Zaprinast stimulates extracellular adenosine accumulation in rat pontine slices.
Adenosine appears to be an endogenous somnogen. The lateral dorsal tegmental/pedunculopontine nucleus (LDT/PPT) located in the mesopontine tegmentum is important in the regulation of arousal. Neurons in this nucleus are strongly hyperpolarized by adenosine and express neuronal nitric oxide synthase. Zaprinast is a cyclic nucleotide phosphodiesterase inhibitor, and has been shown in the hippocampal slice to inhibit the field excitatory postsynaptic potential. This action could be blocked by an adenosine receptor antagonist, and therefore is presumably due to adenosine release stimulated by zaprinast. In the present study we tested the effect of zaprinast on extracellular adenosine accumulation in pontine slices containing the LDT. Zaprinast at 10 microM evoked an increase in extracellular adenosine concentration. This effect was blocked by impermeant inhibitors of 5'-nucleotidase, indicating that the extracellular adenosine was derived from extracellular AMP. However, inhibitors of cAMP degradation had little or no effect on zaprinast-evoked adenosine accumulation, suggesting that extracellular cAMP was not the source. Removal of extracellular calcium inhibited the effect of zaprinast. These results demonstrate that a pathway exists by which zaprinast stimulates extracellular adenosine accumulation, and the presence of this pathway in the pontine slice suggests the possibility that it may be relevant for the regulation of behavioral state.
Le
Minou
M
Department of Neurology and Program in Neuroscience, Enders Research Building, Room 349, Children's Hospital and Harvard Medical School, Longwood Avenue, Boston, MA 02115, USA.
Lu
Yin
Y
Li
Ya
Y
Greene
Robert W
RW
Epstein
Paul M
PM
Rosenberg
Paul A
PA
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D066298:In Vitro Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011149:Pons / Q000187:drug effects* / Q000378:metabolism*; D011688:Purinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D000242:Cyclic AMP; C011145:zaprinast; D006152:Cyclic GMP; D000241:Adenosine