MECHANISMS MEDIATING EFFECTS OF NITRIC OXIDE ON PERIFORNICAL LATERAL HYPOTHALAMIC NEURONS

The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of sleep. Recently we found that NO levels in the PF-LHA are higher during sustained waking and that NO exerts predominantly inhibitory effects, especially on PF-LHA neurons excited by tactile stimulation. The mechanisms underlying this NO-evoked inhibitory action on the PF-LHA neurons were assessed in the present study. We investigated the contributions of adenosinergic, GABAergic, and sGC-cGMP signaling mechanisms in mediating nitrergic influences on the PF-LHA neurons. The extracellular discharge activity of PF-LHA neurons was recorded in combination with microdialytic delivery of pharmacological agents adjacent to the recorded neurons in urethane-anesthetized rats. First, we quantified changes in the discharge activity of the PF-LHA neurons during the blockade of the adenosine A(1) receptor, GABA(A) receptor, and sGC-cGMP pathway. Then, we determined the efficacy of blocking adenosine A(1) receptor, GABA(A) receptor, and sGC signaling mechanisms in attenuating the inhibitory influences of 3,3-bis(aminoethyl)-1-hydroxy-1-oxo-1-triazene (a NO donor) (NOC-18), a NO donor, on the discharge activity of the PF-LHA neurons. We found that NOC-18-induced suppression in the discharge activity of PF-LHA neurons was significantly attenuated during the blockade of adenosine A(1) receptor-, GABA(A) receptor-, and sGC-cGMP-mediated signaling. These findings suggest that NO-evoked inhibition of PF-LHA neurons involves a complex mechanism including, but may not be limited to, adenosinergic, GABAergic and sGC-cGMP signaling pathways. The findings are consistent with a generalized sleep-promoting role of NO within the PF-LHA and, given the sleep-promoting roles of adenosinergic and GABAergic systems in this area, further suggest that this effect may be mediated through nitrergic interactions with other neurotransmitters and neuromodulators. Published by Elsevier Ltd. on behalf of IBRO.