Regulation of muscarinic acetylcholine receptor‐mediated synaptic responses by adenosine receptors in the rat hippocampus

Abstract

1. Intracellular current clamp recordings were made from CA1 pyramidal neurones in rat hippocampal slices. Experiments were performed in the presence of ionotropic glutamate receptor antagonists and ã-aminobutyric acid (GABA) receptor antagonists to block all fast excitatory and inhibitory synaptic transmission. A single stimulus, delivered extracellularly in the stratum oriens, caused a reduction in spike frequency adaptation in response to a depolarizing current step delivered 2 s after the stimulus. A 2-to 10-fold increase in stimulus intensity evoked a slow excitatory postsynaptic potential (EPSP) which was associated with a small increase in input resistance. The peak amplitude of the EPSP occurred approximately 2·5 s after the stimulus and its magnitude (up to 30 mV) and duration (10-50 s) increased with increasing stimulus intensity. 2. The slow EPSP was unaffected by the metabotropic glutamate receptor antagonist (+)-á-methyl-4-carboxyphenylglycine ((+)-MCPG; 1000 ìÒ) but was greatly enhanced by the acetylcholinesterase inhibitor physostigmine (1-5 ìÒ). Both the slow EPSP and the stimulus-evoked reduction in spike frequency adaptation were inhibited by the muscarinic acetylcholine receptor (mAChR) antagonist atropine (1-5 ìÒ). These results are consistent with these effects being mediated by mAChRs. 3. Both the mAChR-mediated EPSP (EPSPm) and the associated reduction in spike frequency adaptation were reversibly depressed (up to 97%) by either adenosine (100 ìÒ) or its nonhydrolysable analogue 2-chloroadenosine (CADO; 0·1-5·0 ìÒ). These effects were often accompanied by postsynaptic hyperpolarization (up to 8 mV) and a reduction in input resistance (up to 11%). The selective adenosine AÔ receptor agonists 2-chloro-NÉ-cyclopentyladenosine (CCPA; 0·1-0·4 ìÒ) and R(−)NÉ-(2-phenylisopropyl)-adenosine (R-PIA; 1 ìÒ) both depressed the EPSPm. In contrast, the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 0·5-1·0 ìÒ) did not significantly affect the EPSPm. 4. The selective adenosine AÔ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0·2 ìÒ) fully reversed the depressant effects of both adenosine (100 ìÒ) and CADO (1 ìÒ) on the EPSPm and the stimulus-evoked reductions in spike frequency adaptation. 5. DPCPX (0·2 ìÒ) alone caused a small but variable mean increase in the EPSPm of 22 ± 19% and enabled activation of an EPSPm by a previously subthreshold stimulus. In contrast, the selective adenosine kinase inhibitor 5-iodotubercidin (5-IT; 10 ìÒ) inhibited the EPSPm by 74 ± 10 %, an effect that was reversed by DPCPX. 6. The concentration-response relationship for the depressant action of CADO on the EPSPm more closely paralleled that for its presynaptic depressant action on glutamate-mediated EPSPs than that for postsynaptic hyperpolarization. The respective mean ICÛÑ and ECÛÑ concentrations for these effects were 0·3, 0·8 and 3·0 ìÒ. 7. CADO (1-5 ìÒ) did not have a significant effect on the postsynaptic depolarization, increase in input ...

Muscarinic stimulation of synaptic activity by protein kinase C is inhibited by adenosine in cultured hippocampal neurons

“…The receptors are mainly expressed in axons of hippocampal neurons (51). A recent report showed that in hippocampal slices adenosine blocks acetylcholine-activated excitatory responses through an A1-receptor dependent mechanism (52). Our results agree with a G protein-dependent inhibition of spontaneous glutamate release by adenosine in untreated cells as well as after potentiation of the release by PKC activation.…”

M1 and M4 Receptors Modulate Hippocampal Pyramidal Neurons

“…4 and Table 2). Similarly, wild-type, M1-lacking, and M3/M5-lacking neurons, but not neurons from M1/M3 double-knockout animals, showed small, but significant, increases in spike number following carbachol application, consistent with previous findings showing that mAChR stimulation reduces spike-frequency adaptation during current steps (Morton and Davies 1997). The mean increases in spike number following carbachol application were ϩ1.2 Ϯ 1.6, ϩ1.2 Ϯ 1.8, and ϩ1.9 Ϯ 2.7 spikes for wild-type, M1-lacking, and M3/M5-lacking neurons, respectively (P Ͻ 0.05 for each genotype; repeated-measures ANOVA with post-tests).…”

Effects of caffeine on learning and memory in rats tested in the Morris water maze

“…Adenosine A 1 receptors are expressed densely in the cerebral cortex and hippocampus (27,28). Activation of adenosine A 1 receptors strongly inhibits the release of acetylcholine from pyramidal hippocampal neurons (29)(30)(31). Acetylcholine has been shown to be important for memory storage (32).…”