Elsevier

Neuropharmacology

Volume 41, Issue 5, October 2001, Pages 565-573
Neuropharmacology

Opioid receptor regulation of muscarinic acetylcholine receptor-mediated synaptic responses in the hippocampus

https://doi.org/10.1016/S0028-3908(01)00108-3Get rights and content

Abstract

A common feature of many synapses is their regulation by neurotransmitters other than those released from the presynaptic terminal. This aspect of synaptic transmission is often mediated by activation of G protein coupled receptors (GPCRs) and has been most extensively studied at amino acid-mediated synapses where ligand gated receptors mediate the postsynaptic signal. Here we have investigated how opioid receptors modulate synaptic transmission mediated by muscarinic acetylcholine receptors (mAChRs) in hippocampal CA1 pyramidal neurones. Using a cocktail of glutamate and γ-amino-butyric acid (GABA) receptor antagonists a slow pirenzepine-sensitive excitatory postsynaptic potential (EPSPM) that was associated with a small increase in cell input resistance could be evoked in isolation. This response was enhanced by the acetylcholine (ACh) esterase inhibitor physostigmine (1 μM) and depressed by the vesicular ACh transport inhibitor vesamicol (50 μM). The μ-opioid receptor agonists DAMGO (1–5 μM) and etonitazene (100 nM), but not the δ- and κ-opioid receptor selective agonists DTLET (1 μM) and U-50488 (1 μM), potentiated this EPSPM (up to 327%) without affecting cell membrane potential or input resistance; an effect that was totally reversed by naloxone (5 μM). In contrast, postsynaptic depolarizations and increases in cell input resistance evoked by carbachol (3 μM) were unaffected by DAMGO (1–5 μM) but were abolished by atropine (1 μM). Taken together these data provide good evidence for a μ-opioid receptor-mediated presynaptic enhancement of mAChR-mediated EPSPs in hippocampal CA1 pyramidal neurones.

Introduction

A particularly common feature of synaptic transmission is its regulation by a range of G protein coupled receptors (GPCRs) (Thompson et al., 1993, Freund and Buzsáki, 1996). Presynaptically, this regulation involves the inhibition/enhancement of one, or more, of the processes involved in converting presynaptic action potential firing into transmitter release (Thompson et al., 1993). However, GPCRs can also regulate synaptic transmission by postsynaptic mechanisms (Harvey and Collingridge, 1993, Harvey et al., 1993). Irrespective of the mechanism employed, GPCRs have the capacity to both negatively and positively control synaptic activity. This regulation is exceptionally elegant in that at each synapse it is specifically tailored to the function of that particular synapse. Thus, for example, two synapses using the same neurotransmitter but impinging on different somatodendritic aspects of the same target neurone can exhibit different profiles of regulation by distinct populations of GPCRs (Lambert and Wilson, 1993, Pearce et al., 1995, Svoboda et al., 1999).

Whilst this type of synaptic control has been commonly studied using pharmacological regimes many of the receptor systems controlling synaptic transmission can be activated by endogenously released neurotransmitters (Deisz and Prince, 1989, Thompson and Gähwiler, 1989, Davies et al., 1990, Davies et al., 1991, Nathan and Lambert, 1991, Davies and Collingridge, 1993, Isaacson et al., 1993, Davies and Collingridge, 1996, Ziakopoulos et al., 2000). In certain cases the neurotransmitter involved originates from the active terminal giving rise to the postsynaptic response itself. In others it is provided by distant terminals that may not necessarily by themselves innervate the target neurone under study (Isaacson et al., 1993, Ziakopoulos et al., 2000). As such, the effectiveness of a synaptic input to modulate the excitability of its target neurone is critically dependent upon several factors including: (1) the complement of GPCRs expressed both on the terminal of the input as well as in proximity to the postsynaptic receptors mediating the synaptic response and (2) the temporal and spatial patterns of its own activation put in the context of that of others.

To define the latter in terms of what occurs physiologically in vivo and, therefore, to enable predictions to be made as to the physiological effects of drugs which modify GPCR function is clearly problematic. As a result, the first step to unravelling this complex puzzle is to establish the precise complement of pre- and postsynaptic receptors that regulate the efficiency and activity of individual synapses. This has been performed most extensively for synapses that utilize ligand gated receptors as the postsynaptic effector, e.g. ATPergic (Robertson and Edwards, 1998), glutamatergic (Thompson and Gähwiler, 1992, Thompson et al., 1992) and GABAergic synapses (Davies et al., 1990, Lambert et al., 1991, Behrends and Ten Bruggencate, 1993, Manuel and Davies, 1998). However, relatively few studies have investigated the regulation of GPCR-mediated synaptic inputs. The aim of the present study, therefore, is to examine how opioid receptor activation modifies mAChR-mediated synaptic transmission in the hippocampus. Some of these data have appeared previously in abstract form (Kearns et al., 1999).

Section snippets

Materials and methods

Female Wistar rats (2–4 weeks old) were sacrificed using Schedule 1 UK Home Office procedures. The brain was removed rapidly and transverse hippocampal slices prepared by hemisecting the whole brain minus the cerebellum and cutting 400 μm thick transverse slices containing hippocampal slices using a vibroslicer (Campden Instruments, Loughborough, UK). The resultant slices were placed on a nylon mesh at the interface of a warmed (32–34°C), perfusing (1–2 ml min−1) artificial cerebrospinal fluid and

Results

Data were obtained from 40 stable intracellular recordings (1–6 h) from CA1 pyramidal neurones with overshooting action potentials, resting membrane potentials more negative than −55 mV and input resistance values of 30 MΩ or greater.

μ-Opioid receptor activation inhibits cholinergic synaptic transmission

The data presented here confirm that stimulation in stratum oriens in the presence of a cocktail of amino acid receptor antagonists can evoke a slow EPSP (Cole and Nicoll, 1983, Cole and Nicoll, 1984). That this response is: (1) antagonized by both the selective mAChR antagonist pirenzepine and the ACh vesicular transporter inhibitor vesamicol, and (2) enhanced by physostigmine demonstrates that it is mediated by ACh activation of mAChRs. Whilst pirenzepine exhibits selectivity for the M1

Concluding remarks

Whatever the mechanism by which μ-opioid receptors enhance the EPSPM, activation of this receptor subtype provides a very effective means of enhancing excitability in the hippocampal CA1 region through this cholinergic input. This promotion of excitability is synergistic to that afforded by the depression of GABAergic synaptic transmission mediated by activation of μ-opioid receptors on inhibitory interneurones (Zieglgansberger et al., 1979, Madison and Nicoll, 1988, Lambert et al., 1991,

Acknowledgements

We thank Dr Mario F. Pozza (Novartis, Basle, Switzerland) for CGP 55845A and CGP 40116. This work was supported by the Wellcome Trust.

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