Elsevier

Brain Research

Volume 650, Issue 2, 11 July 1994, Pages 260-266
Brain Research

Research report
Blockade of hippocampal M1 muscarinic receptors impairs working memory performance of rats

https://doi.org/10.1016/0006-8993(94)91790-6Get rights and content

Abstract

In order to clarify the roles of hippocampal M1 and M2 muscarinic receptors in working and reference memory performance of rats, the effects of intrahippocampal injections of selective antagonists at both receptors on this behavior were examined with a three-panel runway task. In the working memory task, the M1 muscarinic receptor antagonist pirenzepine, injected bilaterally at 0.32 and 1.0 μg/side into the dorsal hippocampus, significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points). This effect of intrahippocampal pirenzepine (1.0 μg/side) on working memory was attenuated by concurrent injection of 10 μg/side AF102B, the selective M1 muscarinic receptor agonist. Intrahippocampal injection of the M2 muscarinic receptor antagonist methoctramine at doses up to 1.0 μg/side had no significant effect on the number of working memory errors. Intrahippocampal methoctramine injection at 3.2 μg/side produced a significant increase in working memory errors, an effect that was reversed by concurrent injection of 10 μg/side AF102B. Concurrent injection of 0.32 μg/side methoctramine significantly reduced the increase in working memory errors induced by intrahippocampal pirenzepine (1.0 μg/side). In the reference memory task, neither pirenzepine nor methoctramine affected the number of errors when injected into the hippocampus at doses up to 1.0 and 3.2 μg/side, respectively. These results suggest that processes mediated by M1 muscarinic receptors in the hippocampus are involved in working memory, but not in reference memory, and that blockade of hippocampal M2 muscarinic receptors ameliorates working memory deficits produced by M1 muscarinic blockade, possibly by increasing acetylcholine release.

References (44)

  • MesulamM.-M. et al.

    Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6)

    Neuroscience

    (1983)
  • MichelA.D. et al.

    Methoctramine, a polymethylene tetraamine, differentiates three subtypes of muscarinic receptor in direct binding studies

    Eur. J. Pharmacol.

    (1988)
  • OhnoM. et al.

    Effect of the κ-receptor agonist, U-50,488H, on cerebral ischemia-induced impairment of working memory assessed in rats by a three-panel runway task

    Eur. J. Pharmacol.

    (1991)
  • OhnoM. et al.

    Deficits in working memory following inhibition of hippocampal nitric oxide synthesis in the rat

    Brain Res.

    (1993)
  • OhnoM. et al.

    Amygdaloid NMDA and muscarinic receptors involved in working memory performance of rats

    Physiol. Behav.

    (1993)
  • PackardM.G. et al.

    Post-training injection of the acetylcholine M2 receptor antagonist AF-DX 116 improves memory

    Brain Res.

    (1990)
  • RinneJ.O. et al.

    Brain muscarinic receptor subtypes are differentially affected in Alzheimer's disease and Parkinson's disease

    Brain Res.

    (1989)
  • SalaM. et al.

    Effect of centrally administered atropine and pirenzepine on radial arm maze performance in the rat

    Eur. J. Pharmacol.

    (1991)
  • SpencerD.G. et al.

    Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections

    Brain Res.

    (1986)
  • StillmanM.J. et al.

    Elevation of hippocampal extracellular acetylcholine levels by methoctramine

    Brain Res. Bull.

    (1993)
  • WilcockG.K. et al.

    Alzheimer's disease: correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities

    J. Neurol. Sci.

    (1982)
  • AraujoD.M. et al.

    Differential alteration of various cholinergic markers in cortical and subcortical regions of human brain in Alzheimer's disease

    J. Neurochem.

    (1988)
  • Cited by (68)

    • The restructuring of muscarinic receptor subtype gene transcripts in c-fos knock-out mice

      2013, Brain Research Bulletin
      Citation Excerpt :

      Muscarinic receptors play important roles in many CNS functions in humans (Ellis et al., 2006) and experimental animals (Bymaster et al., 1993), and these functions have been further confirmed using knock-out studies (Wess, 2003; Wess et al., 2003, 2007). Regarding specific muscarinic receptor subtypes, M1 (Yamasaki et al., 2010), M2 and M4 (Ohno et al., 1994; Tzavara et al., 2003) have been implicated in attention, arousal and cognitive processes. M2 receptors mediate whole body tremor, hypothermia and analgesia (Gomeza et al., 2001).

    • Differential effects of m1 and m2 receptor antagonists in perirhinal cortex on visual recognition memory in monkeys

      2012, Neurobiology of Learning and Memory
      Citation Excerpt :

      A probe test conducted twice in one animal with a much higher dose of methoctramine was also without effect: a mean error rate of 8% after infusing 10.0 mM of the drug vs. 9% after infusing saline. However, according to the in vitro binding data of Buckley et al. (1989), as well as the in vivo findings noted by Ohno et al. (1994), a concentration of methoctramine this high would be nonselective, and so we did not pursue testing this dose in the other animals). Two studies in rodents showed that insular cortex infusions of similar doses of pirenzepine (100 mM) and scopolamine (136–156 mM) led to similar levels of deficit in a conditioned taste aversion task (Naor & Dudai, 1996; Ramirez-Lugo, Miranda, Escobar, Espinosa, & Bermudez-Rattoni, 2003).

    • A role for protein kinase A and protein kinase Mζ in muscarinic acetylcholine receptor-initiated persistent synaptic enhancement in rat hippocampus in vivo

      2008, Neuroscience
      Citation Excerpt :

      Since medial septum cholinergic neurons are spontaneously active in the anesthetized rat there should be sufficient background source of ACh to tonically activate terminal autoreceptors (Apartis et al., 1998; Brazhnik and Fox, 1999). Indeed blockade of cholinergic autoreceptors by muscarinic receptor antagonists increases ACh release both in awake and anesthetized animals (Dudar, 1977; Stillman et al., 1993, 1996; Ohno et al., 1994; Quirion et al., 1995; Vannucchi et al., 1997; Carey et al., 2001). At some cholinergic synapses where there is tonic inhibition of ACh release via M2 receptors there is strong evidence that the activity-dependent initiation and termination of transmitter release is normally controlled by voltage-dependent regulation of the receptor’s coupling to key exocytotic machinery proteins and its affinity for ACh (Parnas and Parnas, 2007).

    View all citing articles on Scopus
    View full text