Neuropharmacology 41 (2001) 565–573 www.elsevier.com/locate/neuropharm Opioid receptor regulation of muscarinic acetylcholine receptor- mediated synaptic responses in the hippocampus I.R. Kearns a , R.A. Morton a , D.O. Bulters a , C.H. Davies a, b,* a Department of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh, Scotland EH8 9JZ, UK b Neurology-CEDD, GlaxoSmithKline, New Frontiers Science Park North, Third Avenue, Harlow, Essex CM19 5AW, UK Received 4 January 2001; received in revised form 11 June 2001; accepted 19 July 2001 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 (EPSP M ) 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 physostig- mine (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 -opioid receptor selective agonists DTLET (1 μM) and U-50488 (1 μM), potentiated this EPSP M (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.  2001 Elsevier Science Ltd. All rights reserved. Keywords: Acetylcholine; μ-Opioid receptor; Hippocampus; Muscarinic acetylcholine receptor; Excitatory postsynaptic potential; Memory 1. Introduction A particularly common feature of synaptic trans- mission is its regulation by a range of G protein coupled receptors (GPCRs) (Thompson et al., 1993; Freund and Buzsa ´ki, 1996). Presynaptically, this regulation involves the inhibition/enhancement of one, or more, of the pro- cesses involved in converting presynaptic action poten- tial 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. * Corresponding author. Tel.: +44-1279-622-999; fax: +44-1279- 622-555. E-mail address: ceriF2Fdavies@gsk.com (C.H. Davies). 0028-3908/01/$ - see front matter  2001 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(01)00108-3 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 differ- ent 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 com- monly studied using pharmacological regimes many of the receptor systems controlling synaptic transmission can be activated by endogenously released neuro- transmitters (Deisz and Prince, 1989; Thompson and Ga ¨hwiler, 1989; Davies et al., 1990, 1991; Nathan and Lambert, 1991; Davies and Collingridge, 1993, 1996; Isaacson et al., 1993; Ziakopoulos et al., 2000). In cer- tain cases the neurotransmitter involved originates from the active terminal giving rise to the postsynaptic response itself. In others it is provided by distant ter-