is currently unknown. Earlier research into the brain structures responsible for the wake-producing actions of modafinil implicated the central nucleus of the amygdala (ACe) as a possible site of action [Neuroscience 87 (1998) 905–911; Neurosci. Lett. 241 (1998) 95–98]. The present experiments were designed to test the hypothesis that the ACe is, at least in part, involved in the wake-producing actions of modafinil. In the first experiment, rats with lesions of the ACe were injected systemically with varying doses of modafinil and sleep was recorded. At the highest dose, modafinil significantly increased waking and decreased sleep. However, there was no interaction between the lesion and the effect of the drug. In the second experiment, varying doses of modafinil were injected directly into the ACe and sleep was recorded. Injection of modafinil into the ACe did not affect sleep architecture. Thus, ACe does not play a simple role in modafinil’s wake-promoting action. We suggest that more complex testing will be required to elucidate its role.

Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action

The hypocretins (orexins) are a newly identified peptide family comprised of two peptides, hypocretin-1 and hypocretin-2. Recent observations suggest an involvement of these peptides in the regulation of behavioral state. For example, these peptides are found in a variety of brain regions associated with the regulation of forebrain neuronal and behavioral activity states. Furthermore, when infused into the lateral ventricles in awake animals, hypocretin-1 elicits increased duration of waking beyond that observed in vehicle-treated animals. Previous studies have been limited to an examination of the sleep–wake effects of hypocretin-1 in awake animals. Currently, the sleep–wake effects of hypocretin-2 and the extent to which hypocretins can initiate waking in the sleeping animal remain unclear. To better characterize the wake-promoting actions of the hypocretins, the current studies examined the sleep–wake effects of varying doses (0.007, 0.07 and 0.7 nmol) of hypocretin-1 and hypocretin-2 when administered into sleeping rats (e.g. remote-controlled infusions). Infusions of hypocretin-1 and hypocretin-2 into the lateral ventricles elicited a short latency (0.7 nmol hypocretin-1; 93±30 s from the start of the 120-s infusion) increase in electroencephalographic, electromyographic, and behavioral indices of waking. These infusions also produced substantial decreases in slow-wave and rapid-eye movement sleep. Hypocretin-1 was more potent than hypocretin-2 in these actions. Interestingly, hypocretin-1 infused into the fourth ventricle elicited less robust waking which occurred with a longer latency than infusions into the lateral ventricles. These latter observations suggest a forebrain site of action participates in hypocretin-1-induced waking. Within the forebrain, a variety of basal forebrain structures, including the medial preoptic area, the medial septal area and the substantia innominata, receive a moderate hypocretin innervation. Therefore, additional studies examined the sleep–wake effects of bilateral hypocretin-1 infusions into these basal forebrain structures. Robust increases in waking were observed following infusions into, but not outside, the medial septal area, the medial preoptic area and the substantia innominata. These results indicate a potentially prominent role of hypocretins in sleep–wake regulation via actions within certain basal forebrain structures and are consistent with studies indicating a prominent role of hypocretins in sleep/arousal disorders.

Dopaminergic Role in Stimulant-Induced Wakefulness

The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.

Differential sensitivity to the wake-promoting actions of norepinephrine within the medial preoptic area and the substantia innominata.

Mapping studies were conducted to delineate the site(s) of action for the arousal-enhancing actions of norepinephrine (NE) within the basal forebrain region encompassing the medial preoptic area (MPOA) and the substantia innominata (SI). Varying doses of NE, the beta-agonist, isoproterenol, or the alpha1-agonist, phenylephrine, were infused into the MPOA or SI in the resting rat. Infusions of NE (4 nmol, 16 nmo/150 nl), isoproterenol (15 nmol/150 nl), and phenylephrine (40 nmol/250 nl) into the MPOA elicited robust increases in waking. In contrast, neither isoproterenol or phenylephrine infusions into the SI altered behavioral state. NE infusions into the SI increased waking only at the highest dose, and at this dose there was an anatomical gradient for NE-induced waking, with infusions placed farther from the MPOA, producing smaller increases in waking. Thus, in contrast to the MPOA, the SI is relatively insensitive to the wake-promoting actions of NE.

Differential sensitivity to the wake-promoting actions of norepinephrine within the medial preoptic area and the substantia innominata.

Differential sensitivity to the wake-promoting actions of norepinephrine within the medial preoptic area and the substantia innominata.