Activation of pedunculopontine tegmental PKA prevents GABAB receptor activation-mediated rapid eye movement sleep suppression in the freely moving rat.
The pedunculopontine tegmental (PPT) GABAergic system plays a crucial role in the regulation of rapid eye movement (REM) sleep. I recently reported that the activation of PPT GABA(B) receptors suppressed REM sleep by inhibiting REM-on cells. One of the important mechanisms for GABA(B) receptor activation-mediated physiological action is the inhibition of the intracellular cAMP-dependent protein kinase A (cAMP-PKA) signaling pathway. Accordingly, I hypothesized that the PPT GABA(B) receptor activation-mediated REM sleep suppression effect could be mediated through inhibition of cAMP-PKA activation. To test this hypothesis, a GABA(B) receptor selective agonist, baclofen hydrochloride (baclofen), cAMP-PKA activator, Sp-adenosine 3',5'-cyclic monophosphothioate triethylamine (SpCAMPS), and vehicle control were microinjected into the PPT in selected combinations to determine effects on sleep-waking states of chronically instrumented, freely moving rats. Microinjection of SpCAMPS (1.5 nmol) induced REM sleep within a short latency (12.1 +/- 3.6 min) compared with vehicle control microinjection (60.0 +/- 6.5 min). On the contrary, microinjection of baclofen (1.5 nmol) suppressed REM sleep by delaying its appearance for approximately 183 min; however, the suppression of REM sleep by baclofen was prevented by a subsequent microinjection of SpCAMPS. These results provide evidence that the activation of cAMP-PKA within the PPT can successfully block the GABA(B) receptor activation-mediated REM sleep suppression effect. These findings suggest that the PPT GABA(B) receptor activation-mediated REM sleep regulating mechanism involves inactivation of cAMP-PKA signaling in the freely moving rat.
Datta
Subimal
S
Sleep and Cognitive Neuroscience Lab., Dept. of Psychiatry, Boston Univ. School of Medicine, M-902, 715 Albany St., Boston, MA 02118, USA. SUBIMAL@BU.EDU
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D008297:Male; D008845:Microinjections / Q000379:methods; D045042:Pedunculopontine Tegmental Nucleus / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000502:physiology*; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014851:Wakefulness
D018755:GABA Agonists; D047428:Protein Kinase Inhibitors; D018079:Receptors, GABA; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D001418:Baclofen