| Summary: | The aim of this investigation was to examine the mechanisms implicated in the processes of learning and memory in the rodent hippocampus using electrophysiological recording techniques to monitor CA1 pyramidal cell activity. In the presence of ionotropic glutamate and g-aminobutyric acid (GABA) receptor antagonists, stimulation of the septohippocampal cholingeric afferents, in <i>stratum oriens,</i> produced a slow excitatory postsynaptic potential (EPSP). Subsequent pharmacological classification established that this response was mediated by activation of muscarine acetylcholine receptors (mAChR) and as such this response was termed an EPSP<sub>M</sub>. Specific blockers of voltage-gated Ca<sup>2+ </sup>channels, w-conotoxin GVIA and w-agatoxin IVA, revealed that the release of ACh necessary to evoke the EPSP<sub>M</sub> was mediated by activation of both N- and P/Q-type Ca<sup>2+ </sup>channels. Blockade of presynaptic 4-AP-senstivie K<sup>+</sup> channels further enhanced the release of ACh. A previous report had shown that mAChR-mediated synaptic transmission could be modulated by adenosine A<sub>1</sub> receptor activation but had not examined the precise cellular mechanisms underlying this effect. Investigations have revealed that the activation of A<sub>1</sub> receptors inhibited the EPSP<sub>M</sub> irrespective of the Ca<sup>2+ </sup>channel supporting this response and that there maybe a partial involvement of 4-AP sensitive K<sup>+</sup> channels. As adenosine A<sub>1</sub> receptors are known to act via the G-protein, G<sub>i/o</sub>, we also investigated the involvement of cAMP in the inhibition of the EPSP<sub>M</sub>. It was demonstrated that forskolin stimulated increases in cAMP partially occluded and 8-Br cAMP application fully occluded the adenosine A<sub>1</sub> receptor-mediated inhibition of the EPSP<sub>M</sub>. Most synapses are under the regulation of a variety of GPCRs. In this respect we also demonstrated that opioid receptor agonists could modulate the EPSP<sub>M</sub>. Interestingly, it was found that opioid agonists acting at a presynaptic m-opioid receptor caused an enhancement of the EPSP<sub>M</sub> although the mechanism of how this is achieved is unclear.
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