Increase of waking and reduction of NREM and REM sleep after nitric oxide synthase inhibition: prevention with GABA(A) or adenosine A(1) receptor agonists.
The effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of enzyme nitric oxide synthase (NOS), on spontaneous sleep during the light period, was studied in adult rats implanted for chronic sleep recordings. L-NAME was injected by subcutaneous (s.c.) route or was infused directly into the dorsal raphe nucleus (DRN). Subcutaneous (46.0--185.0 micromol/kg) administration of L-NAME increased waking (W), slow wave sleep (SWS) and rapid-eye-movement sleep (REMS) latency, whereas SWS, REMS and the number of REM periods were reduced. Direct application of L-NAME into the DRN (0.37--1.1 micromol) induced an increment of W and a reduction of SWS and REMS. Values corresponding to SWS and REMS latency, and the number of REM periods remained within control levels. Subcutaneous administration of the GABA(A) receptor agonist muscimol (1.7--3.5 micromol/kg) or the adenosine A(1) receptor agonist L-PIA [L(-)N(6)-(2-phenylisopropyl)adenosine] (0.1--0.3 micromol/kg) induced slight but inconsistent changes of W, light sleep (LS), SWS and REMS that did not attain significance. Pretreatment with muscimol (1.7--3.5 micromol/kg, s.c.) or L-PIA (0.1--0.3 micromol/kg, s.c.) antagonized the increase of W and reduction of SWS and REMS induced by s.c. (92.0 micromol/kg) or intra-DRN (0.74 micromol) administration of L-NAME. However, neither muscimol nor L-PIA prevented the increase of REMS latency induced by L-NAME 92.0 micromol/kg, s.c. Our findings tend to indicate that the change of behavioral state observed after systemic or intra-DRN administration of L-NAME is partly related to the reduction of GABA and adenosine at critical sites in the CNS.
Monti
J M
JM
Department of Pharmacology and Therapeutics, Clinics Hospital, 2833/602 Zudañez Street, Montevideo 11300, Uruguay. jmonti@mednet.org.uy
Jantos
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Monti
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D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D007279:Injections, Subcutaneous; D008297:Male; D008845:Microinjections; D009118:Muscimol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011903:Raphe Nuclei; D051381:Rats; D012890:Sleep / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects*
D004791:Enzyme Inhibitors; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D058906:Purinergic P1 Receptor Agonists; D009118:Muscimol; D010660:Phenylisopropyladenosine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester