FCSH - DS | Dissertações de Mestrado e Teses de Doutoramento
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- The role of cGMP on adenosine A1 receptor-mediated inhibition of synaptic transmission at the hippocampusPublication . Pinto, Isa Eunice Costa Figueiredo Paula; Cascalheira, José Francisco da Silva; Sebastião, AnaThe adenosine A1 receptor is highly expressed in hippocampus where it inhibits synaptic transmission and has neuroprotective activity. Similar actions are obtained by increasing the concentration of the second messenger cGMP and recently it was found that activation of adenosine A1 receptor increased cGMP levels in the nervous system, but the role of cGMP on adenosine A1 receptor mediated inhibition of synaptic transmission remains to be established. This work addressed if the adenosine A1 receptor inhibitory effect on neurotransmission is dependent on the cGMP pathway. To answer this question investigated in what extent increasing the levels of cGMP (with a phosphodiesterases inhibitor and a cGMP analog), or blocking the cGMP pathway (using nitric oxide synthase, protein kinase G and soluble guanylyl cyclase inhibitors) modify the inhibitory effect of an A1 receptor agonist on synaptic transmission. The hippocampal slice was used as an experimental model and neurotransmission evaluated through extracelular electrophysiological recording technique, specifically by measuring the slope of field excitatory postsynaptic potentials (fEPSPs) evoked by electrical stimulation. N6-cyclopentyladenosine (CPA, 15nM), a selective adenosine A1 receptor agonist, reversibly decreased the fEPSPs by 48% ± 2.1% (n=5; P<0.05). Incubation of the slices with a phosphodiesterase inhibitor Bay 60-7550 (100 nM), in order to prevent cGMP degradation, did not modify the CPA (15 nM) inhibitory effect on fEPSPs (50%±2.8%, n=5; P>0.05 when compared with CPA alone). The presence of a membrane-permeable analog of cGMP, 8-pCPTP-cGMP (10 µM), also did not significantly affect (P>0.05) the CPA (15nM) inhibitory effect on fEPSPs (59.0%±4.5% in the absence and 50%±8.6% in the presence of 8-pCTP-cGMP, n=4). On the other hand, inhibition of nitric oxide synthase (NOS) by L-NAME (200 µM) decreased (P<0.05) the CPA (15nM) inhibitory effect on fEPSPs (54%±5.3% in the absence and 23%±5.7% in the presence of L-NAME, n=5, female rats). In male rats, the presence of a Protein Kinase G (PKG) inhibitor (KT5823, 1nM) decreased the inhibitory effect of CPA (15nM) on fEPSPs by 45.0%±8.9% (n=4, P<0.05 compared with zero); similar results were obtained in females. Finally the effect of an inhibitor of soluble guanylyl cyclase (sGC), ODQ (10 µM), on the CPA (15 nM) inhibitory action on fEPSPs was investigated. In males ODQ decreased (P<0.05) the CPA inhibitory effect (50%±4.3% in the absence and 39%±6.0% in the presence of ODQ, n=4), but only when adenosine deaminase (1 U/ml) was present; similar results were found in females. In conclusion, the results strongly suggest that inhibitory action of adenosine A1 receptors on glutamatergic neurotransmission at the hippocampus is, at least partially, mediated by activation of the NOS/sGC/cGMP/PKG pathway.