The hypocretins (Hcrts, also known as orexins) are two peptides, both synthesized by a small group of neurons, most of which are in the lateral hypothalamic and perifornical regions of the hypothalamus. The hypothalamic Hcrt system directly and strongly innervates and potently excites noradrenergic, dopaminergic, serotonergic, histaminergic, and cholinergic neurons. Hcrt also has a major role in modulating the release of glutamate and other amino acid transmitters. Behavioral investigations have revealed that Hcrt neurons are maximally active in active waking. In rats, hypocretin neuronal activity is maximal during exploration and minimal during quiet waking and sleep. Degeneration of Hcrt neurons or genetic mutations that prevent the normal synthesis of Hcrt or of its receptors causes human and animal narcolepsy. Administration of Hcrt can reverse symptoms of narcolepsy in animals, may be effective in treating human narcolepsy, and may affect a broad range of motivated behaviors.The lateral hypothalamus (LH) has been implicated in wakefulness. One possibility is that it induces wakefulness by driving the basal forebrain (BF) wake-active neurons (Gerashchenko and Shiromani 2004). The activity of the BF wake-active neurons is hypothesized to release the sleep-inducing factor adenosine (AD), which begins to accumulate as wakefulness progresses. The AD is then hypothesized to inhibit the wake-active neurons (Strecker et al. 2000) and their silence allows the VLPO and median preoptic GABAergic sleep-active neurons to fire and sleep ensues. Here we measure AD levels in the BF and test the LH-BF circuit in Sprague-Dawley rats with lesions of the LH induced by hypocretin-2-saporin. 64 days after lesions the rats were implanted with sleep-recording electrodes and a guide cannula into the basal forebrain. Two weeks later, the rats were kept awake (gentle handling) for six hours (ZT 3-9) and microdialysis samples (5 mL) were collected hourly for 9 h (24 h after probe stabilization). AD levels were assessed using HPLC (see Murillo-Rodriguez et al. 2004 for details).Hypocretin-saporin ablated 95% of the hypocretin neurons with a resultant decline in CSF levels (-75% vs. control). AD levels increased with 6 h waking in saline control rats (n = 9), consistent with previous studies in cats (Strecker et al. 2000) and rats (Murillo-Rodriguez et al. 2004). However, in rats with LH lesions (n = 5) such an increase with waking did not occur. The homeostatic response to sleep loss was measured by conducting a rodent version of an MSLT where the rats were kept awake for 20 min and then allowed 20 min to sleep. This protocol was started at ZT2 and continued until lights were turned off. The lesioned rats were found to have more sleep during the 20 min sleep periods indicating a higher sleep drive in these rats.Previously, we (Gerashchenko et al. 2001) found that rats with LH lesions had increased sleep during the night, and here we found that they have increased sleep drive as measured by an MSLT. The increased sleep drive in thes...