Summary
Modulation of acetylcholine release via adenosine receptors was studied in rabbit hippocampal slices, which were preincubated with 3H-choline and then continuously superfused. Electrical field stimulation of the slices elicited a release of acetylcholine, which was inhibited in a concentration-dependent manner by various adenosine receptor agonists. The effects of the agonists were antagonized by the methylxanthines. From the order of potency: cyclohexyladenosine > (−)phenylisopropyl-adenosine ((−)PIA) > 5′-N-ethylcarboxamideadenosine (NECA) > 2-chloradenosine > (+)phenylisopropyladenosine > adenosine, the inhibitory adenosine receptor may be classified as A1-(R1-)receptor. In experiments on rabbit caudate nucleus slices, adenosine receptor agonists only slightly decreased the evoked acetylcholine release.
The presence of an inhibitory tone of endogenous adenosine on hippocampal acetylcholine release is supported by the following findings: 1) the methylxanthines theophylline, 8-phenyltheophylline and 3-isobutylmethyl-xanthine (IBMX) increased the evoked acetylcholine release in concentrations below those required for phosphodiesterase inhibition. 2) Adenosine uptake inhibitors, in contrast, decreased the evoked transmitter release. 3) Deamination of endogenous adenosine by addition of adenosine deaminase to the medium enhanced the acetylcholine release.
In conclusion, acetylcholine release in the hippocampus is depressed at the level of the cholinergic nerve terminals by endogenous adenosine via A1-(Ri-)receptors.
Similar content being viewed by others
References
Bruns RF, Daly JW, Snyder SH (1980) Adenosine receptors in brain membranes: binding of N6-cyclohexyl(3H)adenosine and 1,3-diethyl-8-(3H)phenylxanthine. Proc Natl Acad Sci USA 77:5547–5551
Burnstock G, Brown CM (1981) An introduction to purinergic receptors. In: Burnstock G (ed) Purinergic receptors. Chapman & Hall, London, New York, pp 1–45
Dunwiddie TV, Hoffer BJ, Fredholm BB (1981) Alkylxanthines elevate hippocampal excitability — evidence for a role of endogenous adenosine. Naunyn-Schmiedeberg's Arch Pharmacol 316:326–330
Fredholm BB, Hedqvist P (1980) Modulation of neurotransmission by purine nucleotides and nucleosides. Biochem Pharmacol 29:1635–1643
Fredholm BB, Fuxe K, Agnati L (1976) Effect of some phosphodiesterase inhibitors on central dopamine mechanisms. Eur J Pharmacol 38:31–38
Fredholm BB, Jonzon B, Lindgren E, Lindström K (1982) Adenosine receptors mediating cAMP production in the rat hippocampus. J Neurochem 39:165–175
Fredholm BB, Jonzon B, Lindström K (1983) Adenosine receptor mediated increases and decreases in cyclic AMP in hippocampal slices treated with forskolin. Acta Physiol Scand 117:461–463
Fredholm BB, Dunwiddie TV, Bergman B, Lindström K (1984) Levels of adenosine and adenine nucleotides in slices of rat hippocampus. Brain Res 295:127–136
Goodman RR, Kuhar MJ, Hester L, Snyder SH (1983) Adenosine receptors: Autoradiographic evidence for their location on axon terminals of excitatory neurons. Science 220:967–969
Harms HH, Wardeh G, Mulder AH (1979) Effects of adenosine on depolarization-induced release of various radiolabelled neurotransmitters from slices of rat corpus striatum. Neuropharmacology 18:577–580
Helland S, Broch OJ, Ueland PM (1983) Neurotoxicity of deoxycoformycin: effect of constant infusion on adenosine deaminase, adenosine, 2′-deoxyadenosine and monoamines in the mouse brain. Neuropharmacology 22:915–917
Helmreich I, Reimann W, Hertting G, Starke K (1982) Are presynaptic dopamine autoreceptors and postsynaptic dopamine receptors in the rabbit caudate nucleus pharmacologically different? Neuroscience 7:1559–1566
Hertting G, Zumstein A, Jackisch R, Hoffmann I, Starke K (1980) Modulation by endogenous dopamine of the release of acetylcholine in the caudate nucleus of the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 315:111–117
Jackisch R, Strittmatter H, Fehr R, Hertting G (1983) Modulation of hippocampal noradrenaline and acetylcholine release by endogenous adenosine. Naunyn-Schmiedeberg's Arch Pharmacol 324:R20
Jackisch R, Werle E, Hertting G (1984) Identification of mechanisms involved in the modulation of adrenaline release from rabbit hippocampus in vitro. Neuropharmacology (in press)
Lee KS, Schubert P, Reddington M, Kreutzberg GW (1983) Adenosine receptor density and the depression of evoked neuronal activity in the rat hippocampus in vitro. Neurosci Lett 37:81–85
Londos C, Cooper DMF, Wolff J (1980) Subclasses of adenosine receptors. Proc Natl Acad Sci USA 77:2552–2554
Londos C, Wolff J, Cooper DMF (1983) Adenosine receptors and adenylate cyclase interactions. In: Berne RM, Rall TW, Rubio R (eds) Regulatory function of adenosine. Martinus Nijhoff, The Hague, Boston, London, pp 17–32
McGeer PL, McGeer EG, Fibiger HC, Wickson V (1971) Neostriatal choline acetylase and cholinesterase following selective brain lesions. Brain Res 35:308–314
Murphy KMM, Snyder SH (1982) Heterogeneity of adenosine A1 receptor binding in brain tissue. Mol Pharmacol 22:250–257
Murray TF, Cheney DL (1982) Neuronal location of N6-cyclohexyl-(3H)-adenosine binding sites in rat and guinea pig brain. Neuropharmacology 21:575–580
Murray TF, Blaker WD, Cheney DL, Costa E (1982) Inhibition of acetylcholine turnover rate in rat hippocampus and cortex by intraventricular injection of adenosine analogs. J Pharmacol Exp Ther 222:550–554
Nimit Y, Skolnick P, Daly JW (1981) Adenosine and cAMP in rat cerebral cortical slices: effects of adenosine uptake inhibitors and adenosine deaminase inhibitors. J Neurochem 36:908–912
Pedata F, Pepeu G (1981) Effect of adenosine on acetylcholine output from electrically stimulated brain slices. Br J Pharmacol 74:764P
Pedata F, Antonelli T, Lambertini L, Beani L, Pepeu G (1983a) Effect of adenosine, adenosine triphosphate, adenosine deaminase, dipyridamole and aminophylline on acetylcholine release from electrically-stimulated brain slices. Neuropharmacology 22:609–614
Pedata F, Pepeu G, Spignoli G (1983b) Effects of methylxanthines on acetylcholine release from electrically-stimulated cortical slices. Br J Pharmacol 80:471P
Phillis JW, Edstrom JP (1976) Effects of adenosine analogs on rat cerebral cortical neurons. Life Sci 19:1041–1054
Phillis JW, Wu PH (1982) The effect of various centrally active drugs on adenosine uptake by the central nervous system. Comp Biochem Physiol 72C:179–187
Pons F, Bruns RF, Daly JW (1980) Depolarization-evoked accumulation of cAMP in brain slices: the requisite intermediate adenosine is not derived from hydrolysis of released ATP. J Neurochem 35:1319–1323
Radulovacki M, Virus RM, Djuricic-Nedelson M, Green RD (1984) Adenosine analogs and sleep in rats. J Pharmacol Exp Ther 228:268–274
Schubert P, Lee K, Kreutzberg GW (1982) Neuronal release of adenosine derivatives and modulation of signal processing in the CNS. Prog Brain Res 55:225–238
Schwabe U, Trost T (1980) Characterization of adenosine receptors in rat brain by (−)(3H)N6-phenylisopropyladenosine. Naunyn-Schmiedeberg's Arch Pharmacol 313:179–187
Segal M (1982) Intracellular analysis of postsynaptic action of adenosine in the rat hippocampus. Eur J Pharmacol 79:193–199
Skolnick P, Nimitkitpaisan Y, Stalvey L, Daly JW (1978) Inhibition of brain adenosine deaminase by 2′-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine. J Neurochem 30:1579–1582
Smellie FW, Daly JW, Dunwiddie TV, Hoffer BJ (1979a) The dextro and levorotatory isomers of N-phenylisopropyladenosine: stereospecific effects on cAMP formation and evoked synaptic responses in brain slices. Life Sci 25:1739–1748
Smellie FW, Davis CW, Daly JW, Wells JN (1979b) Alkylxanthines: inhibition of adenosine-elicited accumulation of cAMP in brain slices and of brain phosphodiesterase activity. Life Sci 24:2475–2482
Spignoli G, Pedata F, Pepeu G (1984) A1 and A2adenosine receptos modulate acetylcholine release from brain slices. Eur J Pharmacol 97:341–342
Stone TW (1981) Physiological roles for adenosine and adenosine 5′-triphophate in the nervous system. Neuroscience 6:523–555
Storm-Mathisen J (1977) Localization of putative transmitters in the hippocampal formation. With a note on the connections to septum and hypothalamus. Ciba Found Symp 58:49–86
Strittmatter H, Jackisch R, Hertting G (1982) Role of dopamine receptors in the modulation of acetylcholine release in the rabbit hippocampus. Nauny-Schmiedeberg's Arch Pharmacol 321:195–200
Van Calcker D, Müller M, Hamprecht B (1979) Adenosine regulates via two different receptors, the accumulation of cAMP in cultured brain cells. J Neurochem 33:999–1005
Vizi ES, Knoll J (1976) The inhibitory effect of adenosine and related nucleotides on the release of acetylcholine. Neuroscience 1:391–398
Wojcik WJ, Neff NH (1982) Adenosine measurement by a rapid HPLC-fluorometric method: induced changes of adenosine content in regions of rat brain. J Neurochem 39:280–282
Wojcik WJ, Neff NH (1983) Adenosine A1 receptors are associated with cerebellar granule cells. J Neurochem 41:759–763
Yeung S-MH, Green RD (1984) (3H)5′-N-ethylcarboxamide adenosine bind to both Ra and Ri adenosine receptors in rat striatum. Naunyn-Schmiedeberg's Arch Pharmacol 325:218–225
Zetterström T, Vernet L, Ungerstedt U, Tossman U, Jonzon B, Fredholm BB (1982) Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci Lett 29:111–115
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jackisch, R., Strittmatter, H., Kasakov, L. et al. Endogenous adenosine as a modulator of hippocampal acetylcholine release. Naunyn-Schmiedeberg's Arch. Pharmacol. 327, 319–325 (1984). https://doi.org/10.1007/BF00506243
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00506243