Ž . Brain Research 829 1999 193–196 Short communication Occlusive responses to adenosine A1 receptor and muscarinic M2 receptor activation on hippocampal presynaptic terminals M.-R. Nikbakht, T.W. Stone ) Institute of Biomedical and Life Sciences, West Medical Building, UniÕersity of Glasgow, Glasgow G12 8QQ, Scotland, UK Accepted 9 March 1999 Abstract There is substantial evidence for an interaction between adenosine A1 and muscarinic M1rM3 receptors in some tissues, either at the level of the receptors themselves or at the associated transduction system. We have now addressed the question of whether there is a Ž . similar interaction between A1 and presynaptic M2 receptors in the hippocampus. The effects of cyclopentyladenosine CPA were studied alone or in combination with the M2 receptor agonist oxotremorine-M. The ability of both to depress synaptic transmission presynaptically at the concentrations used was confirmed using paired-pulse inhibition. When combined at a range of concentrations, the effects of the two agents were less than additive, suggesting that they are acting by a common transduction system. The results indicate that the modulatory, antagonistic effects of A1 adenosine receptors are exerted not only on postjunctional M1rM3 receptors but also at M2 presynaptic receptors. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Adenosine; Purines; Acetylcholine; Muscarinic; Paired-pulse interactions Adenosine is able to modulate neuronal activity in the central nervous system by acting at presynaptic and post- Ž w x . synaptic sites see Refs. 33,34 for reviews . The presy- naptic sites may be a combination of A1 and A2 receptors, activation of the former generally inhibiting the release of w x neurotransmitters such as glutamate 8,13,29 , acetyl- w x w x w x choline 32 , dopamine 27,39 , serotonin 14 and nor- w x epinephrine 21 . The A2 receptors tend to increase trans- w x mitter release 9,22,32 . Postsynaptically adenosine and its w x analogues can increase potassium 16,36 and chloride w x w x conductances 1,25 to produce hyperpolarisation 2,35 . In addition, adenosine is able to modulate neuronal sensitivity to classical neurotransmitters such as acetyl- choline. In the rabbit gastric muscle, adenosine enhances w x sensitivity to acetylcholine 15 . On neurones, adenosine can enhance or depress acetylcholine sensitivity. Brooks wx and Stone 7 reported the ability of adenosine to suppress carbachol-induced excitation of hippocampal pyramidal neurones, while on Helix neurones adenosine has a bipha- sic action, facilitating acetylcholine responses at low con- centrations and depressing it at higher concentrations by reducing a calcium current associated with the acetyl- ) Corresponding author. Fax: q44-141-330-4100; E-mail: t.w.stone@bio.gla.ac.uk w x choline response 10,11 . Conversely, the adenosine-media- ted hyperpolarisation of CA3 neurones is suppressed by wx low concentrations of muscarinic agonists 4 . Interactions have been demonstrated at the level of intracellular trans- duction systems. Activators of protein kinase C, for exam- ple, prevent the inhibition of adenylate cyclase by adeno- w x sine 28 . Studies specifically of presynaptic receptors have con- cluded that adenosine A1 receptors are able to suppress the protein kinase C-mediated stimulatory effect of muscarinic receptors on glutamate release in hippocampal neurones, wx an effect which involves M1 receptors 5 . However, the major muscarinic receptor responsible for cholinergic inhi- bition of transmitter release is the M2 subtype and, in the periphery, there is evidence that the regulation of potas- sium conductance by M2 muscarinic receptors is modu- wx lated by adenosine 6 . The present work was designed specifically to address the question of whether any interac- tion occurs between the presynaptic A1 and M2 receptors with respect to transmitter release from hippocampal neu- rones. Ž . Male Wistar rats 150 to 250 g were anaesthetised with urethane and killed by cervical dislocation. The prepara- tion of tissue and the recording system were similar to w x those described previously 19,20 . Briefly, hippocampal Ž . slices were prepared 450 mm thick in artificial CSF ACSF 0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 01365-7