The M1 Muscarinic Agonist CI-1017 Facilitates Trace Eyeblink Conditioning in Aging Rabbits and Increases the Excitability of CA1 Pyramidal Neurons

Weiss, Craig; Preston, Alison R.; Oh, M. Matthew; Schwarz, Roy D.; Welty, Devin; Disterhoft, John F.

doi:10.1523/jneurosci.20-02-00783.2000

Cited by 79 publications

(56 citation statements)

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“…It has been reported that mAChR agonists cause depolarization of hippocampal CA1 pyramidal neurons through activation of M 1 mAChRs (Weiss et al, 2000). Indeed, in rat hippocampal slices, carbachol induced pirenzepine-sensitive single-unit firing in the CA1 region, suggesting that it produced its response through activation of M 1 mAChRs.…”

Section: Discussionmentioning

confidence: 92%

Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1

Langmead

Austin

Branch

et al. 2008

British J Pharmacology

122

137

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Background and purpose: M 1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtypeselective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-nbutyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M 1 mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. Experimental approach: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. Key results: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M 1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M 1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. Conclusions and implications: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M 1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M 1 mAChR. (2008) 154, 1104-1115 doi:10.1038/bjp.2008 published online 5 May 2008 Keywords: muscarinic receptors; selective agonist; allosteric; AC-42; 77-LH-28-1; calcium mobilization; inositol phosphate; cell firing; network oscillations There is a wide array of pharmacological tools with which to study mAChRs. For example, N-methyl scopolamine, quinuclidinylbenzilate, pirenzepine and darifenacin are among numerous mAChR antagonists, and ACh and oxotremorine-M among mAChR agonists, which have been used in unlabelled and radiolabelled forms to characterize the localization, pharmacology and function of mAChRs. Unfortunately, most of these pharmacological tools exhibit poor selectivity between mAChR subtypes (Caulfield and Birdsall, 1998;Ellis, 2002). Those agents that do display high degrees of mAChR subtype selectivity are few in number and when discovered are often shown to interact with an allosteric, rather than the orthosteric, site as exemplified by the highly selective M 1 receptor peptide antagonist MT-7 (muscarinic toxin 7; Olianas et al., 2000). British Journal of PharmacologyTherefore, the identification of selective M 1 mAChR agonists would represent a significant advance in mAChR pharmacology and could offer t...

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Section: Discussionmentioning

confidence: 92%

Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1

Langmead

Austin

Branch

et al. 2008

British J Pharmacology

122

137

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“…Acquisition of either trace EBC (rats and rabbits) or WMZ (rats) results in a reduction of the post-burst AHP in CA1 pyramidal neurons (Moyer Jr. et al 1996;Oh et al 2003;Kuo et al 2004). In addition, systemic administration of compounds that reduce the AHP result in an enhancement of learning hippocampus-dependent tasks (Kronforst-Collins et al 1997;Weiss et al 2000). Based on these findings, we hypothesized that training rats on two hippocampus-dependent tasks would result in facilitation of the second task.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous training on two hippocampus-dependent tasks facilitates acquisition of trace eyeblink conditioning

Kuo¹,

Lee²,

Disterhoft³

2006

Learn. Mem.

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A common cellular alteration, reduced post-burst afterhyperpolarization (AHP) in CA1 neurons, is associated with acquisition of the hippocampus-dependent tasks trace eyeblink conditioning and the Morris water maze. As a similar increase in excitability is correlated with these two learning paradigms, we sought to determine the interactive behavioral effects of training animals on both tasks by using either a consecutive or simultaneous training design. In the consecutive design, animals were trained first on either the trace eyeblink conditioning task for six sessions, followed by training on the water maze task for six sessions, or vice versa. The simultaneous design consisted of six or 11 training days; animals received one session/day of both trace eyeblink conditioning and water maze training. Separate groups were used for consecutive and simultaneous training. Animals trained on both tasks simultaneously were significantly facilitated in their ability to acquire the trace eyeblink conditioning task; no effect of simultaneous training was seen on the water maze task. No effect was seen on acquisition for either task when using the consecutive training design. Taken together, these findings provide insight into how the hippocampus processes information when animals learn multiple hippocampus-dependent tasks.The importance of the hippocampus in learning is well established (Berger et al. 1976;Berger and Thompson 1978;Disterhoft et al. 1999). A number of studies have demonstrated the necessity of the hippocampus in learning spatial and nonspatial tasks, as well as those requiring the association of temporally remote events (Morris et al. 1982;Moyer Jr. et al. 1990;Davidson and Jarrard 1993;McEchron et al. 1998;Bannerman et al. 1999;Weiss et al. 1999a). Two such tasks are trace eyeblink conditioning (EBC) and Morris water maze (WMZ).A common cellular mechanism that underlies learning, increased membrane excitability, has been observed by several investigators. This mechanism is conserved across species, tasks, and brain regions. Trains of action potentials in both hippocampal and cortical neurons are followed by a prolonged post-burst afterhyperpolarization (AHP), which decreases neuronal excitability and inhibits further firing to a sustained depolarizing input (Schwindt et al. 1988;Storm 1990). A reduction in the AHP occurred in both rat and rabbit CA1 pyramidal neurons after acquisition of trace EBC (Moyer Jr. et al. 1996;Kuo et al. 2004). This reduction also occurred in rat CA1 pyramidal neurons after acquisition of another type of hippocampus-dependent task, the spatial Morris WMZ (Oh et al. 2003). Alterations in the AHP with learning have also been observed in rat piriform cortical neurons after acquisition of an odor discrimination task (Saar et al. 1998). In both hippocampus and piriform cortex, the reduced AHP followed a similar time course after learning, with a maximal reduction 24 h after task acquisition and a return to baseline within 7 d of acquisition (Moyer Jr. et al. 1996;Saar et al. 1998).In a...

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“…Increased evidence also suggests that ERK1/2 activation may be necessary for associated memories in the mammalian nervous system. In addition, recent studies have shown that M 1 agonists ameliorate age-related learning and memory impairments, suggesting that M 1 agonists may be an effective therapy for reducing the cognitive deficits that accompany normal aging and/or Alzheimer's disease (53). Therefore, it is interesting to consider that failure of tyrosine phosphorylation of G␣ q/11 , uncoupling of the receptor-G protein-effector, and a defect in ERK1/2 activation by mAChR observed in the current study may be involved in the early stage of impairment of learning and memory function after cerebral ischemia.…”

Section: Resultsmentioning

confidence: 99%

Altered Extracellular Signal-regulated Kinase Signal Transduction by the Muscarinic Acetylcholine and Metabotropic Glutamate Receptors after Cerebral Ischemia

Takagi¹,

Miyake-Takagi²,

Takagi³

et al. 2002

Journal of Biological Chemistry

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To determine whether muscarinic acetylcholine receptors (mAChR) in the post-ischemic hippocampus may be involved in altered extracellular signal-regulated kinases (ERK) signal transduction, we have investigated changes in the activity of ERK1/2 induced by a muscarinic agonist, carbachol. Cerebral ischemia was produced in the rat by injecting 900 microspheres (48 m in diameter) into the right internal carotid artery. Applying carbachol to the contralateral hippocampal slices from ischemic rats increased the phosphorylation of ERK1/2 but did not increase phosphorylation in the ipsilateral hippocampus. Analysis of M 1 mAChR binding showed that there was no significant difference in the number and K d values between the hippocampi from naïve and ischemic rats. Immunoblotting analysis showed no significant difference in the amount of M 1 mAChR in both hemispheres. In contrast to carbachol stimulation, the protein kinase C activator induced an activation of ERK1/2 in the ipsilateral hippocampus. This increase was shown to occur in neurons by immunofluorescence colocalization study. Carbachol-stimulated tyrosine phosphorylation of the G␣ q/11 , inositol 1,4,5-trisphosphate formation, and association of G␣ q/11 with phospholipase C␤1 were attenuated in the ipsilateral hippocampus. We also found that stimulation of group I metabotropic glutamate receptors, which are linked to G␣ q/11 , failed to increase in phosphorylation of ERK1/2 in the ipsilateral hippocampus. These results suggest that failure in receptor-mediated tyrosine phosphorylation of the G␣ q/11 subunit and a defect in receptor-G␣ q/11-effector coupling in the ischemic hippocampus may be involved in alterations of ERK signal transduction.

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The M1 Muscarinic Agonist CI-1017 Facilitates Trace Eyeblink Conditioning in Aging Rabbits and Increases the Excitability of CA1 Pyramidal Neurons

Cited by 79 publications

References 73 publications

Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1

Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1

Simultaneous training on two hippocampus-dependent tasks facilitates acquisition of trace eyeblink conditioning

Altered Extracellular Signal-regulated Kinase Signal Transduction by the Muscarinic Acetylcholine and Metabotropic Glutamate Receptors after Cerebral Ischemia

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The M1 Muscarinic Agonist CI-1017 Facilitates Trace Eyeblink Conditioning in Aging Rabbits and Increases the Excitability of CA1 Pyramidal Neurons

Cited by 79 publications

References 73 publications

Characterization of a CNS penetrant, selective M1muscarinic receptor agonist, 77‐LH‐28‐1

Characterization of a CNS penetrant, selective M1muscarinic receptor agonist, 77‐LH‐28‐1

Simultaneous training on two hippocampus-dependent tasks facilitates acquisition of trace eyeblink conditioning

Altered Extracellular Signal-regulated Kinase Signal Transduction by the Muscarinic Acetylcholine and Metabotropic Glutamate Receptors after Cerebral Ischemia

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Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1

Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1