Orexins/hypocretins excite basal forebrain cholinergic neurones

Abstract

The orexins (orexin A and B, also known as hypocretin 1 and 2) are two recently identified neuropeptides ( de Lecea et al., 1998; Sakurai et al., 1998) which are importantly implicated in the control of wakefulness (for reviews see Hungs and Mignot, 2001; Kilduff and Peyron, 2000; Sutcliffe and de Lecea, 2000; van den Pol, 2000; Willie et al., 2001). Indeed, alteration in these peptides’ precursor, their receptors or the hypothalamic neurones that produce them leads to the sleep disorder narcolepsy ( Chemelli et al., 1999; Lin et al., 1999; Peyron et al., 2000; Thannickal et al., 2000). The mechanisms by which the orexins modulate wakefulness, however, are still unclear. Their presence in fibres coursing from the hypothalamus ( Peyron et al., 1998) up to the preoptic area (POA) and basal forebrain (BF) suggests that they might influence the important sleep and waking neural systems situated there ( Jones, 2000). The present study, performed in rat brain slices, demonstrates, however, that the orexins have no effect on the GABA sleep-promoting neurones of the POA, whereas they have a strong and direct excitatory effect on the cholinergic neurones of the contiguous BF. In addition, by comparing the effects of orexin A and B we demonstrate here that orexins’ action depends upon orexin type 2 receptors (OX 2), which are those lacking in narcoleptic dogs ( Lin et al., 1999). These results suggest that the orexins excite cholinergic neurones that release acetylcholine in the cerebral cortex and thereby contribute to the cortical activation associated with wakefulness.