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The Journal of Neuroscience, October 20, 2004, 24(42):9313-9323; doi:10.1523/JNEUROSCI.1618-04.2004

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Behavioral/Systems/Cognitive
The Effects on Place Cells of Local Scopolamine Dialysis Are Mimicked by a Mixture of Two Specific Muscarinic Antagonists

Elena Brazhnik,¹ Ramie Borgnis,¹ Robert U. Muller,^1,2 and Steven E. Fox¹

¹Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, and ²Medical Research Council Center for Synaptic Plasticity, University of Bristol, Bristol, United Kingdom BS8 1TD

Using a dialysis probe near CA1 hippocampal recording electrodes, we infused nonspecific (scopolamine) and specific (methoctramine, pirenzepine) antagonists of muscarinic cholinergic transmission to determine their effects on the positional firing properties of place cells. Both low (0.5 mM) and high (2.0 or 3.0 mM) scopolamine significantly decreased in-field firing rate, increased the ratio of out-of-field to in-field rate, and reduced the smoothness of rate maps, while tending to increase out-of-field rate. Thus, local nonspecific muscarinic blockade mimicked the effects seen with intracerebroventricular application, suggesting that blockade of receptors local to the recorded cells plays an essential role. Unexpectedly, dialysis of scopolamine reduced locomotor activity, again duplicating the effects of intracerebroventricular administration. Most effects of methoctramine (1.0 mM), which blocks presynaptic m₂ and m₄ receptors, were initially strong but then diminished over hours. Methoctramine produced a significant increase only in out/in ratio and out-of-field rate, whereas it tended to increase in-field rate and monotonically decrease smoothness. Pirenzepine (3.0 mM), which blocks postsynaptic m₁ receptors, produced a significant increase only in out/in ratio, whereas it tended to increase out-of-field rate and decrease in-field rate; all these effects were monotonic with respect to time. A mixture of methoctramine plus pirenzepine recapitulated the place-cell effects of scopolamine, although neither the mixture nor its separate components affected behavior. We conclude that the effects of scopolamine on place cells likely result from a combination of blockade of postsynaptic m₁ receptors, leading to reduced excitability, with blockade of presynaptic m₂ and m₄ receptors, leading to increased out-of-field firing.

Key words: place cell; hippocampus; muscarinic transmission; scopolamine; methoctramine; pirenzepine

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Received April 28, 2004; revised September 10, 2004; accepted September 10, 2004.

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