STUDIES ON THE INTERACTION BETWEEN PRESYNAPTIC ALPHA-2-ADRENOCEPTORS AND ADENOSINE-A1-RECEPTORS LOCATED ON NORADRENERGIC NERVE-TERMINALS

The aim of the present study was to obtain a more detailed understanding of the interaction between presynaptic alpha-2-adrenoceptors and A1 adenosine receptors mediating inhibition of noradrenaline release in the central nervous system. Slices of rabbit hippocampus, prelabelled with [H-3]noradrenaline, were superfused in the presence of the re-uptake inhibitor (+)-oxaprotiline and electrically stimulated during superfusion. During stimulation with 36 pulses at 3 Hz the alpha-2-adrenoceptor antagonist yohimbine induced a five-fold increase of noradrenaline release indicating a pronounced autoinhibition of approximately 80%. In these experiments the inhibition of release caused by R-PIA, a preferential A1 agonist, as well as its facilitation caused by DPCPX, a selective A1 antagonist, were smaller in comparison to the effects of these compounds on release virtually free of autoinhibition (i.e. by stimulating the tissue with 4 pulses at 100 Hz (POP-stimulation) or with 36 pulses at 3 Hz in presence of yohimbine). Clonidine, an alpha-2-adrenoceptor agonist, was used to impose a distinct alpha-2-adrenoceptor-mediated inhibition of release elicited by POP-stimulation. Only, however, in the presence of 30 nmol/l clonidine, causing maximum inhibition of approximately 80% of H-3-overflow, but not in the presence of 6 nmol/l clonidine, causing approximately 50% inhibition, a significant diminution of the inhibitory effect of R-PIA was seen. Similarly, the alpha-2-adrenoceptor mechanism was affected only by 10-mu-mol/l R-PIA causing maximum inhibition of approximately 80%, but remained unchanged in the presence of 30 nmol/l R-PIA diminishing release by 50%. In addition, the alpha-2-adrenoceptor-mediated inhibition remained unaffected in the presence of DPCPX, indicating that the concentration of endogenous adenosine attained was not sufficient to influence the alpha-2-adrenoceptor mechanism. In conclusion, the present results suggest that activation of the presynaptic alpha-2 and A1 receptors inhibits depolarization-induced noradrenaline release in an additive manner. Only extensive (near maximal or maximal) activation of one receptor mechanism impairs the inhibition due to activation of the other.