Activation of Pedunculopontine Tegmental PKA Prevents GABAB Receptor Activation–Mediated Rapid Eye Movement Sleep Suppression in the Freely Moving Rat

Abstract

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 GABAB receptors suppressed REM sleep by inhibiting REM-on cells. One of the important mechanisms for GABAB 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 GABAB receptor activation–mediated REM sleep suppression effect could be mediated through inhibition of cAMP-PKA activation. To test this hypothesis, a GABAB 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 ∼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 GABAB receptor activation–mediated REM sleep suppression effect. These findings suggest that the PPT GABAB receptor activation–mediated REM sleep regulating mechanism involves inactivation of cAMP-PKA signaling in the freely moving rat.