Interaction of forskolin with the effect of N-6-cyclopentyladenosine on norepinephrine release in rat hippocampus

ABSTRACT

As it has been reported that the depolarization-induced norepinephrine (NE) release is modulated by activation of presynaptic A-1-adenosine heteroreceptor and various lines of evidence indicate the involvement of adenylate cyclase system in A-1-adenosine post-receptor mechanism in hippocampus, it was attempted to delineate the role of adenylate cyclase system in the A-1-receptor-mediated control of NE release in this study. Slices from rat hippocampus were equilibrated with (3H)-NE and the release of the labelled products was evoked by electrical stimulation (3 Hz, 5 V cm-1, 2 ms, rectangular pulses). The influence of various agents on the evoked tritium-outflow was investigated. N-6-Cyclopentyladenosine (CPA), a specific A-1-adenosine receptor agonist, in concentrations ranging from 0.1 to 10 micrometer decreased the (3H)-NE release in a dose-dependent manner without any change of basal rate of release. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 micrometer), a selective A-1-receptor antagonist, inhibited the CPA effect. The responses to N-ethylmaleimide (3 & 10 micrometer), a SH-alkylating agent of G-protein, were characterized by increments of the evoked NE-release and the CPA effects were completely abolished by NEM pretreatment. Forskolin, a specific adenylate cyclase activator, in concentrations ranging from 0.1 to 30 micrometer increased the evoked and basal rate of NE release in a dose-dependent manner and the CPA effects were inhibited by forskolin pretreatment. Rolipram (1 & 10 micrometer), a phosphodiesterase inhibitor, did not affect the evoked NE release, but reduced the CPA effect. And 8-bromo-cAMP (100 & 300 micrometer), a membrane permeable cAMP analogue, inhibited the CPA effect significantly. These results suggest that the A-1-adenosine heteroreceptor plays an important role in NE-release via nucleotide-binding protein G-i in the rat hippocampus and that the adenylate cyclase system might be participated in this process.