The M1 muscarinic agonist CI-1017 facilitates trace eyeblink conditioning in aging rabbits and increases the excitability of CA1 pyramidal neurons - PubMed (original) (raw)

C Weiss et al. J Neurosci. 2000.

Abstract

The M1 muscarinic agonist CI-1017 was administered intravenously to aging rabbits on a daily basis before and during hippocampally dependent trace eyeblink conditioning sessions. Circulating levels of CI-1017 were significantly related to the drug dose. The drug was found to significantly increase the rate and amount of learning in a dose-dependent manner with no significant effects on the amplitude, area, or latency of conditioned responses. There was no evidence of pseudoconditioning at the highest drug concentration, and the minimally effective dose produced only mild and temporary hypersalivation as a side effect. CI-1017 (10 microM) was also found to increase the excitability of CA1 pyramidal neurons recorded from hippocampal slices from young and aging naive rabbits as measured by changes in spike-frequency adaptation and the postburst afterhyperpolarization. These biophysical changes were reversed with either atropine (1 microM) or pirenzepine (1 microM). These results suggest that M1 agonists ameliorate age-related learning and memory impairments at least in part by reducing the afterhyperpolarization and spike-frequency adaptation of hippocampal pyramidal neurons and that M1 agonists may be an effective therapy for reducing the cognitive deficits that accompany normal aging and/or Alzheimer's disease.

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Figures

Fig. 1.

Fig. 1.

A, A graph of the percent of trials with CRs across 15 daily training sessions as a function of drug dose. B, The two higher doses (5 and 1 mg/ml) exhibited significantly more CRs than the two lower doses (0 and 0.5 mg/ml). Data are means ± SE. Error bars are omitted from A for clarity.

Fig. 2.

Fig. 2.

A, A graph of the peak amplitude of response during the CS–US period on trials in which there was a CR.B, A graph of the area of response during the CS–US interval on trials in which there was a CR. C, A graph of the mean amplitude of response during the UR period. There was a significant increase in all three measures across sessions, but no significant differences among the groups and no significant interaction of dose and session were found. A comparison of these data with those in Figure 1 indicate that the high-dose rabbits showed more CRs, rather than CRs with different characteristics. The _y_-axis is shown in integrated units.

Fig. 3.

Fig. 3.

A, CI-1017 had no significant effect on the percent of trials with apparent CRs during 15 behavioral control sessions that presented unpaired tones and air puffs, i.e., there was no pseudoconditioning. B, CI-1017 had no significant effect on the rate of learning when the same rabbits were subsequently switched to the delay conditioning paradigm for five daily sessions. D, Drug at 5 mg/ml; V, vehicle control.

Fig. 4.

Fig. 4.

CI-1017 increased the excitability of both young and aging hippocampal pyramidal neurons by significantly reducing the amplitude of the AHP and spike-frequency adaptation. A, CI-1017 (10 μ

m

) significantly reduced the mean amplitude of the AHP in neurons from aging rabbits, and the effect was significantly reversed after application of the m1-specific antagonist pirenzepine (1 μ

m

). B, CI-1017 significantly reduced the spike-frequency adaptation of neurons from aging rabbits after application of the drug (10 μ

m

) to the bath; the effect was significantly reversed by the addition of pirenzepine (1 μ

m

). C, CI-1017 (10 μ

m

) reduced the mean amplitude of the AHP in neurons from young rabbits; the effect was reversed after application of the cholinergic antagonist atropine (1 μ

m

). D, CI-1017 (10 μ

m

) significantly reduced the spike-frequency adaptation of neurons from young rabbits; the effect was significantly reversed by the addition of atropine (1 μ

m

).

Fig. 5.

Fig. 5.

Typical examples of the effects of CI-1017 on biophysical properties from a single hippocampal CA1 pyramidal neuron from a young naive rabbit. An 800 msec pulse was used to examine accommodation after a burst of four action potentials.A, Accommodation of the neuron in aCSF.B, Accommodation is reduced by the addition of CI-1017, i.e., the cell is more excitable. C, The excitability change due to CI-1017 is reversed by the addition of the muscarinic antagonist atropine. D, Examples of the postburst AHP during control (aCSF), drug (CI-1017), and reversal (CI-1017 plus atropine) conditions.

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